Hezhou Li
Anand Thirupathi- 1School of Physical Education and Health, Wenzhou University, Wenzhou, Zhejiang, China
- 2Faculty of Sports Science, Ningbo University, Ningbo, China
The dual role of interleukin-6 (IL-6) as beneficial in physiological conditions and detrimental in pathological conditions has been a subject of research interest since its discovery. This has surpassed the traditional view of IL-6 as a pro-inflammatory cytokine, primarily due to its multifunctionality. To coordinate this multiple effect, several downstream signaling pathways are involved. Physical exercise mediates these downstream signals and accentuates the pleiotropic effects of IL-6 by enabling cross-talk between various organs, including muscles and the brain. In addition, IL-6 itself is a crucial signaling molecule that enhances exercise performance by maintaining muscle energy homeostasis. However, the specific mechanisms by which this molecule modulates overall brain physiology under different exercise conditions remain unclear. For example, chronic exercise with different exercise protocols could increase chronic plasma levels of IL-6, which could have an impact on brain health. Most studies in the literature have established the beneficial effects of exercise-mediated IL-6, but the impact of chronic elevation of IL-6 by exercise remains unclear. Additionally, the level of IL-6 determines the nature of molecular signaling that underlies all IL-6-mediated functions. This can be achieved by understanding both classic and IL-6 trans-signaling in different physio-pathological conditions. However, the mechanism by which exercise activates these two different classic and IL-6 trans-signaling pathways is less understood. Therefore, this review presents a comprehensive overview of how different exercises mediate IL-6-mediated benefits by discussing the full array of molecular signaling pathways.
Introduction
The pleiotropic effects of cytokines arise from cross-reactivity and shared molecular signaling pathways, which may complicate the untangling of the molecular mechanisms of cytokines. Additionally, the perception of cytokines involved in disease progression as merely pro-inflammatory has shifted, as they play a crucial role in regulating metabolism, inflammation, and the immune response (1). However, the mechanisms by which cytokines execute these functions remain elusive in the realm of cytokine biology. Interleukin-6 (IL-6) is a crucial cytokine with multiple pleiotropic effects, enabling it to carry out a wide range of complex physiological functions. However, the activity of IL-6 may depend on the nature of IL-6 signaling (2). Mainly, three different signaling mechanisms, at least these conditions, are used to induce IL-6 response by the cells, termed classical IL-6R signaling that activates signaling pathways like Janus kinase/Signal transducer and activator of transcription 3 (JAK/STAT3) and phosphoinositide 3-kinases/protein kinase B (PI3K/AKT), IL-6 trans signaling, which induces a more sustained response of IL-6, and IL-6 trans presentation, which involves a cell–cell interaction (3). The discovery of IL-6 began in the late 1960s with the involvement of T-cells in antibody production (4, 5). In 1986, this T-cell-derived soluble factor, later renamed as B-cell stimulatory factor-2, became known as IL-6 (6, 7). Since then, this pleiotropic cytokine has maintained strong research interest due to its diverse biological roles (Table 1). Conversely, it has redundancy effects through its receptor-specific systems, called receptor-specific for IL-6 and gp130 (8).
Table 1. A complete chronological sequence of IL-6 response to exercise from its discovery to exercise-mediated targeted therapies.
Following the discovery of IL-6, its role in brain cells, including astrocytes and glial cells, has been demonstrated in several studies involving various signaling pathways, such as the JAK/STAT, mitogen-activated protein kinase (MAPK), nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB), PKC, Ca2+/calmodulin-dependent kinases, and the Prostaglandin E1 pathways (3, 9). However, all these signaling pathways act in both physiological and pathological conditions. Therefore, understanding their involvement in activating or deactivating IL-6 expression could provide a potential therapeutic target for treating brain diseases. Although pharmaceutical agents, such as antibodies and engineered fusion proteins, have been reported to block IL-6 in various models, including genetic knock-in strains and Drosophila (3, 9, 10), the mechanistic involvement of IL-6 signaling in diverse health and disease states remains poorly understood, especially in the brain. Therefore, elucidating the downstream targets of IL-6 could help to frame the contribution of IL-6 to brain health and diseases. Studies have reported that IL-6-mediated activation of STAT1 and STAT3 plays various pathological roles by triggering brain inflammation, which can promote brain apoptosis and lead to brain damage (11, 12). Nevertheless, it has also been implicated in neuronal survival (13). Therefore, designing a drug that simply targets the downstream signaling of IL-6 could also have deleterious effects in sensitive cells, such as those in the brain. In this context, physical exercise is one of the non-invasive remedies that can help sustained release of IL-6 via targeting its upstream signals like c-jun gene (14, 15). Additionally, chronic exercise may help regulate the IL-6 downstream targets without exaggerating the action of IL-6 (16); otherwise, it can also activate other downstream signaling pathways, such as PI3K/AKT, to induce neurodegeneration (17). This condition can be elucidated through resistance exercise, which modifies STAT3 signaling in the brain by regulating IL-6 levels to facilitate neuroprotection (16). This may be the mechanism through which exercise mediates the binding of STAT3 to brain-derived neurotrophic factor (BDNF) and protein Interacting with C Kinase - 1 (PICK1), thereby enhancing neural plasticity via the IL-6 response (18). However, high-intensity exercise disrupts the IL-6 response and the redox balance, which adversely affects insulin signaling in the brain via the PI3K/AKT pathway (19–21). Other signaling molecules, such as protein kinase C (PKC), are known to be increased by exercise in response to interleukin-6 (IL-6), which induces neuroinflammation, oxidative stress, and apoptosis (22). Conversely, PKC regulates neuronal activity and survival by activating prostaglandin E2 (PGE2) through the EP4 receptor (23); exercise is also known to regulate PGE2 (24). However, the mechanisms by which different exercise protocols mediate this effect via IL-6 in improving neuronal survival are unknown. Exercise types, such as aerobic exercise, may also inhibit the IL-6-mediated STAT3 signaling pathway by blocking the JAK2/STAT3 pathway, thereby enhancing cognitive function and neuroprotection (25). However, it is important to elucidate the involvement of other antiinflammatory cytokines to ensure the IL-6-mediated benefits. Additionally, the effect of exercise protocols, such as intensity, duration, and type, on the IL-6 response to activate IL-6-mediated downstream targets is poorly understood. Therefore, this review aims to discuss the potential downstream targets of IL-6 for maintaining brain health during exercise.
How do the downstream effects of IL-6 signaling mediate the brain physiopathology- role of exercise
Depending on the stress response employed by the cells, IL-6 can be defined as an adipokine, myokine, monokine, or neurotrophic factor (26). This response may be triggered by exercise, infection, trauma, or specific disease conditions, such as cancer or autoimmunity. As mentioned, exercise regulates the IL-6 signaling mechanisms to elicit the controlled response of IL-6 within the muscle and to other organs (26). For example, exercise primarily utilizes the classical IL-6R signaling pathway to activate IL-6-mediated downstream signaling, thereby enhancing performance by maintaining energy homeostasis and providing anti-inflammatory benefits associated with exercise (26, 27). Mainly, the exercise-induced local effects of IL-6 lead to the systemic effects via mbIL-6R in skeletal muscle, mediated by 5’ AMP-activated protein kinase (AMPK) activation, as evidenced by the increased expression of mbIL-6R in the myocytes of resistance-trained individuals (27, 28). Thus, exercise-mediated IL-6 classical signaling may induce systemic effects in the brain by facilitating the interaction of IL-6/gp130 to target its downstream signaling, such as JAK/STAT (27, 28) (Figure 1).
Figure 1. Effect of physical exercise on IL-6 signaling in brain. (A) Physical exercise increases the sgp130 to decrease IL-6 trans-signaling, thereby inducing sustained release of IL-6 in the brain to activate JAK/STAT3, which in turn triggers BDNF and PICK1 to increase neural plasticity, neuronal survival, and neurogenesis. Additionally, exercise targets the c-Jun protein to regulate the IL-6 response in the brain. (B) Exercise-induced classical signaling of IL-6 activates its downstream targets, such as JAK/STAT3, to improve neurogenesis. (C) Exercise-induced IL-6 inhibits GSK-3β through the PI3K/AKT/mTOR pathways to decrease neural apoptosis via the GRPR. Additionally, exercise-mediated IL-6 triggers FOXO1 signaling, which in turn activates TLR4 to increase IL-6 production. However, overexpression of this may induce ischemia and inflammation in the brain, and the role of shutting down these molecules under exercised conditions in preventing ischemia and neuroinflammation is unknown. (D) Exercise-induced OSM enhances mitochondrial respiration, thereby improving energy homeostasis in the brain. (E) PI3/AKT/FOXO3-induced oxidative damage in the brain is prevented by the exercise-mediated IL-6 response by CDKN2A/REDD1, which targets mTORC1 and FOXOs. (F) Exercise influences the expression of heat-shock protein 90 (HSP-90) and caveolin-1, thereby activating the STATs pathways, which is mediated by exercise-triggered IL-6.
