Timothy B. Niewold
Julia S. Lehman
Iva Gunnarsson3,4
Alexander Meves
Vilija Oke- 1Barbara Volcker Center for Women and Rheumatic Disease, Hospital for Special Surgery, New York, NY, United States
- 2Department of Dermatology, Mayo Clinic, Rochester, MN, United States
- 3Rheumatology Unit, Department of Meidicine, Karolinska Institutet, Stockholm, Sweden
- 4Rheumatology, Theme Inflammation and Aging, Karolinska University Hospital, Stockholm, Sweden
- 5Academic Specialist Center, Stockholm Region, Stockholm, Sweden
Interleukin (IL)-16 is expressed mostly by the cells of the human immune system. Upon cell activation IL-16 is cleaved, forming two functional proteins, one regulating cell cycle and the other acting as chemoattractant for the cells carrying CD4 or CD9. Increased levels of IL-16 are found in the circulation and at the sites of inflammation, infection and cancer. Polymorphisms in the IL-16 gene have been coupled to several of these conditions and high IL-16 has been suggested as a disease biomarker. Using unbiased proteomic approach we and others independently identified IL-16 as a biomarker of severe lupus nephritis, and top-expressed cytokine in skin lesions of lupus erythematosus. Recently, an unbiased investigation identified IL-16 as a top candidate for novel drug target. Blockade of IL-16 showed positive therapeutic effects in several animal models of human disease with low rate of side effects. Importantly, it has been recently demonstrated that IL-16 can be released during pyroptosis, a proinflammatory cell death pathway. This finding disclosed a novel role of IL-16 as a mediator of response to the proinflammatory cell death and may explain why IL-16 is detected at the sites of inflammation, infection or cancer. In this review we cover the knowledge on the biology of IL-16 and its importance in human diseases. We aim that this manuscript will be informative and prove benefits of possible therapeutic blockade of IL-16.
1 Biology of IL-16
1.1 Characteristics of IL-16 protein
The human IL-16 gene is encoded on chromosome 15q26.3, is 153 kilobase pair (kbp) long and consists of seven exons and six introns (1). IL-16 protein is highly conserved among species. Two translated IL-16 proteins have been found in humans: one is restricted to the central nervous system, entitled neuronal NIL-16 (130 kilo daltons (kDa) or 141kD according different sources) (2). The 80 kDa IL-16 is found in many other organ tissues, particularly lymphoid, and is generated as a 631-amino-acid precursor IL-16 molecule. After cell stimulation caspase-3 (casp-3) may cleave IL-16 at residue asparagine253 into 66kDa N terminal also called pro-IL-16 and 14kDa C terminal mature IL-16 (Figure 1A) (3–5). IL-16 is highly conserved, up to 96-98%, across the species close to humans such as Rhesus, Macaques and monkeys (3, 6).It is reported that functional activity of the secreted mature IL-16 is localized at the hydrophylic region of the carboxyterminal, and before secretion 14kDA chains form 56kDa homotetramers (Figure 1B) (6). The N terminus of IL-16 can be located in either the cytosol or the nucleus of the cells and may regulate cell growth (7, 8). Cleaved or mature IL-16 is supposed to be secreted; however, certain cell types (i.e. cluster differentiation (CD) 8+ T cells) may contain cytoplasmic stores of mature, bioactive IL-16 which can be released upon stimulation, saving time from new synthesis (9, 10). Secretion of bioactive IL-16 is regulated by mitogen-activated protein (MAP) kinase and has been postulated to be likened to secretion of IL-1β following cleavage by caspase-1 (11). IL-16 mRNA is regulated in calcineurin dependent manner (12). Casp-3 activation and IL-16 cleavage is not necessarily associated with the induction of apoptosis, but recently release of IL-16 has been described in endometriosis via Gasdermin (GASDM) E pyroptotic pathway (Figure 2) (9, 13).
Figure 1. (A) Structure of IL-16 protein. (B) Processing of IL-16 within a cell. The cytoplasmic IL-16 is cleaved by active caspase-3 and mature C terminal IL-16 forms homo-tetramers than can be secreted and ligate its receptors CD4, CD9 or CCR5. N terminal pro-IL-16 enters nucleus and regulate cell cycle.
Figure 2. Schematic illustration of classical pyroptosis pathway (left) and a relatively novel gasdermin-E (GSDME) pyroptosis pathway (right) resulting in IL-16 cleavage and release. The classical pyroptosis pathway is induced by recognition of danger associated molecular patterns (DAMPS), activation of inflammasome, cleavage of procaspase-1 to caspase -1, subsequent cleavage of GASDM-E and pro-IL-1b/18, multimerization of GASDME-N terminal products and a cell pore formation and release of proinflammatory mediators including IL-1b/18. The GASDME pathway can be activated by several stimuli including granzyme A and B, iron overload, extrinsic and intrinsic death receptors, and mitochondrial damage.
1.2 Cellular expression of IL-16 in healthy tissues and their cells
Physiologically IL-16 is expressed by cells of lymphoid organs: bone marrow, spleen, lymph nodes, thymus, tonsils and appendix, while tissues of the lower gastrointestinal tract express IL-16, but at a lower level. The majority of other tissues express mRNA for IL-16, and presumably can translate and secrete IL-16 under certain conditions. Among other tissue cells IL-16 has been found in cutaneous, cardial, renal fibroblasts and bronchial epithelial cells (14–16).
The majority of the immune cell types can express IL-16 protein. The CD4+ and CD8 positive T cells are the best studied expressors of IL-16, but also neutrophils, B-cells, eosinophils, dendritic cells, mast cells, macrophages and monocytes, natural killer cells all are found to express IL-16 (9, 17–20). Microglial cells and astrocytes are also found to express IL-16, while neurons did not show IL-16 expression (21).
It seems that IL-16 is a rapid response cytokine in certain cell types, for example in CD8+ T cells, eosinophils and also mast cells, where circulating cells carry an already pre-synthesized protein and are ready to release it immediately after stimulation with vasoactive amines, such as serotonin or histamine (22).
Reports indicate that same types of cells express and secrete IL-16 in various categories of human diseases including infectious, inflammatory diseases and cancers. The overall data point that levels of circulating IL-16 are increased in the investigated diseases. Knowledge on what cell types are the producers and responders in respective conditions are limited and is covered in more details below. Data indicates that mechanisms which tune IL-16 are of importance and modulation might have therapeutic effect.
1.3 Receptors of the IL-16
Several receptors for IL-16 have been identified: CD4, CD9 and CCR5 (3, 23, 24). CD4 is regarded as the major receptor as it is expressed by a range of hematopoietic and immune cells, as well on neuronal cells (3). The main ligand of IL-16 is D4 domain of CD4 (3). Many types of lymphoid cells including T cells, eosinophils, dendritic cells, B cells, as well as mast cells, macrophages and monocytes respond to IL-16, but it is not completely clear what receptors IL-16 binds (15, 19, 24–28). In the spinal cord CD4 is expressed in microglia, located close to astrocytes and neurons (29). The best described cellular function of IL-16 is mediated by CD4 binding, which induces cell migration via chemoattraction. Upon binding to the D4 domain of CD4, IL-16 activates the CD4-associated src-related tyrosine kinase p56lck via autocatalysis (30). Protein kinase C subsequently translocate to the membrane, inducing downstream signaling pathways in the target cell, including a rise in intracellular calcium, inositol trisphosphate (IP) 3 and phosphoinositide 3-kinase (PI3K) activation (30, 31). Additionally, IL-16 has also been shown to activate signal transducer and activator of transcription (STAT) 6 following interaction with CD4, though downstream signaling pathways and subsequent cellular responses have not yet been identified (31). Co-ligation of C-C chemokine receptor type 5 (CCR5) enhances cell response to the IL-16 signaling, and importantly CCR5 is preferentially expressed on T helper (Th) 1 cells, what seems to enhance migratory IL-16 effects on these cells (24). Findings indicate that before secretion, IL-16 preferentially forms multimers (homodimers or homo-tetramers) to mediate its effects more efficiently (4). Multimerization of IL-16 facilitates crosslinking of CD4 and CCR5 on the target cells and enhances cell signaling (4). Several studies have shown that IL-16/CD4 ligation may result in desensitization for other chemokine receptors, such as CCR5-, C-X-C chemokine receptor type (CXCR) 3 and CXCR4-induced migration (32), impairing macrophage inflammatory protein-1 beta (MIP-1b) and stromal cell-derived factor 1 (SDF-1a) mediated T cell chemoattraction (23, 24, 32, 33). In the presence of IL-16, the chemokine ligands for receptors including C-C motif chemokine ligand 5 (CCL5 or RANTES), MIP-1a, MIP-1, and SDF-1a are unable to recruit T cells, which indicates that IL-16 may direct what cells should be recruited (9).
The cells of monocyte and epithelial origin may respond to IL-16 via CD9 receptor as demonstrated in vitro on primary cells, cell lines and also in mouse models (15, 25, 34, 35).
1.4 The physiologic importance of IL-16 in the regulation cell cycle and cell growth
Both the N-terminal pro-IL-16 and the secreted mature IL-16 may impact cell growth. Cleaved N-terminal or pro-IL-16 fragment translocate into the nucleus and has been suggested to serve as cell cycle regulator (10). Repeated studies confirmed that pro-IL-16 has a cell cycle regulator function in T cells: high nuclear expression of pro-IL-16 induces cell cycle arrest G0/G1, inhibit cell proliferation and is associated with increased levels of cyclin-dependent kinase inhibitor p27Kip1 (36). During T cell activation, mRNA of IL-16 is downregulated and less IL-16 is observed in cell nuclei, which may result in expression of S-phase kinase-associated protein 2 (Skp2), degradation of p27Kip1 and enable the cell to enter cell cycle (36).
It could render stimulated and pre-exposed T cells refractory to antigenic stimulation, promoting anergy (37).
2 The major cellular sources of IL-16 is the human immune system
All major types of immune cells express IL-16. Overview of data is presented in Table 1.
Table 1. Expression of IL-16 in different immune cell types.
2.1 IL-16 and T cells
Human T cells are the most studied source and target of IL-16. T cell activation by antigens, mitogens or vasoactive amines (like histamine or serotonin) may result in activation of casp-3 and cleavage of mature IL-16, which can be secreted. This process was described in both CD4+ and CD8+ T cells. While casp-3 is constantly active in CD8+ cells, continuously produced and cleaved IL-16 is stored in secretory vesicles, activation of casp-3 in CD4+ T cells must be induced by a stimuli, and thereafter IL-16 can be cleaved (34). Interestingly, it may take different amount of time from cell stimulation to IL-16 secretion depending on what stimuli the CD8+ cell receives: for histamine and serotonin it takes several hours, while for antigens and mitogens it requires 12–24 hours. Importantly, addition of transcription and translation inhibitors may block IL-16 secretion from CD4+, but not from CD8+ cells (reviewed in (4)). In vitro, IL-16 treatment of human peripheral CD4+T lymphocytes induces upregulation of IL-2Ra (CD25) and IL-2Rb within 24 h, enhancing IL-2 mediated T cell proliferation (9, 47). Binding of bioactive IL-16 to CD4 preferentially induces chemotaxis of CD4+Th1 type T cells, rather than Th2 type (24). In the presence of CCR5 the response to IL-16 is enhanced, while IL-16 could not bind to CCR5 without CD4. CD4+CCR5+ cells are the typical Th1cells that are prevalent at the sites of inflammation and this mechanism likely plays a pivotal role for recruitment and activation of T cells (24). After the cells attraction the CCR5 receptor is desensitized, possibly in order to terminate the process. Interestingly, the pre-treatment of cells with MIP-1β, SDF-1α/CXCR4 resulted in loss of responsiveness to IL-16 stimulation (23). In a diabetes mellitus (DM) model, T cells are attracted to the place of insulitis via CCL4, and inhibition of CCL4 and IL-16 were protective from DM (48).
2.2 IL-16 and B cells
Peripheral B cells express IL-16 at different proportions, ranging widely from 1.5%-94.4% (38). B cells express IL-16 mRNA and synthesize bioactive IL-16 protein, as observed in lymph node follicles (39). B cell supernatants induce migration of CD4+ Th cells, monocyte-derived DCs, and circulating DCs, which can be blocked via neutralization of IL-16. IL-16 seems important B-cell derived chemotactic factor involved in cellular cross-talk among T lymphocytes and DCs and their recruitment (39).
2.3 IL-16 and neutrophils
Neutrophils express IL-16 and are active secretors of IL-16, while IL-16 is a potent attractor of neutrophils to the site of inflammatory damage (40). In addition, secondary necrotic neutrophils may passively release interleukin-16 (41).
2.4 IL-16 in monocytes and macrophages
Human CD14+ monocytes constitutively express IL-16. If unstimulated within 6–8 h in vitro monocytes undergo apoptosis due to activation of casp-3, and release IL-16. It is not clear what is the stimulus and mechanism of this spontaneous release (42).
Monocyte cell line THP-1 infected with methicillin-resistant staphylococcus aureus (MRSA) secrete IL-16 (43), which can be blocked with anti-epidermal growth factor receptor (EGFR), anti-FasL antibodies (Ab), while pan-casp inhibitor (Z-VAD-FMK) or casp-3 inhibitors (43). In MRSA infected mouse lungs infiltrating immune cells express IL-16 and neutralizing anti-IL-16 Ab improved clearance of MRSA pneumonia in mice (43).
In vitro, stimulation with IFN-γ+LPS induce IL-16 mRNA upregulation in THP-1 monocyte cell line. Incubation of M0 macrophages with rIL-16 (150ng/ml) increase phagocytosis by 150%, and skew cytokine expression with upregulated IL-1α, IL-6 and IL-12, but downregulate IL-10; without affecting THP-1 cell proliferation (49).