The increase in IL-6 levels is associated with age-related pathological consequences. For instance, a study found that IL-6 concentration increased from 1.4 pg./mL in the 65–74 year age group to 3.5 pg./mL in those aged 85 years among men (29). Similarly, women showed an increase in IL-6 levels from 1.1 to 2.1 pg./mL over the same age range (29). Importantly, this rise in IL-6 is independent of residual confounding factors that influence the development of age-related neurodegenerative diseases (30). One possible explanation for this increase is that elevated reactive oxygen species (ROS) production or reduced clearance of ROS may stimulate IL-6 production (29). This, in turn, can worsen IL-6-mediated pathological effects through the IL-6/JAK/STAT3 signaling pathway, which is a significant driver of glioblastoma. While IL-6 activates STAT3 and can offer neuroprotective effects, both the neuroprotective and oncogenic impacts of IL-6 depend on the dosage and duration of its presence. For example, low levels of IL-6 are beneficial for neuronal survival, while elevated or prolonged IL-6 exposure can promote tumor growth by activating STAT3 signaling (31). Moreover, the activation of the IL-6/STAT3 pathway influences downstream targets that can either induce neuroprotection or contribute to oncogenic effects. For example, IL-6/STAT3 triggers the activation of BDNF and TrkB, which in turn enhances STAT3 activation, thereby improving BDNF expression through a positive feedback loop mechanism that promotes neuroprotection (32). Whereas IL-6/STAT3 promotes the Bcl-XL, Mcl-1, and VEGF, to inhibit apoptosis and promote cell survival by increasing angiogenesis and blood supply to the tumor (33). Additionally, the tumor microenvironment plays a crucial role in triggering the pro-tumorigenic effects of IL-6 and STAT3 (34).
Exercise can also influence the upregulation of sgp130, leading to the inhibition of IL-6 trans-signaling (27). This can decrease the sickness behavior induced by LPS, improve brain recovery from injury, cognitive functions, and reduce anxiety by inhibiting IL-6 trans-signaling in the murine microglia cell line and mouse model (35, 36). Downstream targets of IL-6, mainly JAK/STAT, regulate neuroinflammation and affect the survival of neuronal and glial cells, as evidenced by the dysregulation of JAK/STAT pathway in brain disorders, such as brain cancers, ischemia, and Alzheimer’s disease (AD). Exercise mitigates this condition by targeting the membrane-proximal region of the receptors to interrupt the interaction of IL-6-mediated JAK/STAT activation (37). For example, resistance exercise for 12 weeks transiently increases IL-6 and STAT3, facilitating adaptive responses to high-intensity exercise (37). However, no studies in the literature have discussed how exercise affects this highly conserved membrane-proximal region of the receptors, thereby interrupting the IL-6-mediated JAK/STAT signaling in brain diseases.
Additionally, IL-6 trans-signaling alters the toll-like receptor 4 (TLR4)-dependent signaling in the gp130 (F/F) knock-in mutant mice to modulate the inflammatory response through STAT3 signaling (38). Treadmill exercise reduces TLR4 overexpression in cerebral ischemia, thereby lowering IL-6 secretion through the HMGB1/TLR4-mediated mechanism (39, 40). Additionally, exercise influences the expression of heat-shock protein 90 (HSP-90) and caveolin-1, thereby activating the STATs pathways, which is mediated by exercise-triggered IL-6 (41, 42). For instance, treadmill exercise for 28 days increases the caveolin-1 and vascular endothelial growth factor (VEGF) signaling to promote neurogenesis in the ischemic rats, possibly through an exercise-mediated IL-6 mechanism (41, 42). However, caveolin-1 upregulation inhibits the STAT3 signaling in brain metastasis (43), and further research is required to determine whether IL-6 shuts off STAT3 signaling to activate caveolin-1-mediated benefits in the brain upon exercise. It is known that IL-6 activates HSP90 to suppress protein aggregation and facilitate Aβ clearance in AD conditions (44). Additionally, an acute bout of exercise activates HSP90 by upregulating IL-6 (45). Oncostatin M (OSM) is associated with muscle atrophy, and the muscle-specific deletion of OSMR may prevent muscle atrophy via the IL-6-mediated JAK/STAT3 pathway (46). In the context of brain physiology, OSM disrupts the blood–brain barrier function by activating the JAK/STAT3 signaling pathway in vitro (47). Conversely, OSMR regulates the brain tumor stem cells’ proliferation via interacting with NADH ubiquinone, NADH ubiquinone oxidoreductase 1/2 (NDUFS1/2) of complex I to promote mitochondrial respiration, suggesting the dual role of this OSMR (48). However, the involvement of IL-6 in this context upon exercise requires further exploration. IL-6 activates other signaling pathways, such as the PI3K/AKT/the mammalian target of rapamycin (mTOR) glycogen synthase kinase-3 beta (GSK-3β) and gastrin-releasing peptide (GRP) receptor (GRPR) pathways, in hippocampal neurons of mice with autism spectrum disorder (49). It has been reported that exercise regulates these signaling to improve brain health. For example, the PI3K/AKT signaling pathway is crucial for brain function by activating its downstream targets, including GSK-3β, mTORc, FOXOs, and CREB (50). Treadmill exercise for 30 min increased the expression of PI3K/AKT proteins in the rat’s brain by inhibiting GSK-3β, thereby improving depression (51). However, this study did not investigate whether IL-6 mediated this response to improve depression symptoms. Studies have reported that the elevation of GSK-3β is associated with the loss of dopaminergic neurons, an increase in amyloid beta production, and the formation of neurofibrillary tangles (52, 53). The inhibition of GSK-3β via targeting the IL-6-mediated PI3/AKT/mTOR pathway decreases neural apoptosis and affects autism spectrum disorder via GRPR (52, 53). Exercise-induced mTOR activation improved cognition and emotional behavior in mice models with IL-6 overexpression (26, 54, 55). Studies have reported that mTOR regulates protein synthesis and degradation in the context of Alzheimer’s disease (AD) pathogenesis (56).
Moreover, activation of the PI3K/AKT pathway via IL-6 triggers FOXO1 signaling, which can further activate TLR4, thereby increasing the expression of IL-6; this vicious cycle may be involved in regulating the inflammatory process in the brain (57). For instance, aerobic exercise downregulates FOXO1 to reduce neural apoptosis in the hippocampus region through the CDKN2A/REDD1 pathway, and this may occur via exercise-mediated activation of death-associated protein kinase 1 (58). In addition, exercise-induced IL-6 activates CREB via the PI3K/AKT pathway to decrease depressive disorder, primarily by activating BDNF signaling in the hippocampus (59). This entire downstream target is manipulated by exercise-activated IL-6, without the release of other proinflammatory cytokines; however, it may be linked to lactate formation during exercise (60). Conversely, exercise-induced IL-6 mediates the PI3K/AKT pathway, which may activate an anti-inflammatory response to reduce oxidative stress and neuronal damage by targeting FOXO3 and NF-κB (61). Additionally, this condition enhances insulin sensitivity, facilitating increased glucose uptake by neurons and glycogen synthesis to maintain energy homeostasis in brain cells (62). The 2IL-6, ROS, and NF-κB play a crucial role in neurodegeneration by creating a positive feedback loop that triggers inflammation and neuronal damage. For instance, reduced levels of IL-6 and NF-κB have been shown to decrease neuroinflammation induced by LPS in BV2 cells (63). Additionally, a study indicated that sulforaphane, known for its antioxidant properties and ability to reduce ROS, lowers IL-6 and NF-κB levels in a rat model of AD, suggesting that IL-6-induced ROS activation triggers the NF-κB and vice versa (64). Furthermore, chronic treadmill exercise for 12 weeks, five days a week, mitigated IL-6 and NF-κB levels in an AD mouse model, likely by reducing ROS formation through the modulation of IL-6 and NF-κB (65). Therefore, targeting this pathway may provide therapeutic value for neurodegenerative diseases.
The role of IL-6 in targeting BDNF responses for neuroregeneration and the treatment of depressive disorders is critical, particularly as exercise is associated with elevated BDNF levels (66). For instance, unaccustomed exercise has been observed to reduce BDNF responses, with this decrease persisting for at least 24 h following the unaccustomed stretch-shortening activity (67). Notably, these changes do not correlate with IL-6 levels, indicating that specific exercise modalities may regulate BDNF responses independently of IL-6 activation (67). Moreover, the activation of CREB by CRTC1 has been linked to improvements in mood disorders (68), with evidence that CREB can bind to the promoter region of the IL-6 gene, thus influencing IL-6 transcription. While exercise is known to enhance CREB activation, physiological hypertrophy resulting from exercise may also impact this activation (69), potentially affecting IL-6 levels and reversing inflammatory responses in neurodegenerative conditions. Stress-induced proteins, such as Regulated in Development and DNA Damage-Response 1 (REDD1), are associated with metabolic disorders and neurodegeneration, while also contributing to oxidative stress and autophagy (70). This may be dependent or independent of mTORC1, but IL-6 may be crucial for activating REDD1 by carrying out mTOR-dependent or its other downstream target STAT3 to regulate REDD1 (70, 71). In this case, exercise-mediated hypoxia could activate REDD1, either triggering IL-6 or hypoxia induced by exercise, to increase REDD1 without IL-6 response in the brain (72). Treadmill exercise increased the expression of REDD1 via decreasing mTORC1 in the rats (72). Receptor-interacting protein kinase 1 (RIPK1) regulates neural apoptosis (73). Treadmill exercise modulates RIPK1 to regulate the IL-6-mediated response via MAP3K5/JNK and NF-κB, thereby decreasing neuroinflammation in the hippocampus of aged mice (73).
How exercise triggers the of IL-6 response for altering brain functions?