2.5 IL-16 and dendritic cells and Langerhans cells
Interleukin-16 has an important role in DC differentiation. In vitro IL-16 can induce human cord blood cells and CD34(+) hematopoietic cells to proliferate and differentiate into phenotypically and functionally mature DCs (50). Monocyte exposure to IL-16 and thrombopoetin may lead to monocyte maturation to DCs (51).
In atopic dermatitis IgE-bound allergens are presented to epidermal LCs via the high affinity IgE receptor, FcϵRI and induces expression of IL-16, what results in chemoattraction of DCs, CD4+ T cells and eosinophils (44). Importantly casp-1, but not casp-3, further process IL-16 in epidermal DCs.
2.6 IL-16 and mast cells
Mast cells express CD9 and lack CD4 receptor. Ligation of CD9 by IL-16 on MCs induces their chemotaxis and activation (25). Cell treatment with anti-CD9 mAbs inhibit the IL-16–mediated chemotactic response of human (H) MC-1 line and its activation, same effects were observed on non-transformed human cord blood–derived MCs and mouse bone marrow–derived MCs by 50% to 60% (25).
2.7 IL-16 and natural killer cells
NK cells can also express and produce IL-16, and smokers display decreased levels of IL-16 in circulating NK cells. What biological function IL-16 mediates in NK cells requires further studies (38).
2.8 IL-16 and eosinophils
Interleukin-16 (IL-16) is known as a highly potent chemotactic and chemoattractant molecule for eosinophils (45). Tissue infiltrating eosinophils in eosinophilic conditions such as chronic eosinophilic rhinitis (ECRS) express IL-16 protein in parallel to other infiltrating cells such as MCs, lymphocytes and tissue epithelial cells. Data suggest that IL-16 may stimulate the migration and persistence of activated eosinophils in ECRS (46).
2.9 Epithelial cells
Keratinocytes and intestinal and respiratory epithelial and endothelial cells express IL-16 (52). The IL-16 ligand on these cells is CD9 receptor (15, 34, 35). What is the IL-16 function in or on these cells is not known.
2.10 Spontaneous release and targeted secretion of IL-16
Data indicate that IL-16 can be spontaneously released by unstimulated PBMCs in samples drawn and kept in rooms temperature. Importantly, this significant increase is observed in EDTA plasma, slighter increase in citrate plasma, but not at all in serum (53). Investigators suggested that abundant release of IL-16 in EDTA plasma could be due to presence of granulocytes as they are abundant in EDTA but not in citrate, and absent in serum. Investigators suggested that measuring IL-16 (and IL-8) in plasma could be an indicator of quality control if the samples were handled correctly prior to analysis. From the biological point of view these findings raise a relevant question: what environmental factor triggers release of IL-16 and if this process serves any physiologic function.
3 IL-16 in human disease
IL-16 has been implicated in multiple human conditions including inflammatory, autoimmune diseases, infections and cancers. Importantly, a recent major screening study for novel drug target evaluation identified IL-16 as a novel protein with causal evidence in multiple human diseases, a protein that has not been targeted so far (54). This finding sets a platform for this review, and IL-16 targeting could be of interest in multiple conditions. Overview data is summarized in Table 2.
Table 2. The expression patterns and studied functions of IL-16 in the different pathologies.
3.1 Acute myocardial infarction and heart failure
Increased circulating levels of IL-16 are found in patients with ST-elevation AMI, with those without ST-elevation having lower circulating levels (55). In addition, IL-16 levels correlated positively with C-reactive protein (CRP), leukocyte count, NT-proBNP, high sensitivity troponin T levels and negatively with amount of circulating DCs (55). Interleukin-16 (IL-16) has also been reported to mediate left ventricular myocardial fibrosis and stiffening in patients with heart failure with preserved ejection fraction (55).
3.2 Rheumatoid arthritis
The importance of IL-16 in rheumatoid arthritis (RA) has been demonstrated by several investigators (93, 94). High levels of IL-16 are found in the synovial fluid of RA joints and the lining layer of RA synovia (27). It is considered that IL-16 is produced by fibroblasts and attracts CD4+ cells to the synovial infiltrates (14). In vitro, dexamethasone treatment blocked RA patient derived immunoglobulins (IgG) induced T cell migration and IL-16 expression (94). Importantly in SOMAscan™ assay IL-16 was identified out of 1128 serum proteins as the best predictor of treatment response at 12 weeks: IL-16 levels were significantly reduced after MTX treatment in MTX-naïve patients, and by abatacept or tocilizumab treatment in patients with inadequate response to MTX (56).
3.3 Psoriasis
In psoriasis, a common immune-mediated skin disease, serum levels of IL-16 correlate with disease severity measured by psoriasis area and severity index (PASI). Cutaneous inflammatory infiltrates have abundant IL-16 carrying and producing cells, the majority of which express CD4 (57).
3.4 Inflammatory bowel disease
Increased levels of IL-16 are observed in colonic mucosal biopsies in patients with Crohn disease and ulcerative colitis. Treatment with steroids efficiently reduced IL-16 expression in the gut mucosa to the levels as low as in controls (58). Anti–IL-16 mAb treatment significantly reduced signs of disease in an animal colitis model (trinitrobenzenensulfonic acid (TNBS)-induced), such as weight loss, mucosal ulceration, myeloperoxidase activity (P < 0.001), as well as reduced mucosal levels of IL-1β and tumor necrosis factor-α (TNF-α) (59).
3.5 Systemic lupus erythematosus
Implications of the IL-16 role in SLE were reported several decades ago (95). Lately, two independent groups identified IL-16 as the key cytokine in cutaneous and renal involvement in lupus erythematosus (60–62), and also in mouse model of SLE-like pulmonary inflammation (40). Our group has performed an unbiased proteome analysis of cutaneous inflammatory infiltrates in cutaneous LE (CLE), and IL-16 was identified as the top expressed cytokine (96). A urine proteome study using unbiased methods identified IL-16 as a marker of the most severe lupus nephritis (62). We independently confirmed their findings using ELISA and immunohistochemistry in Swedish SLE cohort (60). Independent investigators suggested IL-16 as pro-inflammatory driver, being a SLE disease biomarker of severe renal engagement, and have proposed it as a promising therapeutic target (60–62).
3.6 Vasculitis
Antineutrophil cytoplasmic antibody associated (ANCA) vasculitis, a group of rare, but life threatening, systemic diseases affecting small vessels, including those of vital organs, has been associated with high levels of circulating IL-16; in addition, circulating IL-16 levels correlated with disease damage (63). In Takayashu vasculitis, inflammation affects the walls of large vessels and IL-16 expression was observed both in the circulation and intramural inflammatory infiltrates, and IL-16 levels correlated with amounts of CD4+ cells infiltrating large vessel walls, which induce arterial lesions (64).
3.7 Systemic sclerosis
SSc (also known as scleroderma), a rheumatic disease manifesting as vasculopathy and fibrosis of connective tissue. The serum IL-16 levels in SSc patients are significantly elevated (65). In the diffuse form, the amount of skin infiltrating IL-16 positive cells were higher than in those with the limited SSc form or controls, indicating that high IL-16 associate with a more severe SSc (65).
3.8 Idiopathic thrombocytopenic purpura
In patients with ITP autoimmune mechanisms destroy thrombocytes and confer risk for major bleeding, while purpura is an early diagnostic sign. Increased levels of IL-16 are observed in circulation of patients with ITP, and levels decrease after high dose dexamethasone therapy (66). Besides high protein concentrations, IL-16 mRNA was also found to be upregulated and to correspond to casp-3 mRNA levels, which also dropped after treatment (66).
3.9 Graves’ disease
In GD autoimmune inflammation target the thyroid and connective tissues in the orbit where auto-Abs induce hyperfunction, inflammation and subsequent risk of destruction and hypofunction of thyroid gland. Thyrocytes express mRNA for IL-16, and casp-3 and proIL-16 can be detected in thyrocyte cultures (67). Immunoglobulin (Ig)G from patients with GD induces IL-16 and the chemokine RANTES expression in cultured human thyrocytes, which may contribute to lymphocyte recruitment to the thyroid and promotion of autoimmune insult (97).
3.10 Cow milk protein allergy
Infants who develop CMPA have cytokine disbalance: increased IL-16, and IL-17A, decreased IL-12, while cow milk avoidance led to increase of IL-12, and decrease in IL-16 and IL-17A. Serum IL-12, IL-16, and IL-17A levels have been proposed as diagnostic biomarkers in CMPA (68).
3.11 Endometriosis
Endometriosis, a gynecological condition where ectopic endometrial foci induce inflammation, abdominal pain and reduced fertility, is associated with high peritoneal IL-16 (69). In an unbiased analysis of endometriotic cyst fluid proteins, IL-16 ranked as third most abundant cytokine. Moreover investigators discovered that IL-16 release in endometrial cysts is a result of iron overload induced cell pyroptosis (70) (Figure 2). Abundant IL-16 contributes to local inflammation and abdominal pain in endometriosis.
As reviewed above, circulating levels of IL-16 are increased in multiple autoimmune diseases, however studies demonstrated impaired or defected function of casp-3 or regulation or expression of IL-16 in several autoimmune conditions, what could subsequently lead to defective IL-16 processing and secretion (98). The hypothesis, that there could be alternative mechanisms of IL-16 release is supported by findings of the recent study in endometriosis as pyroptosis could be one of novel pathways of IL-16 secretion (70). Interestingly, pyroptosis is implicated in multiple autoimmune diseases, as triggers that activate inflammasome may lead to pyroptosis.
3.12 Neuronal IL-16 and its role in inflammatory diseases of nervous system, psychiatric conditions and pain
A larger splice variant (141 kD) of IL-16, found within CD4+ post-mitotic granule neurons in the cerebellum and hippocampus, is entitled neuronal IL-16 (NIL-16) (21). Similarly to pro-IL-16, proN-IL-16 is posttranslationally cleaved by casp-3. The NIL-16 contains two additional PDZ domains in its N-terminal portion, which interact with neuronal ion channels, while the C-terminal portion is identical to the lymphocyte bioactive IL-16. The role of NIL-16 in maintenance of the processes in CNS has been explored in several studies in human conditions (71).
3.12.1 Multiple sclerosis
MS, a chronic inflammatory demyelinating and degenerative disease of the CNS, also appears to be affected by IL-16 (71). In the brain lesions of relapsing and remitting (RRMS) lesions CD4+, CD8+, CD83+, DCs and B cells have been observed to express IL-16, as well as casp-3 (71). Circulating levels of IL-16 correlate to markers of axonal damage (such as medium and heavy chains of neurofilaments) and cells carrying IL-16 are found in proximity to MS lesions (72), while levels of serum IL-16 drop after successful treatment with IFNβ-1a and was suggested as a marker of clinical response (73). Anti-IL-16 Ab injection had therapeutic value in a mouse model of MS (EAE) (74).
3.12.2 Psychiatric conditions
Depressive symptoms and major depressive disorder, anxiety, insomnia and phsychosomatic symptoms, fatigue-fibromyalgia symptoms and melancholia have been found to be associated with circulating levels of IL-16 and activation of Th1 immune response (75, 76). Authors suggested that IL-16 could be seen as “psychocutaneous” cytokine and could link depression in psoriasis patients. Based to the finding of the current study on association of IL-16 and fatigue-fibromyalgia symptoms, one could hypothesize that high IL-16 levels could stand for fatigue symptoms common in patients with other autoimmune, inflammatory diseases or even cancer, and coins further studies.
3.12.3 IL-16 and pain
Several investigators studied the role of IL-16 in mouse nociception. Both local and systemic administration of IL-16 in mouse induce hyperalgesia, which can be inhibited by non-steroid anti-inflammatory drugs or IL-16 neutralizing Ab (77). In another mouse model of nociceptive pain, IL-16 has been identified to be involved in astrocyte and glial activation and enhanced nociceptive neuron excitability and promoted inflammatory pain (78). In a mouse model of neuropathic pain induced by using spinal nerve ligation, it was found female specific IL-16 mRNA upregulation (29). In this mouse model, stimulation with IL-16 induced astrocyte activation via CD4+ T cells and targeting this pathway was proposed as a therapeutic possibility for future treatment of neuropathic pain in females (29).
3.13 IL-16 in severe human infections
Increased levels of IL-16 are found in multiple infections. In Clostridium difficile infection it was suggested as a biomarker of more severe disease (79). Cells overexpressing IL-16 are resistant to HIV-1 infection, and IL-16 has been explored as a co-enhancer of HIV-1 virus eradication (80, 81). Low expression of IL-16, among other cytokines, was one of several identified factors for poor outcomes of COVID-19 (82). IL-16 seems to have a specific role in Mycobacterium tuberculosis (Mtb) infection, since IL-16 is produced by Mtb infected macrophages, but may inhibit phagosome maturation and uptake of Mtb and promote the intracellular survival of the pathogen. The recent study found that Mtb hijacks the host-macrophages derived IL-16 and suggested that IL-16 might have immunosuppressive role in Mtb infection (83). In sepsis, circulating levels of IL-16 are increased, while neutralization of IL-16 with Abs reduced mouse mortality and sepsis induced cardiac injury (84). Different single nucleotide polymorphisms of IL-16 are associated with susceptibility for hepatitis B and C infections (5, 85).
3.14 IL-16 in human malignancies
The issue of IL-16 and malignancy, first reviewed in 2014 (34), has since been the topic of over 100 original papers. In brief, a role of IL-16 has been identified in multiple malignancies, including hematological and solid tumors. The role of IL-16 in tumors could be mediated by different functions or loss thereof.