The prompt synthesis of IL-6 could carry pleiotropic effects by modulating various cytokines and growth factors. Physical exercise can accelerate this process. For example, prolonged exercise induces the release of IL-6 from skeletal muscle, which is then released into circulation to modify the secretion of other proteins, such as TLR-4, thereby regulating physiological processes in the brain, including neurogenesis (74). However, these two molecules can also play a role in inducing an inflammatory response that leads to neuronal damage, and the role of physical exercise in this condition is ambiguous. Transforming growth factor-β (TGF-β) contributes to AD pathogenesis during brain injury, in combination with IL-6, by promoting the expression of ROR-γt to regulate IL-17 (75). This elicits anxiety and affects social behavior (76). However, exercise can reverse this condition by increasing adaptive signaling, including PGC-1α, mTOR, and AMPK, without altering the IL-6-mediated benefits (27). For example, recreationally active individuals have reduced levels of sIL-6R, which favors adaptive signaling to exercise, resulting in a balance shift toward higher classical signaling and less trans-signaling, thereby avoiding a pro-inflammatory response to the exercise program (27). In addition, combined training decreased the expression of IL-17 in the plasma of multiple sclerosis patients (77), which could reciprocally decrease the expression of TGF-β without triggering IL-6 (78). In addition, elevated levels of IL-6 are linked to increased levels of Th17/Treg ratio, which disrupts the immune tolerance in the brain cells and causes neurological disorders (79) (Figure 2). The Th17/Treg ratio imbalance exacerbates cognitive impairment by modulating STAT3 activation in mice, potentially illustrating the immune regulatory effects of STAT3 through IL-6-mediated Th17/Treg levels (80). Treadmill exercise for 4 weeks (5 days/week) in adult ischemic rats regulates the ratio of Th17/Treg by decreasing neuronal apoptosis via inhibition of the IL-6-mediated signaling pathway, such as JAK2/STAT3 (81).
Figure 2. Effect of exercise on mediating pleiotrophic functions of IL-6 in the brain. (A) Physical exercise induces TGF-beta, which in turn stimulates IL-6, thereby regulating the ratio of TH17 to Treg cells, while also increasing IL-17 to enhance brain function. (B) Exercise-mediated IL-6 response alters the iron metabolism via targeting hepcidin. (C) Energy demand under exercised conditions activates the AMPK and YAP to induce the positive effect of NOTCH, which can induce neurogenesis in the brain by activating autophagy and preventing brain aging.
Next, IL-6 contributes to the development of T follicular helper cells (Tfh), which can be linked to the pathophysiology of neuromyelitis optica spectrum disorders (82). Karnowski et al. reported that Tfh cells were reduced in IL-6 knockout mice with the absence of IL-21, which is linked to the driving of neuroinflammation and fat accumulation in microglia (83). However, specific condition for exercise-mediated IL-6-induced Tfh development need to be reported, along with the corresponding mechanisms. IL-6 induced recruitment of gp130 triggers the yes-associated protein 1 (YAP) signaling and neurogenic locus notch homolog protein (NOTCH) signaling to promote glioblastoma growth in the human brain (84, 85). Exercise has been reported to regulate the YAP, especially in energy-deprived conditions, via AMPK, which phosphorylates the YAP (86). Additionally, various types of exercise activate the NOTCH signaling pathway, thereby decreasing brain aging by promoting autophagy and hippocampal neurogenesis, which in turn improves spatial learning and memory in rats (87). Nevertheless, the role of the IL-6 mechanism in this condition needs to be established. IL-6 also has metabolic controls in the brain by regulating glucose concentration in HFD mice (88). Mainly, IL-6 trans-signaling regulates systemic glucose homeostasis in hypothalamic neurons (89). IL-6 regulates energy expenditure in the hypothalamic region, as evidenced by the modulation of fat metabolism in obese conditions (90). Studies have shown that schizophrenia disorder is linked to altered glucose and fat metabolism, and the infusion of IL-6 in IL-6 knock-out mice failed to induce schizophrenia disorder (91, 92), indicating that IL-6 elevation could be a general feature of major depressive disorders like schizophrenia. However, the precise mechanism by which IL-6 is linked to these disorders remains elusive. Due to its diverse roles as both pro-inflammatory and anti-inflammatory mediator in the brain, IL-6 can contribute to a range of outcomes from neuroprotection to neurodegeneration. These effects likely stem from complex molecular interactions within the central nervous system, as well as the actively working skeletal muscle, which is primarily influenced by the cellular environment, blood–brain barrier permeability, and the specific IL-6 signaling pathways that are activated during exercise. Exercise elevates the circulating IL-6, indicating that working skeletal muscle is the predominant source of IL-6. However, astrocytes are another major source of IL-6, especially in conditions such as brain injury, hypoxia, and inflammation. This suggests that muscle-derived IL-6 is generally considered beneficial during exercise, while brain-derived IL-6 has both beneficial and detrimental effects, which can potentially contribute to increased neurodegeneration (93). Moreover, the IL-6-mediated metabolic boost can be utilized by the exercised brain to enhance energy homeostasis (16), while also ensuring a constant supply of glucose and fats to the working muscles (94). Moreover, IL-6 plays a crucial role in brain iron metabolism, as evidenced by the decrease in serum iron and the increase in IL-6 levels in the serum (95). Sterling et al. showed that IL-6 induces iron sequestration in neurons in response to pathological alpha-synuclein in both humans and mice with PD (96). Regular running exercise triggered the redistribution of iron in altered brain iron metabolism by decreasing cortical hepcidin levels, coupled with increased IL-6 levels in the cortex and plasma, in an AD mouse model, possibly through an IL-6/STAT3/JAK1 pathway-mediated mechanism (97).
Therapeutic possibilities of IL-6- role of exercise
The level of IL-6 obviously contributes to the pathogenesis of brain diseases. Regular physical exercise can decrease IL-6, while also helping to block downstream signalings of IL-6. For example, the increase in IL-6 in cerebrospinal fluid affects neuroplasticity in MS patients, and physical exercise can inhibit this condition by regulating IL-6 (98–100). Next, targeting IL-6 signaling, such as STAT3, could alleviate memory impairment and glucose intolerance in AD, and exercise may serve as a STAT3 inhibitor to improve this condition (20). A study has shown that exercise, such as resistance training, decreases the STAT3 signaling in muscle atrophy (20). Whereas running exercise improves STAT3 signaling by targeting GPC6 to elicit neuroprotection in a mouse model of cerebral artery occlusion (101), indicating that each exercise protocol elicits different effects to target the IL-6-mediated signaling. Designing an exercise strategy that targets gp130-mediated signaling could have therapeutic application in brain tumors like glioblastoma by influencing endothelial-mediated actions (102), and decreasing neuronal loss and hyperinflammation (103), evidenced by the increase of gp130 by running exercise, which suppresses the STAT3 signaling to improve mitochondrial quality (104). Moreover, finding the association between exercise training and different protocols on single-nucleotide polymorphisms (SNPs), such as rs2228145 SNP, could modify the expression of sIl-6R, which might extend the half-life of IL-6 from minutes to hours; thus, it can transiently increase its effects from its production site to distant regions of the brain to produce systemic effects to target neurodegenerative diseases (27).
Engaging in 30 min of aerobic treadmill exercise per day, starting at an initial running speed of 2 m/min and gradually increasing to 8 m/min for 20 min, can activate the PI3K/AKT pathway. This activity may inhibit GSK-3β through a potential increase in IL-6, which in turn can decrease neurofibrillary tangles by hyperphosphorylating tau protein (55, 105). Additionally, treadmill exercise influences the IL-6-induced inhibition of mTOR via AMPK without activating STAT signaling (55). This mechanism is crucial in driving the pathogenesis of AD (105). In contrast, 12 weeks of resistance training—conducted 3 days a week with a 48-h rest interval between sessions—was shown to increase IL-6 levels with aging, thereby exacerbating the pro-inflammatory response (106). However, this response can be reversed with regular exercise training (106). Studies have indicated that both aerobic and resistance exercises affect the circulation of IL-6 by increasing levels of irisin (107, 108). For instance, cycling exercise performed three times a week for 55 min at 70% VO2 max enhanced the irisin response (108), while running three times a week for 60 min also increased irisin levels (107). Furthermore, resistance training for 12 weeks, twice a week for 55 min, resulted in an increased irisin response (107). Although these studies did not specifically assess IL-6, a study demonstrated that the release of irisin reduces IL-6 in astrocytes, decreases the expression of COX-2, and inhibits the phosphorylation of AKT by blocking NFκB activation (109). This process helps to protect neurons from Aβ toxicity in AD (109), suggesting that the exercise-induced hormone irisin plays a crucial role in regulating the IL-6-mediated response in neurodegenerative diseases. Activities such as walking, running, cycling, or swimming can increase the release of IL-6 and other anti-inflammatory cytokines, thereby improving insulin sensitivity (137). Insulin resistance is a hallmark of various neurodegenerative diseases, such as AD and PD. Additionally, resistance training enhances muscle strength, contributing to overall health and mobility in individuals with different neurodegenerative conditions. Therefore, performing both aerobic exercise (3 to 5 days per week, 30–40 min at 60–80% intensity) and resistance training (2–3 days per week) can improve outcomes for individuals with neurodegenerative conditions (110) (Table 2). However, personalized interventions should be tailored to individual circumstances.
Table 2. Aerobic versus resistance training protocols and their effects on IL-6 response in neurodegenerative conditions.
Does exercise duration and intensity influence the IL-6 response?