The importance of IL-16 in regulation of cell cycle and growth is underscored by the findings that the cells of certain cancers lack the IL-16 gene or have mutations in nuclear localization sequence of the protein, preventing its entrance to the nucleus and resulting in hyperproliferative states (86, 87), as was demonstrated in cutaneous T cell lymphoma (CTCL) (88). In mycosis fungoides IL-16 was demonstrated to attract malignant effector memory T cells (CCR4+TSLPR+CD4+CCR7-CD31+) to the skin (89).
Loss of nuclear IL-16 in cancer cells has been associated with increase in cytoplasmic IL-16, which has been considered to act as a growth factor for malignant T cells, and also was associated with decreased rate of cancer transformed cell apoptosis (34). Overexpression of IL-16 in multiple myeloma bone marrow has been showed to function as growth factor for CD4 and C9 expressing malignant plasma cells (90). Addition of neutralizing anti-IL-16 Abs resulted in significant reduction of cell proliferation.
In bladder cancer it was shown that IL-16 enhances the suppressive T regs capacity within sentinel lymph nodes and could contribute as tumor immune escape mechanism (91). Extracellular IL-16 in cancer patients is a potent chemoattractant of immune cells and that IL-16 participates in development of immunotolerance to malignant cells, since inhibition of IL-16 improved prognosis in those models (92). Blocking or neutralizing IL-16 could enhance antitumor effects of several substances and has been proposed as an adjuvant target by several investigators (99). For example tumor intrinsic Aurora-A promotes the cytotoxic activity of CD8+T cells in immune-hot chemotherapy resistant cancer (CRC) via negative regulation of interleukin-16 (IL-16). The upregulation of IL-16 was suggested as tumor escape mechanism and impaired the therapeutic effect of Aurora-A inhibition. Neutralization of IL-16 could promote therapeutic effect of Aurora-A inhibitor (99).
4 IL-16 and pyroptosis
As reviewed above, circulating levels of IL-16 are increased in multiple autoimmune diseases, which have also been associated with impaired expression and regulation of both casp-3 and IL-16 (98). Thus, there could be alternative mechanisms of IL-16 cleavage and release. A recent study in endometriosis demonstrated that IL-16 can be cleaved and released during iron overload induced pyroptotic cell death via non-classical GASDME mediated pathway (70). Interestingly, pyroptosis is implicated in multiple autoimmune diseases and common triggers of autoimmunity such as immune-complexes, secondary necrotic cell debris, extracellular damaged DNA could possibly trigger pyroptosis, and hypothetical IL-16 release (Figure 2) (100).
In cancer, the expression of GASDME is lower in most tumor cells due to the epigenetic inactivation caused by methylation, while chemotherapy may activate casp-3, GADSME expression and facilitate tumor cell pyroptosis (101, 102). It is not clear if cancer pyroptotic cell death results in release of cleaved IL-16, as was proven in the case in endometriosis (Figure 2) (70).
5 Genetic polymorphisms of IL-16 gene
Several polymorphisms of IL-16 gene have been associated with cancer and autoimmune diseases. Two meta-analysis confirmed association of cancers with rs11556218T>G, and one meta-analysis confirmed association of cancers with rs4778889T>C polymorphisms. The rs11556218T>G polymorphism was also associated with the risk of cardiovascular disease in Chinese population (103, 104). Genetic studies in autoimmune diseases found associations with polymorphisms in the same loci, but did not reach genome-wide association study power and will not be reviewed in this paper.
6 Successful outcomes in IL-16 inhibition in mouse models of human diseases
So far inhibition of IL-16 has been addressed only in animal models. In a model of spontaneous diabetes in NOD female mice, blockade of IL-16 with neutralizing Abs prevented insulitis, destruction of insulin-producing pancreatic islets and inhibited development of type 1 diabetes (48). Experimental autoimmune encephalomyelitis (EAE) is the typical model to study multiple sclerosis. In this model the majority of the immune cells infiltrating central nervous system express IL-16. Blockade of IL-16 with neutralizing Ab led to successful outcomes - reversed paralysis, ameliorated relapsing disease, reduced infiltration by CD4+ T cells and demyelination (74). In models of sepsis or cardiac injury, blockade of IL-16 reduced mortality and improved survival and reduced damage via activation of antioxidant pathways (84, 105). Importantly neutralization of IL-16 proved adjuvant effect on novel cytostatic drugs and could improve outcomes in oncologic diseases (99).
7 Possible therapeutic approaches to IL-16 inhibition
Neutralization of cytokines with in vitro produced anti-cytokine Abs has been used in daily practice in rheumatology and cancer care over the last several decades. It could be one of the modalities chosen for therapeutic inhibition of IL-16 function, as in experimental animal models described in section 6 anti-IL16 neutralizing Abs showed positive results (48, 74, 84, 99, 105). An alternative approach could be to block IL-16 receptor with anti-receptor Abs. The inhibition of CD4 receptor is not possible, as this receptor is vital for its role in protection against infections. However inhibition of CD9 or CD4 co-receptor CCR5 could be novel potential target. Hypothetically inhibition of CCR5 could reduce the potency of IL-16 stimulus to CD4 and could still guarantee the vital IL-16 signal. Data on hypothesis of possible therapeutic interventions is summarized in graphical abstract (Figure 3).
Figure 3. Graphical abstract. Panel (A) illustrates what immune cells express IL-16 and its receptors. ? – indicates that it is not clear if the cell type expresses any receptor for IL-16. NK - natural killer cell, Th1 – T helper 1 cell. Panel (B) illustrates overview of IL-16 roles in inflammation, infection and cancer (left) and possible outcomes of therapeutic IL-16 inhibition (right): neutralization of extracellular IL-16 could attenuate inflammation and cell recruitment to the inflammatory sites (upper panel); there is no clear information whether IL-16 targeting could benefit infections (middle panel); in cancers IL-16 inhibition could allow anti-tumour immune response and possibly block cell cycle progression (lower panel).
In conclusion, the IL-16 protein has multiple functions in the human immune system, and impaired protein regulation or function or genetic polymorphisms are associated with a variety of life-threatening acute and chronic conditions. Overall data in inflammatory diseases indicate that inhibition of IL-16 could attenuate inflammatory responses and reduce recruitment of target cells to the inflammatory sites. In cancers, loss of nuclear IL-16 leads to hyperproliferative states, which are more difficult to target, but neutralization of secreted IL-16 could improve outcomes of chemotherapy and modulate tumor escape mechanism.
Author contributions
TN: Conceptualization, Writing – original draft, Writing – review & editing, Data curation. JL: Writing – original draft, Writing – review & editing, Conceptualization, Data curation. IG: Conceptualization, Data curation, Writing – original draft, Writing – review & editing. AM: Writing – original draft, Writing – review & editing, Conceptualization, Data curation. VO: Writing – original draft, Writing – review & editing, Conceptualization, Data curation, Formal analysis, Investigation, Supervision, Visualization.