Although exercise is strongly associated with IL-6 response, the duration and intensity of exercise as contributing factors in determining the IL-6 response, especially in brain physiology, are unknown. Some studies have shown that a longer duration with moderate intensity significantly increases the IL-6 response within skeletal muscle and its surrounding interstitial fluid, thereby eliciting its pleiotropic effects on the brain (16, 111). This is evidenced by a greater increase in IL-6, approximately 8,000-fold, after a foot race of up to 246 km (111). In addition, prolonged exercise induces the release of IL-6 from the brain, evidenced by the no release of IL-6 from brain after 15 min of exercise, while 60 min the same exercise induced the small release of IL-6 and this was increased upto fivefold after the second bout of exercise in the brain (16). Moreover, exercise intensity is another factor that greatly elevates the IL-6 response (112). For example, cycling exercise at low intensity for 35 min increased the IL-6 response by up to 1.4-fold, whereas the same exercise at high intensity elevated the IL-6 response by up to 2.7-fold (27). However, all these studies are used aerobic training and the role of resistance exercise with higher intensity on IL-6 response is limited when compared to aerobic exercise, and exploring future research on resistance training on the brain functions, especially with neurodegenerative populations such as AD, PD and dementia could effectively integrate the types of exercise, which improve the functional outcomes of those people. Other factors, such as glycogen availability and the training status of the individuals, as well as the mode of exercise in relation to intensity and duration, also influence the IL-6 response. The possible mechanism that involves increasing the IL-6 response using these factors may be mediated by AMPK signaling that elevates IL-6 under a low-energy state and vice versa. Another mechanism involves increasing calcium signaling through exercise, particularly chronic exercise that can induce the IL-6 response, thereby regulating iron efflux (113, 114). This mechanism also decreases exercise-induced fatigue by astrocytes (115).
Why do exercise protocols matter for IL-6 signaling in AD/PD?
Exercise protocols play a crucial role in maintaining IL-6 signaling in AD and PD by modifying the inflammatory process (133–135). These protocols affect various signaling pathways, which can help slow disease progression. For instance, acute exercise increases the IL-6 response and elevates anti-inflammatory factors such as IL-1RA and IL-10. These factors, in turn, downregulate pro-inflammatory cytokines, including TNF-α and IL-1β, in individuals with AD (116). On the other hand, chronic exercise reduces the elevated levels of IL-6, TNF-α, iNOS, and COX-2, thereby alleviating neuroinflammation in AD (65). Regular exercise is also beneficial for maintaining brain volume in the elderly, which can help prevent AD and dementia (136). The intensity and frequency of exercise can significantly influence both the magnitude and duration of IL-6 release. Additionally, the type of exercise performed can affect the release of IL-6 and help mitigate the pro-inflammatory response. For example, resistance-type exercise has been shown to decrease the activation of NF-kB in mice with PD by lowering IL-6 levels (117). This reduction can improve short-term memory, and the effects of resistance exercise are comparable to levodopa treatment in PD (117). Moreover, an increase in IL-6 is correlated with poor physical functioning, weakness, and fatigue in PD patients, likely due to heightened muscle catabolism that contributes to sarcopenia (118). Additionally, a single bout of resistance exercise performed three times a week for 12 weeks can enhance the IL-6 response, activating downstream targets such as STAT3, c-MYC, c-FOS, and SOCS3 (37, 119), which are associated with the aging process. Therefore, carefully selecting and tailoring exercise protocols may help minimize the detrimental effects of IL-6 signaling while harnessing its beneficial effects to enhance outcomes for individuals with AD and PD.
Limitations
Prescribing exercise to individuals with specific neurodegenerative conditions presents several limitations and challenges. For example, in conditions like PD, the progressive loss of motor function can make it difficult for individuals to perform even basic exercises as the disease advances. Additionally, cognitive impairments in individuals with AD can hinder their ability to understand and follow exercise programs. The benefits of exercise and the tolerance for it can vary widely among individuals with different neurodegenerative conditions. Furthermore, there is a lack of established exercise protocols that have been proven safe and effective in alleviating symptoms of neurodegenerative diseases. The feasibility of patients engaging in exercise often depends on the specific disease condition, its severity, and the individual’s overall health status. Comorbidities associated with neurodegenerative diseases, such as hypertension and osteoarthritis, can also significantly impact exercise performance. Individuals with these comorbidities may have decreased exercise tolerance. Moreover, genetic factors like IL-6 polymorphisms (for instance, rs2228145) can influence an individual’s response to exercise by altering the risk of disease progression through changes in IL-6 signaling. Therefore, understanding the relationship between IL-6 and rs2228145 could greatly assist clinicians and exercise professionals in personalizing exercise programs for individuals with neurodegenerative diseases. A multidisciplinary approach that includes physical therapy, neuropsychological rehabilitation, or occupational therapy can further optimize exercise programs and improve patient outcomes.
Conclusion
The pleiotropic effects of IL-6 impede the development of strategies that can target the IL-6 response in brain diseases. Evidence suggests that inhibiting the downstream targets of IL-6, such as JAK/STAT3 and PI3K/AKT, may mitigate the normal physiological functions of the brain, as these pathways also play roles in enhancing physiological functions. Therefore, careful attention is necessary before designing potential therapeutic targets. Although pharmaceutical agents have been successfully used to block IL-6 in various models, the mechanistic involvement of IL-6 signaling is poorly understood. Utilizing physical exercise as a therapeutic tool could mitigate the deleterious effects of these downstream targets of IL-6 without exacerbating IL-6 levels. However, exercise protocols, such as intensity and duration, are linked to the direct elevation of IL-6 in the muscle and circulation. This may shift the effects of IL-6 toward pathological signaling in the brain, indicating a need for a more comprehensive understanding of exercise protocols related to IL-6 signaling, which could present additional therapeutic opportunities for treating neurological disorders.
Author contributions
AT: Conceptualization, Writing – review & editing. HL: Conceptualization, Writing – original draft, Writing – review & editing.
Funding
The author(s) declare that no financial support was received for the research and/or publication of this article.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Generative AI statement
The authors declare that no Gen AI was used in the creation of this manuscript.
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
References
1. McFarlane, A, Pohler, E, and Moraga, I. Molecular and cellular factors determining the functional pleiotropy of cytokines. FEBS J. (2023) 290:2525–52. doi: 10.1111/febs.16420
2. Tanaka, T, Narazaki, M, and Kishimoto, T. IL-6 in inflammation, immunity, and disease. Cold Spring Harb Perspect Biol. (2014) 6:a016295. doi: 10.1101/cshperspect.a016295
3. Rose-John, S, Jenkins, BJ, Garbers, C, Moll, JM, and Scheller, J. Targeting IL-6 trans-signalling: past, present and future prospects. Nat Rev Immunol. (2023) 23:666–81. doi: 10.1038/s41577-023-00856-y
4. Claman, HN, Chaperon, EA, and Selner, JC. Thymusmarrow immunocompetence. 3. The requirement for living thymus cells. Proc Soc Exp Biol Med. (1968) 127:462–6. doi: 10.3181/00379727-127-32715
5. Miller, JF, and Mitchell, GF. Cell to cell interaction in the immune response. I. Hemolysin-forming cells in neonatally thymectomized mice reconstituted with thymus or thoracic duct lymphocytes. J Exp Med. (1968) 128:801–20. doi: 10.1084/jem.128.4.801
6. Hirano, T, Yasukawa, K, Harada, H, Taga, T, Watanabe, Y, Matsuda, T, et al. Complementary DNA for a novel human interleukin (BSF-2) that induces B lymphocytes to produce immunoglobulin. Nature. (1986) 324:73–6. doi: 10.1038/324073a0
7. Kishimoto, T. IL-6: from its discovery to clinical applications. Int Immunol. (2010) 22:347–52. doi: 10.1093/intimm/dxq030
8. Burger, R, Günther, A, Klausz, K, Staudinger, M, Peipp, M, Penas, EM, et al. Due to interleukin-6 type cytokine redundancy only glycoprotein 130 receptor blockade efficiently inhibits myeloma growth. Haematologica. (2017) 102:381–90. doi: 10.3324/haematol.2016.145060
9. Ageeva, T, Rizvanov, A, and Mukhamedshina, Y. NF-κB and JAK/STAT signaling pathways as crucial regulators of Neuroinflammation and astrocyte modulation in spinal cord injury. Cells. (2024) 13:581. doi: 10.3390/cells13070581
10. Jenkins, RH, Hughes, STO, Figueras, AC, and Jones, SA. Unravelling the broader complexity of IL-6 involvement in health and disease. Cytokine. (2021) 148:155684. doi: 10.1016/j.cyto.2021.155684
11. Huang, B, Lang, X, and Li, X. The role of IL-6/JAK2/STAT3 signaling pathway in cancers. Front Oncol. (2022) 12:1023177. doi: 10.3389/fonc.2022.1023177
12. West, AJ, Tsui, V, Stylli, SS, Nguyen, HPT, Morokoff, AP, Kaye, AH, et al. The role of interleukin-6-STAT3 signalling in glioblastoma. Oncol Lett. (2018) 16:4095–104. doi: 10.3892/ol.2018.9227
13. Dimberg, LY, Dimberg, A, Ivarsson, K, Fryknäs, M, Rickardson, L, Tobin, G, et al. Stat1 activation attenuates IL-6 induced Stat3 activity but does not alter apoptosis sensitivity in multiple myeloma. BMC Cancer. (2012) 12:318. doi: 10.1186/1471-2407-12-318
14. Boppart, MD, Aronson, D, Gibson, L, Roubenoff, R, Abad, LW, Bean, J, et al. Eccentric exercise markedly increases c-Jun NH(2)-terminal kinase activity in human skeletal muscle. J Appl Physiol (1985). (1999) 87:1668–73. doi: 10.1152/jappl.1999.87.5.1668
15. Chauhan, D, Kharbanda, S, Uchiyama, H, Urashima, M, Fragoso, R, Sen, J, et al. Identification of upstream signals regulating interleukin-6 gene expression during in vitro treatment of human B cells with pokeweed mitogen. Blood. (1994) 84:2243–52. doi: 10.1182/blood.V84.7.2243.2243
16. Nybo, L, Nielsen, B, Pedersen, BK, Møller, K, and Secher, NH. Interleukin-6 release from the human brain during prolonged exercise. J Physiol. (2002) 542:991–5. doi: 10.1113/jphysiol.2002.022285
17. Razani, E, Pourbagheri-Sigaroodi, A, Safaroghli-Azar, A, Zoghi, A, Shanaki-Bavarsad, M, and Bashash, D. The PI3K/Akt signaling axis in Alzheimer's disease: a valuable target to stimulate or suppress? Cell Stress Chaperones. (2021) 26:871–87. doi: 10.1007/s12192-021-01231-3
18. Tang, QP, Shen, Q, Wu, LX, Feng, XL, Liu, H, Wu, B, et al. STAT3 signal that mediates the neural plasticity is involved in willed-movement training in focal ischemic rats. J Zhejiang Univ Sci B. (2016) 17:493–502. doi: 10.1631/jzus.B1500297
19. Gabbouj, S, Ryhänen, S, Marttinen, M, Wittrahm, R, Takalo, M, Kemppainen, S, et al. Altered insulin signaling in Alzheimer's disease brain - special emphasis on PI3K-Akt pathway. Front Neurosci. (2019) 13:629. doi: 10.3389/fnins.2019.00629
20. Testa, MTJ, Cella, PS, Marinello, PC, Frajacomo, FTT, Padilha, CS, Perandini, PC, et al. Resistance training attenuates activation of STAT3 and muscle atrophy in tumor-bearing mice. Front Oncol. (2022) 12:880787. doi: 10.3389/fonc.2022.880787
21. Tsai, SH, Cheng, HC, Little, JP, Islam, H, and Liu, HW. Elevated plasma IL-6 coincides with activation of STAT3 in PBMC after acute resistance exercise. Med Sci Sports Exerc. (2024) 56:2117–24. doi: 10.1249/MSS.0000000000003503
22. Sallam, N, and Laher, I. Exercise modulates oxidative stress and inflammation in aging and cardiovascular diseases. Oxidative Med Cell Longev. (2016) 2016:7239639. doi: 10.1155/2016/7239639
23. Alix, E, Schmitt, C, Strazielle, N, and Ghersi-Egea, JF. Prostaglandin E2 metabolism in rat brain: role of the blood-brain interfaces. Cerebrospinal Fluid Res. (2008) 5:5. doi: 10.1186/1743-8454-5-5
24. Martínez, ME, Heddens, D, Earnest, DL, Bogert, CL, Roe, D, Einspahr, J, et al. Physical activity, body mass index, and prostaglandin E2 levels in rectal mucosa. J Natl Cancer Inst. (1999) 91:950–3. doi: 10.1093/jnci/91.11.950
25. Lin, L, Wang, Y, Xu, W, Huang, C, Hu, J, Chen, X, et al. Aerobic exercise improves type 2 diabetes mellitus-related cognitive impairment by inhibiting JAK2/STAT3 and enhancing AMPK/SIRT1 pathways in mice. Dis Markers. (2022) 2022:1–15. doi: 10.1155/2022/6010504
26. Petersen, AMW, and Pedersen, BK. The role of IL-6 in mediating the anti-inflammatory effects of exercise. J Physiol Pharmacol. (2006) 57:43–51. doi: 10.1249/00005768-200605001-00226
27. Hughes, D, Butcher, MG, Aicheler, L, Smith, R, Cullen, P, and Webb, R. IL-6 signaling in acute exercise and chronic training: potential consequences for health and athletic performance. Scand J Med Sci Sports. (2023) 33:4–19. doi: 10.1111/sms.14241
28. Keller, C, Steensberg, A, Hansen, AK, Fischer, CP, Plomgaard, P, and Pedersen, BK. Effect of exercise, training, and glycogen availability on IL-6 receptor expression in human skeletal muscle. J Appl Physiol (1985). (2005) 99:2075–9. doi: 10.1152/japplphysiol.00590.2005
29. Maggio, M, Guralnik, JM, Longo, DL, and Ferrucci, L. Interleukin-6 in aging and chronic disease: a magnificent pathway. J Gerontol A Biol Sci Med Sci. (2006) 61:575–84. doi: 10.1093/gerona/61.6.575
30. Ferrucci, L, Corsi, A, Lauretani, F, Bandinelli, S, Bartali, B, Taub, DD, et al. The origins of age-related proinflammatory state. Blood. (2005) 105:2294–9. doi: 10.1182/blood-2004-07-2599
31. Fu, C, Wang, L, and Cai, W. IL6 receptor inhibitors: exploring the therapeutic potential across multiple diseases through drug target Mendelian randomization. Front Immunol. (2024) 15:1452849. doi: 10.3389/fimmu.2024.1452849
32. Chen, B, Liang, Y, He, Z, An, Y, Zhao, W, and Wu, J. Autocrine activity of BDNF induced by the STAT3 signaling pathway causes prolonged TrkB activation and promotes human non-small-cell lung cancer proliferation. Sci Rep. (2016) 6:30404. doi: 10.1038/srep30404
33. Sreenivasan, L, Wang, H, Yap, SQ, Leclair, P, Tam, A, and Lim, CJ. Autocrine IL-6/STAT3 signaling aids development of acquired drug resistance in group 3 medulloblastoma. Cell Death Dis. (2020) 11:1035. doi: 10.1038/s41419-020-03241-y
34. Kim, JE, Patel, M, Ruzevick, J, Jackson, CM, and Lim, M. STAT3 activation in glioblastoma: biochemical and therapeutic implications. Cancers (Basel). (2014) 6:376–95. doi: 10.3390/cancers6010376
35. Burton, MD, Sparkman, NL, and Johnson, RW. Inhibition of interleukin-6 trans-signaling in the brain facilitates recovery from lipopolysaccharide-induced sickness behavior. J Neuroinflammation. (2011) 8:54. doi: 10.1186/1742-2094-8-54
36. Gober, IG, Russell, AL, Shick, TJ, Vagni, VA, Carlson, JC, Kochanek, PM, et al. Exploratory assessment of the effect of systemic administration of soluble glycoprotein 130 on cognitive performance and chemokine levels in a mouse model of experimental traumatic brain injury. J Neuroinflammation. (2024) 21:149. doi: 10.1186/s12974-024-03129-0
37. Trenerry, MK, Della Gatta, PA, Larsen, AE, Garnham, AP, and Cameron-Smith, D. Impact of resistance exercise training on interleukin-6 and JAK/STAT in young men. Muscle Nerve. (2011) 43:385–92. doi: 10.1002/mus.21875
38. Greenhill, CJ, Rose-John, S, Lissilaa, R, Ferlin, W, Ernst, M, Hertzog, PJ, et al. IL-6 trans-signaling modulates TLR4-dependent inflammatory responses via STAT3. J Immunol. (2011) 186:1199–208. doi: 10.4049/jimmunol.1002971
39. Ma, Y, He, M, and Qiang, L. Exercise therapy downregulates the overexpression of TLR4, TLR2, MyD88 and NF-κB after cerebral ischemia in rats. Int J Mol Sci. (2013) 14:3718–33. doi: 10.3390/ijms14023718