Funding
The author(s) declare that financial support was received for the research and/or publication of this article. This study was supported by FoUU fund at CRF, ASC, 2024; doctor Margareta Nillson research fund, 2022; Swedish Rheumatism association project grant, 2019; KI funds 2019, project grant Sunds fund 2018.
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.
The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.
Generative AI statement
The author(s) declare that no Generative AI was used in the creation of this manuscript.
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References
1. Kim HS. Assignment of human interleukin 16 (IL16) to chromosome 15q26.3 by radiation hybrid mapping. Cytogenet Cell Genet. (1999) 84:93. doi: 10.1159/000015224
2. Kurschner C and Yuzaki M. Neuronal interleukin-16 (NIL-16): A dual function PDZ domain protein. J Neurosci. (1999) 19:7770–80. doi: 10.1523/jneurosci.19-18-07770.1999
3. Cruikshank WW, Kornfeld H, and Center DM. Interleukin-16. J Leukoc Biol. (2000) 67:757–66. doi: 10.1002/jlb.67.6.757
4. Center DM, Kornfeld H, and Cruikshank WW. Interleukin-16. Int J Biochem Cell Biol. (1997) 29:1231–4. doi: 10.1016/s1357-2725(97)00053-8
5. Ludwiczek O, Kaser A, Koch RO, Vogel W, Cruikshank WW, and Tilg H. Activation of caspase-3 by interferon alpha causes interleukin-16 secretion but fails to modulate activation induced cell death. Eur Cytokine Netw. (2001) 12:478–86.
6. Nicoll J, Cruikshank WW, Brazer W, Liu Y, Center DM, and Kornfeld H. Identification of domains in IL-16 critical for biological activity. J Immunol (Baltim Md: 1950). (1999) 163:1827–32. doi: 10.4049/jimmunol.163.4.1827
7. Center DM, Cruikshank WW, and Zhang Y. Nuclear pro-IL-16 regulation of T cell proliferation: p27KIP1-dependent G0/G1 arrest mediated by inhibition of skp2 transcription. J Immunol. (2004) 172:1654–60. doi: 10.4049/jimmunol.172.3.1654
8. Mühlhahn P, Zweckstetter M, Georgescu J, Ciosto C, Renner C, Lanzendörfer M, et al. Structure of interleukin 16 resembles a PDZ domain with an occluded peptide binding site. Nat Struct Biol. (1998) 5:682–6. doi: 10.1038/1376
9. Wilson KC, Center DM, and Cruikshank WW. The effect of interleukin-16 and its precursor on T lymphocyte activation and growth. Growth Factors Chur Switz. (2004) 22:97–104. doi: 10.1080/08977190410001704679
10. Wu DM, Zhang Y, Parada NA, Kornfeld H, Nicoll J, Center DM, et al. Processing and release of IL-16 from CD4+ but not CD8+ T cells is activation dependent. J Immunol (Baltim Md: 1950). (1999) 162:1287–93. doi: 10.4049/jimmunol.162.3.1287
11. Laurence A, Astoul E, Hanrahan S, Totty N, and Cantrell D. Identification of pro-interleukin 16 as a novel target of MAP kinases in activated T lymphocytes. Eur J Immunol. (2004) 34:587–97. doi: 10.1002/eji.200324598
12. Ren F, Zhan X, Martens G, Lee J, Center D, Hanson SK, et al. Pro-IL-16 regulation in activated murine CD4+ Lymphocytes. J Immunol. (2005) 174:2738–45. doi: 10.4049/jimmunol.174.5.2738
13. Zhang Y, Center DM, Wu D MH, Cruikshank WW, Yuan J, Andrews DW, et al. Processing and activation of pro-interleukin-16 by caspase-3*. J Biol Chem. (1998) 273:1144–9. doi: 10.1074/jbc.273.2.1144
14. Sciaky D, Brazer W, Center DM, Cruikshank WW, and Smith TJ. Cultured human fibroblasts express constitutive IL-16 mRNA: cytokine induction of active IL-16 protein synthesis through a caspase-3-dependent mechanism. J Immunol. (2000) 164:3806–14. doi: 10.4049/jimmunol.164.7.3806
15. Yadav S, Shi Y, and Wang H. IL-16 effects on A549 lung epithelial cells: Dependence on CD9 as an IL-16 receptor? J Immunotoxicol. (2010) 7:183–93. doi: 10.3109/15476911003649346
16. Human Protein Atlas . Available online at: https://www.proteinatlas.org/ENSG00000172349-IL16/tissue (Accessed September 24, 2024).
17. Lim KG, Wan HC, Bozza PT, Resnick MB, Wong DT, Cruikshank WW, et al. Human eosinophils elaborate the lymphocyte chemoattractants. IL-16 (lymphocyte chemoattractant factor) and RANTES. J Immunol. (1996) 156:2566–70. doi: 10.4049/jimmunol.156.7.2566
18. Cruikshank WW, Lim K, Theodore AC, Cook J, Fine G, Weller PF, et al. IL-16 inhibition of CD3-dependent lymphocyte activation and proliferation. J Immunol (Baltim Md: 1950). (1996) 157:5240–8. doi: 10.4049/jimmunol.157.12.5240
19. Rumsaeng V, Cruikshank WW, Foster B, Prussin C, Kirshenbaum AS, Davis TA, et al. Human mast cells produce the CD4+ T lymphocyte chemoattractant factor, IL-16. J Immunol. (1997) 159:2904–10. doi: 10.4049/jimmunol.159.6.2904
20. Kaser A, Dunzendorfer S, Offner FA, Ryan T, Schwabegger A, Cruikshank WW, et al. A role for IL-16 in the cross-talk between dendritic cells and T cells. J Immunol (Baltim Md: 1950). (1999) 163:3232–8. doi: 10.4049/jimmunol.163.6.3232
21. Skundric DS, Cruikshank WW, and Drulovic J. Role of IL-16 in CD4+ T cell-mediated regulation of relapsing multiple sclerosis. J Neuroinflamm. (2015) 12:78. doi: 10.1186/s12974-015-0292-x
22. Laberge S, Cruikshank WW, Beer DJ, and Center DM. Secretion of IL-16 (lymphocyte chemoattractant factor) from serotonin-stimulated CD8+ T cells in vitro. J Immunol (Baltim Md: 1950). (1996) 156:310–5. doi: 10.4049/jimmunol.156.1.310
23. Mashikian MV, Ryan TC, Seman A, Brazer W, Center DM, and Cruikshank WW. Reciprocal desensitization of CCR5 and CD4 is mediated by IL-16 and macrophage-inflammatory protein-1β, respectively. J Immunol. (1999) 163:3123–30. doi: 10.4049/jimmunol.163.6.3123