40. Shimizu, S, Kouzaki, H, Kato, T, Tojima, I, and Shimizu, T. HMGB1-TLR4 signaling contributes to the secretion of interleukin 6 and interleukin 8 by nasal epithelial cells. Am J Rhinol Allergy. (2016) 30:167–72. doi: 10.2500/ajra.2016.30.4300
41. Shah, M, Patel, K, Fried, VA, and Sehgal, PB. Interactions of STAT3 with caveolin-1 and heat shock protein 90 in plasma membrane raft and cytosolic complexes. Preservation of cytokine signaling during fever. J Biol Chem. (2002) 277:45662–9. doi: 10.1074/jbc.M205935200
42. Zhao, Y, Pang, Q, Liu, M, Pan, J, Xiang, B, Huang, T, et al. Treadmill exercise promotes neurogenesis in ischemic rat brains via Caveolin-1/VEGF signaling pathways. Neurochem Res. (2017) 42:389–97. doi: 10.1007/s11064-016-2081-z
43. Chiu, WT, Lee, HT, Huang, FJ, Aldape, KD, Yao, J, Steeg, PS, et al. Caveolin-1 upregulation mediates suppression of primary breast tumor growth and brain metastases by stat3 inhibition. Cancer Res. (2011) 71:4932–43. doi: 10.1158/0008-5472.CAN-10-4249
44. Ou, JR, Tan, MS, Xie, AM, Yu, JT, and Tan, L. Heat shock protein 90 in Alzheimer's disease. Biomed Res Int. (2014) 2014:796869. doi: 10.1155/2014/796869
45. Krüger, K, Reichel, T, and Zeilinger, C. Role of heat shock proteins 70/90 in exercise physiology and exercise immunology and their diagnostic potential in sports. J Appl Physiol (1985). (2019) 126:916–27. doi: 10.1152/japplphysiol.01052.2018
46. Domaniku-Waraich, A, Agca, S, Toledo, B, Sucuoglu, M, Özen, SD, Bilgic, SN, et al. Oncostatin M signaling drives cancer-associated skeletal muscle wasting. Cell Rep, Med. (2024) 5:101498. doi: 10.1016/j.xcrm.2024.101498
47. Takata, F, Dohgu, S, Sakaguchi, S, Sakai, K, Yamanaka, G, Iwao, T, et al. Oncostatin-M-reactive Pericytes aggravate blood-brain barrier dysfunction by activating JAK/STAT3 signaling in vitro. Neuroscience. (2019) 422:12–20. doi: 10.1016/j.neuroscience.2019.10.014
48. Sharanek, A, Burban, A, Laaper, M, Heckel, E, Joyal, JS, Soleimani, VD, et al. OSMR controls glioma stem cell respiration and confers resistance of glioblastoma to ionizing radiation. Nat Commun. (2020) 11:4116. doi: 10.1038/s41467-020-17885-z
49. Li, H, Wang, X, Hu, C, Cui, J, Li, H, Luo, X, et al. IL-6 enhances the activation of PI3K-AKT/mTOR-GSK-3β by upregulating GRPR in hippocampal neurons of autistic mice. J Neuroimmune Pharmacol. (2024) 19:12. doi: 10.1007/s11481-024-10111-3
50. Long, HZ, Cheng, Y, Zhou, ZW, Luo, HY, Wen, DD, and Gao, LC. PI3K/AKT signal pathway: a target of natural products in the prevention and treatment of Alzheimer's disease and Parkinson's disease. Front Pharmacol. (2021) 12:648636. doi: 10.3389/fphar.2021.648636
51. Wang, LR, and Baek, SS. Treadmill exercise activates PI3K/Akt signaling pathway leading to GSK-3β inhibition in the social isolated rat pups. J. Exerc. Rehabil. (2018) 14:4–9. doi: 10.12965/jer.1836054.027
52. Li, J, Ma, S, Chen, J, Hu, K, Li, Y, Zhang, Z, et al. GSK-3β contributes to parkinsonian dopaminergic neuron death: evidence from conditional knockout mice and Tideglusib. Front Mol Neurosci. (2020) 13:81. doi: 10.3389/fnmol.2020.00081
53. Turkistani, A, Al-kuraishy, HM, Al-Gareeb, AI, Albuhadily, AK, Alexiou, A, Papadakis, M, et al. Therapeutic potential effect of glycogen synthase kinase 3 Beta (GSK-3β) inhibitors in Parkinson disease: exploring an overlooked avenue. Mol Neurobiol. (2024) 61:7092–108. doi: 10.1007/s12035-024-04003-z
54. Lloyd, BA, Hake, HS, Ishiwata, T, Farmer, CE, Loetz, EC, Fleshner, M, et al. Exercise increases mTOR signaling in brain regions involved in cognition and emotional behavior. Behav Brain Res. (2017) 323:56–67. doi: 10.1016/j.bbr.2017.01.033
55. White, JP, Puppa, MJ, Gao, S, Sato, S, Welle, SL, and Carson, JA. Muscle mTORC1 suppression by IL-6 during cancer cachexia: a role for AMPK. Am J Physiol Endocrinol Metab. (2013) 304:E1042–52. doi: 10.1152/ajpendo.00410.2012
56. Perluigi, M, Di Domenico, F, Barone, E, and Butterfield, DA. mTOR in Alzheimer disease and its earlier stages: links to oxidative damage in the progression of this dementing disorder. Free Radic Biol Med. (2021) 169:382–96. doi: 10.1016/j.freeradbiomed.2021.04.025
57. Fan, W, Morinaga, H, Kim, JJ, Bae, E, Spann, NJ, Heinz, S, et al. FoxO1 regulates Tlr4 inflammatory pathway signalling in macrophages. EMBO J. (2010) 29:4223–36. doi: 10.1038/emboj.2010.268
58. Liu, Y, Guo, W, and Hong, SL. Aerobic exercise mitigates hippocampal neuronal apoptosis by regulating DAPK1/CDKN2A/REDD1/FoXO1/FasL signaling pathway in D-galactose-induced aging mice. FASEB J. (2023) 37:e23205. doi: 10.1096/fj.202300847RR
59. Li, P, Hu, Y, Tong, L, and Bi, X. High-intensity training on CREB activation for improving brain health: a narrative review of possible molecular talks. Front Endocrinol. (2025) 15:1498495. doi: 10.3389/fendo.2024.1498495
60. de Melo Madureira, ÁN, de Oliveira, JRS, and de Menezes Lima, VL. The role of IL-6 released during exercise to insulin sensitivity and muscle hypertrophy. Mini Rev Med Chem. (2022) 22:2419–28. doi: 10.2174/1389557522666220309161245
61. Liu, HW, and Chang, SJ. Moderate exercise suppresses NF-κB signaling and activates the SIRT1-AMPK-PGC1α Axis to attenuate muscle loss in diabetic db/db mice. Front Physiol. (2018) 9:636. doi: 10.3389/fphys.2018.00636
62. Sajan, M, Hansen, B, Ivey, R, Sajan, J, Ari, C, Song, S, et al. Brain insulin signaling is increased in insulin-resistant states and decreases in FOXOs and PGC-1α and increases in Aβ1-40/42 and phospho-tau may abet Alzheimer development. Diabetes. (2016) 65:1892–903. doi: 10.2337/db15-1428
63. You, Z, Yang, Z, Cao, S, Deng, S, and Chen, Y. The novel KLF4/BIG1 regulates LPS-mediated neuro-inflammation and migration in BV2 cells via PI3K/Akt/NF-kB signaling pathway. Neuroscience. (2022) 488:102–11. doi: 10.1016/j.neuroscience.2022.01.014
64. Yang, W, Liu, Y, Xu, QQ, Xian, YF, and Lin, ZX. Sulforaphene ameliorates neuroinflammation and hyperphosphorylated tau protein via regulating the PI3K/Akt/GSK-3β pathway in experimental models of Alzheimer's disease. Oxidative Med Cell Longev. (2020):4754195. doi: 10.1155/2020/4754195
65. Leem, YH, Lee, YI, Son, HJ, and Lee, SH. Chronic exercise ameliorates the neuroinflammation in mice carrying NSE/htau23. Biochem Biophys Res Commun. (2011) 406:359–65. doi: 10.1016/j.bbrc.2011.02.046
66. Murphy, PG, Borthwick, LA, Altares, M, Gauldie, J, Kaplan, D, and Richardson, PM. Reciprocal actions of interleukin-6 and brain-derived neurotrophic factor on rat and mouse primary sensory neurons. Eur J Neurosci. (2000) 12:1891–9. doi: 10.1046/j.1460-9568.2000.00074.x
67. Verbickas, V, Kamandulis, S, Snieckus, A, Venckunas, T, Baranauskiene, N, Brazaitis, M, et al. Serum brain-derived neurotrophic factor and interleukin-6 response to high-volume mechanically demanding exercise. Muscle Nerve. (2018) 57:E46–51. doi: 10.1002/mus.25687
68. Cherix, A, Poitry-Yamate, C, Lanz, B, Zanoletti, O, Grosse, J, Sandi, C, et al. Deletion of Crtc1 leads to hippocampal neuroenergetic impairments associated with depressive-like behavior. Mol Psychiatry. (2022) 27:4485–501. doi: 10.1038/s41380-022-01791-5
69. Watson, PA, Reusch, JE, McCune, SA, Leinwand, LA, Luckey, SW, Konhilas, JP, et al. Restoration of CREB function is linked to completion and stabilization of adaptive cardiac hypertrophy in response to exercise. Am J Physiol Heart Circ Physiol. (2007) 293:H246–59. doi: 10.1152/ajpheart.00734.2006
70. Pinno, J, Bongartz, H, Klepsch, O, Wundrack, N, Poli, V, Schaper, F, et al. Interleukin-6 influences stress-signalling by reducing the expression of the mTOR-inhibitor REDD1 in a STAT3-dependent manner. Cell Signal. (2016) 28:907–16. doi: 10.1016/j.cellsig.2016.04.004
71. Kim, JY, Kwon, YG, and Kim, YM. The stress-responsive protein REDD1 and its pathophysiological functions. Exp Mol Med. (2023) 55:1933–44. doi: 10.1038/s12276-023-01056-3
72. Hayasaka, M, Tsunekawa, H, Yoshinaga, M, and Murakami, T. Endurance exercise induces REDD1 expression and transiently decreases mTORC1 signaling in rat skeletal muscle. Physiol Rep. (2014) 2:e12254. doi: 10.14814/phy2.12254
73. Liu, Y, Meng, X, Tang, C, Zheng, L, Tao, K, and Guo, W. Aerobic exercise modulates RIPK1-mediated MAP3K5/JNK and NF-κB pathways to suppress microglia activation and neuroinflammation in the hippocampus of D-gal-induced accelerated aging mice. Physiol Behav. (2024) 286:114676. doi: 10.1016/j.physbeh.2024.114676
74. Welc, SS, and Clanton, TL. The regulation of interleukin-6 implicates skeletal muscle as an integrative stress sensor and endocrine organ. Exp Physiol. (2013) 98:359–71. doi: 10.1113/expphysiol.2012.068189
75. Oberstein, TJ, Taha, L, Spitzer, P, Hellstern, J, Herrmann, M, Kornhuber, J, et al. Imbalance of circulating Th17 and regulatory T cells in Alzheimer's disease: a case control study. Front Immunol. (2018) 9:1213. doi: 10.3389/fimmu.2018.01213
76. Lee, B, Kwon, JT, Jeong, Y, Caris, H, Oh, D, Feng, M, et al. Inflammatory and anti-inflammatory cytokines bidirectionally modulate amygdala circuits regulating anxiety. Cell. (2025) 188:2190–2202.e15. doi: 10.1016/j.cell.2025.03.005
77. Golzari, Z, Shabkhiz, F, Soudi, S, Kordi, MR, and Hashemi, SM. Combined exercise training reduces IFN-γ and IL-17 levels in the plasma and the supernatant of peripheral blood mononuclear cells in women with multiple sclerosis. Int Immunopharmacol. (2010) 10:1415–9. doi: 10.1016/j.intimp.2010.08.008
78. Hou, W, Jin, YH, Kang, HS, and Kim, BS. Interleukin-6 (IL-6) and IL-17 synergistically promote viral persistence by inhibiting cellular apoptosis and cytotoxic T cell function. J Virol. (2014) 88:8479–89. doi: 10.1128/JVI.00724-14
79. Shi, Y, Wei, B, Li, L, Wang, B, and Sun, M. Th17 cells and inflammation in neurological disorders: possible mechanisms of action. Front Immunol. (2022) 13:932152. doi: 10.3389/fimmu.2022.932152
80. Zhang, X, Zhang, X, Qiu, C, Shen, H, Zhang, H, He, Z, et al. The imbalance of Th17/Treg via STAT3 activation modulates cognitive impairment in P. gingivalis LPS-induced periodontitis mice. J Leukoc Biol. (2021) 110:511–24. doi: 10.1002/JLB.3MA0521-742RRR
81. Shan, Y, Wang, L, Sun, J, Chang, S, Di, W, and Lv, H. Exercise preconditioning attenuates cerebral ischemia-induced neuronal apoptosis, Th17/Treg imbalance, and inflammation in rats by inhibiting the JAK2/STAT3 pathway. Brain Behav. 13:e3030. doi: 10.1002/brb3.3030
82. Yick, LW, Ma, OK, Chan, EY, Yau, KX, Kwan, JS, and Chan, KH. T follicular helper cells contribute to pathophysiology in a model of neuromyelitis optica spectrum disorders. JCI Insight. (2023) 8:e161003. doi: 10.1172/jci.insight.161003
83. Oyamada, H, Ying, Y, Agrawal, S, Liu, A, Subramanian, VS, de Melo Bento, CA, et al. Chronic IL-21 drives neuroinflammation and promotes lipid accumulation in microglia. Immun Ageing. (2025) 22:15. doi: 10.1186/s12979-025-00510-2
84. Orr, BA, Bai, H, Odia, Y, Jain, D, Anders, RA, and Eberhart, CG. Yes-associated protein 1 is widely expressed in human brain tumors and promotes glioblastoma growth. J Neuropathol Exp Neurol. (2011) 70:568–77. doi: 10.1097/NEN.0b013e31821ff8d8
85. Taniguchi, K, Wu, LW, Grivennikov, S, Grivennikov, SI, de Jong, PR, Lian, I, et al. A gp130–Src–YAP module links inflammation to epithelial regeneration. Nature. (2015) 519:57–62. doi: 10.1038/nature14228
86. Limyati, Y, Sanjaya, A, Lucretia, T, Gunadi, JW, Biben, V, Jasaputra, DK, et al. Potential role of exercise in regulating YAP and TAZ during cardiomyocytes aging. Curr Cardiol Rev. (2022) 18:24–33. doi: 10.2174/1573403X18666220404152924
87. Chen, D, Guo, Y, Zhang, M, Liu, X, Zhang, B, and Kou, X. Exercise alleviates cognitive decline of natural aging rats by upregulating notch-mediated autophagy signaling. Brain Res. (2025) 1850:149398. doi: 10.1016/j.brainres.2024.149398
88. McNeilly, AD, Yianakas, A, Gallagher, JG, Tarlton, J, Ashford, ML, and McCrimmon, RJ. Central deficiency of IL-6Ra in mice impairs glucose-stimulated insulin secretion. Mol Metab. (2022) 61:101488. doi: 10.1016/j.molmet.2022.101488
89. Timper, K, Denson, JL, Steculorum, SM, Heilinger, C, Engström-Ruud, L, Wunderlich, CM, et al. IL-6 improves energy and glucose homeostasis in obesity via enhanced central IL-6 trans-signaling. Cell Rep. (2017) 19:267–80. doi: 10.1016/j.celrep.2017.03.043
90. Bobbo, VC, Engel, DF, Jara, CP, Mendes, NF, Haddad-Tovolli, R, Prado, TP, et al. Interleukin-6 actions in the hypothalamus protects against obesity and is involved in the regulation of neurogenesis. J Neuroinflammation. (2021) 18:192. doi: 10.1186/s12974-021-02242-8
91. Klemettilä, JP, Kampman, O, Seppälä, N, Viikki, M, Hämäläinen, M, Moilanen, E, et al. Cytokine and adipokine alterations in patients with schizophrenia treated with clozapine. Psychiatry Res. (2014) 218:277–83. doi: 10.1016/j.psychres.2014.04.049
92. Smith, SE, Li, J, Garbett, K, Mirnics, K, and Patterson, PH. Maternal immune activation alters fetal brain development through interleukin-6. J Neurosci. (2007) 27:10695–702. doi: 10.1523/JNEUROSCI.2178-07.2007
93. Kummer, KK, Zeidler, M, Kalpachidou, T, and Kress, M. Role of IL-6 in the regulation of neuronal development, survival and function. Cytokine. (2021) 144:155582. doi: 10.1016/j.cyto.2021.155582
94. Muñoz-Cánoves, P, Scheele, C, Pedersen, BK, and Serrano, AL. Interleukin-6 myokine signaling in skeletal muscle: a double-edged sword? FEBS J. (2013) 280:4131–48. doi: 10.1111/febs.12338
95. Nakagawa, H, Tamura, T, Mitsuda, Y, Goto, Y, Kamiya, Y, Kondo, T, et al. Inverse correlation between serum interleukin-6 and iron levels among Japanese adults: a cross-sectional study. BMC Hematol. (2014) 14:6. doi: 10.1186/2052-1839-14-6
96. Sterling, JK, Kam, TI, Guttha, S, Park, H, Baumann, B, Mehrabani-Tabari, AA, et al. Interleukin-6 triggers toxic neuronal iron sequestration in response to pathological α-synuclein. Cell Rep. (2022) 38:110358. doi: 10.1016/j.celrep.2022.110358
97. Belaya, I, Kucháriková, N, Górová, V, Kysenius, K, Hare, DJ, Crouch, PJ, et al. Regular physical exercise modulates iron homeostasis in the 5xFAD mouse model of Alzheimer's disease. Int J Mol Sci. (2021) 22:8715. doi: 10.3390/ijms22168715
98. Briken, S, Rosenkranz, SC, Keminer, O, Patra, S, Ketels, G, Heesen, C, et al. Effects of exercise on Irisin, BDNF and IL-6 serum levels in patients with progressive multiple sclerosis. J Neuroimmunol. (2016) 299:53–8. doi: 10.1016/j.jneuroim.2016.08.007
99. Devasahayam, AJ, Kelly, LP, Williams, JB, Moore, CS, and Ploughman, M. Fitness shifts the balance of BDNF and IL-6 from inflammation to repair among people with progressive multiple sclerosis. Biomolecules. (2021) 11:504. doi: 10.3390/biom11040504
100. Mee-Inta, O, Zhao, ZW, and Kuo, YM. Physical exercise inhibits inflammation and microglial activation. Cells. (2019) 8:691. doi: 10.3390/cells8070691
101. Chen, Z, Gao, M, Su, Y, Liu, P, and Sun, B. Running promotes transformation of brain astrocytes into neuroprotective reactive astrocytes and synaptic formation by targeting Gpc6 through the STAT3 pathway. Front Physiol. (2021) 12:633618. doi: 10.3389/fphys.2021.633618
102. Jacobs, K, Harford-Wright, E, and Gavard, J. Neutralizing gp130 interferes with endothelial-mediated effects on glioblastoma stem-like cells. Cell Death Differ. (2017) 24:384. doi: 10.1038/cdd.2016.163
103. Händel, U, Brunn, A, Drögemüller, K, Müller, W, Deckert, M, and Schlüter, D. Neuronal gp130 expression is crucial to prevent neuronal loss, hyperinflammation, and lethal course of murine toxoplasma encephalitis. Am J Pathol. (2012) 181:163–73. doi: 10.1016/j.ajpath.2012.03.029
104. Fix, DK, Hardee, JP, Gao, S, VanderVeen, BN, Velázquez, KT, and Carson, JA. Role of gp130 in basal and exercise-trained skeletal muscle mitochondrial quality control. J Appl Physiol (1985). 124:1456–70. doi: 10.1152/japplphysiol.01063.2017
105. Cai, Z, Chen, G, He, W, Xiao, M, and Yan, LJ. Activation of mTOR: a culprit of Alzheimer's disease? Neuropsychiatr Dis Treat. (2015) 11:1015–30. doi: 10.2147/NDT.S75717
106. Della Gatta, PA, Garnham, AP, Peake, JM, and Cameron-Smith, D. Effect of exercise training on skeletal muscle cytokine expression in the elderly. Brain Behav Immun. (2014) 39:80–6. doi: 10.1016/j.bbi.2014.01.006