24. Lynch EA, Heijens CAW, Horst NF, Center DM, and Cruikshank WW. Cutting edge: IL-16/CD4 preferentially induces th1 cell migration: requirement of CCR5. J Immunol. (2003) 171:4965–8. doi: 10.4049/jimmunol.171.10.4965
25. Qi JC, Wang J, Mandadi S, Tanaka K, Roufogalis BD, Madigan MC, et al. Human and mouse mast cells use the tetraspanin CD9 as an alternate interleukin-16 receptor. Blood. (2005) 107:135–42. doi: 10.1182/blood-2005-03-1312
26. Stoitzner P, Ratzinger G, Koch F, Janke K, Fritsch P, Romani N, et al. Interleukin-16 supports the migration of langerhans cells, partly in a CD4-independent way. J Invest Dermatol. (2001) 116:641–9. doi: 10.1046/j.1523-1747.2001.01328.x
27. Franz JK, Kolb SA, Hummel KM, Lahrtz F, Neidhart M, Aicher WK, et al. Interleukin-16, produced by synovial fibroblasts, mediates chemoattraction for CD4+ T lymphocytes in rheumatoid arthritis. Eur J Immunol. (1998) 28:2661–71. doi: 10.1002/(sici)1521-4141(199809)28:09<2661::aid-immu2661>3.0.co;2-n
28. Sharma V, Sparks JL, and Vail JD. Human B-cell lines constitutively express and secrete interleukin-16. Immunology. (2000) 99:266–71. doi: 10.1046/j.1365-2567.2000.00959.x
29. Zhu X, Li X, Liu S, Zhao Y-H, Liu X-R, Liu X-Y, et al. Enhanced interleukin-16-CD4 signaling in CD3 T cell mediates neuropathic pain via activating astrocytes in female mice. Neuropharmacology. (2024) 259:110115. doi: 10.1016/j.neuropharm.2024.110115
30. Parada NA, Cruikshank WW, Danis HL, Ryan TC, and Center DM. IL-16- and other CD4 ligand-induced migration is dependent upon protein kinase C. Cell Immunol. (1996) 168:100–6. doi: 10.1006/cimm.1996.0054
31. Liu Y, Cruikshank WW, O’Reilly P, Center DM, Kornfeld H, and O’Loughlin T. Identification of a CD4 domain required for interleukin-16 binding and lymphocyte activation*. J Biol Chem. (1999) 274:23387–95. doi: 10.1074/jbc.274.33.23387
32. Rahangdale S, Morgan R, Heijens C, Ryan TC, Yamasaki H, Bentley E, et al. Chemokine receptor CXCR3 desensitization by IL-16/CD4 signaling is dependent on CCR5 and intact membrane cholesterol. J Immunol. (2006) 176:2337–45. doi: 10.4049/jimmunol.176.4.2337
33. Drenth CV, Jenkins A, Ledwich L, Ryan TC, Mashikian MV, Brazer W, et al. Desensitization of CXC chemokine receptor 4, mediated by IL-16/CD4, is independent of p56lck enzymatic activity. J Immunol. (2000) 165:6356–63. doi: 10.4049/jimmunol.165.11.6356
34. Richmond J, Tuzova M, Cruikshank W, and Center D. Regulation of cellular processes by interleukin-16 in homeostasis and cancer. J Cell Physiol. (2014) 229:139–47. doi: 10.1002/jcp.24441
35. Liu J, Zhu G, Jia N, Wang W, Wang Y, Yin M, et al. CD9 regulates keratinocyte migration by negatively modulating the sheddase activity of ADAM17. Int J Biol Sci. (2019) 15:493–506. doi: 10.7150/ijbs.29404
36. Wilson KC, Cattel DJ, Wan Z, Rahangdale S, Ren F, Kornfeld H, et al. Regulation of nuclear Prointerleukin-16 and p27Kip1 in primary human T lymphocytes. Cell Immunol. (2005) 237:17–27. doi: 10.1016/j.cellimm.2005.09.003
37. Ogasawara T-H, Sekigawa H, and Kaneko H. Inhibitory effect of interleukin-16 on interleukin-2 production by CD4+ T cells. Immunology. (1999) 96:215–9. doi: 10.1046/j.1365-2567.1999.00693.x
38. Andersson A, Malmhäll C, Houltz B, Tengvall S, Sjöstrand M, Qvarfordt I, et al. Interleukin-16-producing NK cells and T-cells in the blood of tobacco smokers with and without COPD. Int J Chronic Obstr. (2016) 11:2245–58. doi: 10.2147/copd.s103758
39. Kaser A, Dunzendorfer S, Offner FA, Ludwiczek O, Enrich B, Koch RO, et al. B lymphocyte-derived IL-16 attracts dendritic cells and th cells. J Immunol. (2000) 165:2474–80. doi: 10.4049/jimmunol.165.5.2474
40. Smith S, Wu PW, Seo JJ, Fernando T, Jin M, Contreras J, et al. IL-16/miR-125a axis controls neutrophil recruitment in pristane-induced lung inflammation. JCI Insight. (2018) 3:e120798. doi: 10.1172/jci.insight.120798
41. Roth S, Agthe M, Eickhoff S, Möller S, Karsten CM, Borregaard N, et al. Secondary necrotic neutrophils release interleukin-16C and macrophage migration inhibitory factor from stores in the cytosol. Cell Death Discov. (2015) 1:15056. doi: 10.1038/cddiscovery.2015.56
42. Elssner A, Doseff AI, Duncan M, Kotur M, and Wewers MD. IL-16 is constitutively present in peripheral blood monocytes and spontaneously released during apoptosis. J Immunol. (2004) 172:7721–5. doi: 10.4049/jimmunol.172.12.7721
43. Ahn D, Parker D, Planet PJ, Nieto PA, Bueno SM, and Prince A. Secretion of IL-16 through TNFR1 and calpain-caspase signaling contributes to MRSA pneumonia. Mucosal Immunol. (2014) 7:1366–74. doi: 10.1038/mi.2014.24
44. Reich K, Heine A, Hugo S, Blaschke V, Middel P, Kaser A, et al. Engagement of the Fc epsilon RI stimulates the production of IL-16 in Langerhans cell-like dendritic cells. J Immunol (Baltim Md: 1950). (2001) 167:6321–9. doi: 10.4049/jimmunol.167.11.6321
45. Ma M, Percopo CM, Sturdevant DE, Sek AC, Komarow HD, and Rosenberg HF. Cytokine diversity in human peripheral blood eosinophils: profound variability of IL-16. J Immunol. (2019) 203:520–31. doi: 10.4049/jimmunol.1900101
46. Lackner A, Raggam RB, Stammberger H, Beham A, Braun H, Kleinhappl B, et al. The role of interleukin-16 in eosinophilic chronic rhinosinusitis. Eur Arch Oto-Rhino-Laryngol. (2007) 264:887–93. doi: 10.1007/s00405-007-0300-6