107. Amanat, S, Sinaei, E, Panji, M, MohammadporHodki, R, Bagheri-Hosseinabadi, Z, Asadimehr, H, et al. Randomized controlled trial on the effects of 12 weeks of aerobic, resistance, and combined exercises training on the serum levels of Nesfatin-1, Irisin-1 and HOMA-IR. Front Physiol. (2020):11. doi: 10.3389/fphys.2020.562895
108. Miyamoto-Mikami, E, Sato, K, Kurihara, T, Hasegawa, N, Fujie, S, Fujita, S, et al. Endurance training-induced increase in circulating irisin levels is associated with reduction of abdominal visceral fat in middle-aged and older adults. PLoS One. (2015) 10:2–13. doi: 10.1371/journal.pone.0120354
109. Wang, K, Li, H, Wang, H, Wang, JH, Song, F, and Sun, Y. Irisin exerts neuroprotective effects on cultured neurons by regulating astrocytes. Mediat Inflamm. (2018) 2018:1–7. doi: 10.1155/2018/9070341
110. Alberts, JL, and Rosenfeldt, AB. The universal prescription for Parkinson's disease: exercise. J Parkinsons Dis. (2020) 10:S21–7. doi: 10.3233/JPD-202100
111. Goussetis, E, Spiropoulos, A, Tsironi, M, Skenderi, K, Margeli, A, Graphakos, S, et al. Spartathlon, a 246 kilometer foot race: effects of acute in flammation induced by prolonged exercise on circulating progenitor reparative cells. Blood Cells Mol Dis. (2009) 42:294–9. doi: 10.1016/j.bcmd.2009.01.003
112. Ostrowski, K, Schjerling, P, and Pedersen, BK. Physical activity and plasma interleukin-6 in humans - effect of intensity of exercise. Eur J Appl Physiol. (2000) 83:512–5. doi: 10.1007/s004210000312
113. Jen, CJ, Chan, HP, and Chen, HI. Chronic exercise improves endothelial calcium signaling and vasodilatation in hypercholesterolemic rabbit femoral artery. Arterioscler Thromb Vasc Biol. (2002) 22:1219–24. doi: 10.1161/01.ATV.0000021955.23461.CD
114. Rosenblum, SL, Bailey, DK, and Kosman, DJ. Calcium and IL-6 regulate the anterograde trafficking and plasma membrane residence of the iron exporter ferroportin to modulate iron efflux. J Biol Chem. (2024) 300:107348. doi: 10.1016/j.jbc.2024.107348
115. Xiang, L, Zhao, Y, Li, X, Shi, R, Zhou, W, Xu, X, et al. Astrocytic calcium signals are associated with exercise-induced fatigue in mice. Neuroscience. (2025) 564:306–18. doi: 10.1016/j.neuroscience.2024.11.033
116. Pahlavani, HA. Exercise therapy to prevent and treat Alzheimer's disease. Front Aging Neurosci. (2023) 15:1243869. doi: 10.3389/fnagi.2023.1243869
117. Kim, SH, Ko, YJ, and Baek, SS. Resistance exercise improves short-term memory through inactivation of NF-κB pathway in mice with Parkinson disease. J Exerc Rehabil. (2021) 17:81–7. doi: 10.12965/jer.2142188.094
118. Scalzo, P, Kümmer, A, Cardoso, F, and Teixeira, AL. Serum levels of interleukin-6 are elevated in patients with Parkinson's disease and correlate with physical performance. Neurosci Lett. (2010) 468:56–8. doi: 10.1016/j.neulet.2009.10.062
119. Trenerry, MK, Carey, KA, Ward, AC, Farnfield, MM, and Cameron-Smith, D. Exercise-induced activation of STAT3 signaling is increased with age. Rejuvenation Res. (2008) 11:717–24. doi: 10.1089/rej.2007.0643
120. Haahr, PM, Pedersen, BK, Fomsgaard, A, Tvede, N, Diamant, M, Klarlund, K, et al. Effect of physical exercise on in vitro production of interleukin 1, interleukin 6, tumour necrosis factor-alpha, interleukin 2 and interferon-gamma. Int J Sports Med. (1991) 12:223–7. doi: 10.1055/s-2007-1024672
121. Stuerenburg, J, Jung, H, Jung, R, and Schoser, BG. Age effects on interleukin-6 and interleukin-1beta responses to endurance exercise in patients with neuromuscular diseases. Arch Gerontol Geriatr. (1999) 29:21–7.
122. Pérez Navero, JL, Jaraba Caballero, S, Ibarra de la Rosa, I, Jaraba Caballero, MP, Guillén del Castillo, M, Montilla López, P, et al. Repercusión del ejercicio físico competitivo en la respuesta neuroendocrina y liberación de interleuquina-6 en niños [Effects of competitive physical exercise on neuroendocrine response and interleukin-6 liberation in children]. An Esp Pediatr. (1999) 51:267–72.
123. Kelly, M, Keller, C, Avilucea, PR, Keller, P, Luo, Z, Xiang, X, et al. AMPK activity is diminished in tissues of IL-6 knockout mice: the effect of exercise. Biochem Biophys Res Commun. (2004) 320:449–54. doi: 10.1016/j.bbrc.2004.05.188
124. Christensen, RH, Wedell-Neergaard, AS, Lehrskov, LL, Legård, GE, Dorph, EB, Nymand, S, et al. The role of exercise combined with tocilizumab in visceral and epicardial adipose tissue and gastric emptying rate in abdominally obese participants: protocol for a randomised controlled trial. Trials. (2018) 19:266. doi: 10.1186/s13063-018-2637-0
125. Rizzo, FR, Guadalupi, L, Sanna, K, Vanni, V, Fresegna, D, De Vito, F, et al. Exercise protects from hippocampal inflammation and neurodegeneration in experimental autoimmune encephalomyelitis. Brain Behav Immun. (2021) 98:13–27. doi: 10.1016/j.bbi.2021.08.212
126. Vints, WAJ, Šeikinaitė, J, Gökçe, E, Kušleikienė, S, Šarkinaite, M, Valatkeviciene, K, et al. Resistance exercise effects on hippocampus subfield volumes and biomarkers of neuroplasticity and neuroinflammation in older adults with low and high risk of mild cognitive impairment: a randomized controlled trial. Geroscience. (2024) 46:3971–91. doi: 10.1007/s11357-024-01110-6
127. Henrique, JS, França, EF, Cardoso, FDS, Serra, FT, de Almeida, AA, Fernandes, J, et al. Cortical and hippocampal expression of inflammatory and intracellular signaling proteins in aged rats submitted to aerobic and resistance physical training. Exp Gerontol. (2018) 110:284–90. doi: 10.1016/j.exger.2018.06.025
128. Li, DJ, Li, YH, Yuan, HB, Qu, LF, and Wang, P. The novel exercise-induced hormone irisin protects against neuronal injury via activation of the Akt and ERK1/2 signaling pathways and contributes to the neuroprotection of physical exercise in cerebral ischemia. Metabolism. (2017) 68:31–42. doi: 10.1016/j.metabol.2016.12.003
129. Zhang, BW, Li, Y, and Kou, XJ. Resistance exercise regulates hippocampal microglia polarization through TREM2/NF-κB/STAT3 signal pathway to improve cognitive dysfunction in T2DM mice. Sheng Li Xue Bao. (2024) 76:717–31. doi: 10.13294/j.aps.2024.0034
130. Krüger, K, Bredehöft, J, Mooren, FC, and Rummel, C. Different effects of strength and endurance exercise training on COX-2 and mPGES expression in mouse brain are independent of peripheral inflammation. J Appl Physiol (1985). (2016) 121:248–54. doi: 10.1152/japplphysiol.00284.2016
131. Choi, SH, Bylykbashi, E, Chatila, ZK, Lee, SW, Pulli, B, Clemenson, GD, et al. Combined adult neurogenesis and BDNF mimic exercise effects on cognition in an Alzheimer's mouse model. Science. (2018) 361:eaan8821. doi: 10.1126/science.aan8821
132. Hashiguchi, D, Campos, HC, Wuo-Silva, R, Faber, J, Gomes da Silva, S, Coppi, AA, et al. Resistance exercise decreases amyloid load and modulates inflammatory responses in the APP/PS1 mouse model for Alzheimer's disease. J Alzheimer's Dis. (2020) 73:1525–39. doi: 10.3233/JAD-190729
133. Chen, Y, Chen, X, Luo, Z, Kang, X, Ge, Y, Wan, R, et al. Exercise-induced reduction of IGF1R Sumoylation attenuates Neuroinflammation in APP/PS1 transgenic mice. J Adv Res. (2025) 69:279–97. doi: 10.1016/j.jare.2024.03.025
134. Smith, LL. Cytokine hypothesis of overtraining: a physiological adaptation to excessive stress? Med Sci Sports Exerc. (2000) 32:317–31. doi: 10.1097/00005768-200002000-00011
135. Zhang, S, Fan, Y, Cao, X, Deng, C, Xu, J, Zhou, Q, et al. Treadmill exercise improves cerebral ischemia injury by regulating microglia polarization via downregulation of MMP12. Int Immunopharmacol. (2024) 142:113210. doi: 10.1016/j.intimp.2024.113210
136. Barnes, JN. Exercise, cognitive function, and aging. Adv Physiol Educ. (2015) 39:55–62. doi: 10.1152/advan.00101.2014
Keywords: interleukin-6, physical exercise, brain, molecular signaling, neurodegeneration
Citation: Li H and Thirupathi A (2025) Exercise-mediated IL-6 downstream effects modulate brain pathology–can exercise training protocols influence the downstream effects? Front. Neurol. 16:1639427. doi: 10.3389/fneur.2025.1639427
Edited by:
Wojciech Piotr Paslawski, Karolinska Institutet (KI), SwedenReviewed by:
Rahul Mallick, University of Eastern Finland, FinlandCopyright © 2025 Li and Thirupathi. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Hezhou Li, bGh6MDA5QDE2My5jb20=