47. Parada NA, Center DM, Kornfeld H, Rodriguez WL, Cook J, Vallen M, et al. Synergistic activation of CD4+ T cells by IL-16 and IL-2. J Immunol (Baltim Md: 1950). (1998) 160:2115–20. doi: 10.4049/jimmunol.160.5.2115
48. Meagher C, Beilke J, Arreaza G, Mi Q-S, Chen W, Salojin K, et al. Neutralization of interleukin-16 protects nonobese diabetic mice from autoimmune type 1 diabetes by a CCL4-dependent mechanism. Diabetes. (2010) 59:2862–71. doi: 10.2337/db09-0131
49. Huang Y, Du KL, Guo PY, Zhao RM, Wang B, Zhao XL, et al. IL-16 regulates macrophage polarization as a target gene of mir-145-3p. Mol Immunol. (2019) 107:1–9. doi: 10.1016/j.molimm.2018.12.027
50. Rofani C, Luchetti L, Testa G, Lasorella R, Isacchi G, Bottazzo GF, et al. IL-16 can synergize with early acting cytokines to expand ex vivo CD34 isolated from cord blood. Stem Cells Dev. (2009) 18:671–82. doi: 10.1089/scd.2008.0187
51. Bella SD, Nicola S, Timofeeva I, Villa ML, Santoro A, and Berardi AC. Are interleukin-16 and thrombopoietin new tools for the in vitro generation of dendritic cells? Blood. (2004) 104:4020–8. doi: 10.1182/blood-2004-03-0885
52. Frezzolini A, Cianchini G, Ruffelli M, Cadoni S, Puddu P, and Pità OD. Interleukin-16 expression and release in bullous pemphigoid. Clin Exp Immunol. (2004) 137:595–600. doi: 10.1111/j.1365-2249.2004.02570.x
53. Kofanova O, Henry E, Quesada RA, Bulla A, Linares HN, Lescuyer P, et al. IL8 and IL16 levels indicate serum and plasma quality. Clin Chem Lab Med (CCLM). (2018) 56:1054–62. doi: 10.1515/cclm-2017-1047
54. Folkersen L, Gustafsson S, Wang Q, Hansen DH, Hedman ÅK, Schork A, et al. Genomic and drug target evaluation of 90 cardiovascular proteins in 30,931 individuals. Nat Metab. (2020) 2:1135–48. doi: 10.1038/s42255-020-00287-2
55. Schernthaner C, Paar V, Wernly B, Pistulli R, Rohm I, Jung C, et al. Elevated plasma levels of interleukin-16 in patients with acute myocardial infarction. Medicine. (2017) 96:e8396. doi: 10.1097/md.0000000000008396
56. Murota A, Suzuki K, Kassai Y, Miyazaki T, Morita R, Kondo Y, et al. Serum proteomic analysis identifies interleukin 16 as a biomarker for clinical response during early treatment of rheumatoid arthritis. Cytokine. (2016) 78:87–93. doi: 10.1016/j.cyto.2015.12.002
57. Purzycka-Bohdan D, Szczerkowska-Dobosz A, Zablotna M, Wierzbicka J, Piotrowska A, Zmijewski MA, et al. Assessment of interleukin 16 serum levels and skin expression in psoriasis patients in correlation with clinical severity of the disease. PloS One. (2016) 11:e0165577. doi: 10.1371/journal.pone.0165577
58. Seegert D, Rosenstiel P, Pfahler H, Pfefferkorn P, Nikolaus S, and Schreiber S. Increased expression of IL-16 in inflammatory bowel disease. Gut. (2001) 48:326. doi: 10.1136/gut.48.3.326
59. Keates AC, Castagliuolo I, Cruickshank WW, Qiu B, Arseneau KO, Brazer W, et al. Interleukin 16 is up-regulated in Crohn’s disease and participates in TNBS colitis in mice. Gastroenterology. (2000) 119:972–82. doi: 10.1053/gast.2000.18164
60. Häyry A, Faustini F, Zickert A, Larsson A, Niewold TB, Svenungsson E, et al. Interleukin (IL) 16: a candidate urinary biomarker for proliferative lupus nephritis. Lupus Sci Med. (2022) 9:e000744. doi: 10.1136/lupus-2022-000744
61. Idborg H, Eketjäll S, Pettersson S, Gustafsson JT, Zickert A, Kvarnström M, et al. TNF-α and plasma albumin as biomarkers of disease activity in systemic lupus erythematosus. Lupus Sci Med. (2018) 5:e000260. doi: 10.1136/lupus-2018-000260
62. Fava A, Rao DA, Mohan C, Zhang T, Rosenberg A, Fenaroli P, et al. Urine proteomics and renal single cell transcriptomics implicate IL-16 in lupus nephritis. Arthritis Rheumatol. (2021) 74(5):829–39. doi: 10.1002/art.42023
63. Yoon T, Pyo JY, Ahn SS, Song JJ, Park Y-B, and Lee S-W. Serum interleukin-16 significantly correlates with the Vasculitis Damage Index in antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Res Ther. (2020) 22:73. doi: 10.1186/s13075-020-02172-5
64. Kong X, Wu S, Dai X, Yu W, Wang J, Sun Y, et al. A comprehensive profile of chemokines in the peripheral blood and vascular tissue of patients with Takayasu arteritis. Arthritis Res Ther. (2021) 24:49. doi: 10.1186/s13075-022-02740-x
65. Kawabata K, Makino T, Makino K, Kajihara I, Fukushima S, and Ihn H. IL-16 expression is increased in the skin and sera of patients with systemic sclerosis. Rheumatology. (2019) 59:519–23. doi: 10.1093/rheumatology/kez318
66. Wang X, Li L, Wang Y, Li X, Feng Q, Hou Y, et al. High-dose dexamethasone alters the increase in interleukin-16 level in adult immune thrombocytopenia. Front Immunol. (2019) 10:451. doi: 10.3389/fimmu.2019.00451
67. Gianoukakis AG, Martino LJ, Horst N, Cruikshank WW, and Smith TJ. Cytokine-induced lymphocyte chemoattraction from cultured human thyrocytes: evidence for interleukin-16 and regulated upon activation, normal T cell expressed, and secreted expression. Endocrinology. (2003) 144:2856–64. doi: 10.1210/en.2003-0199
68. Mao K, Li D, Liu J, Sun J, and Zhang R. Investigation of serum IL-12, IL-16, and IL-17A as diagnostic biomarkers in children with cow’s milk protein allergy. Allergol Immunopath. (2022) 50:162–8. doi: 10.15586/aei.v50i5.592
69. Koga K, Osuga Y, Yoshino O, Hirota Y, Yano T, Tsutsumi O, et al. Elevated interleukin-16 levels in the peritoneal fluid of women with endometriosis may be a mechanism for inflammatory reactions associated with endometriosis. Fertil Steril. (2005) 83:878–82. doi: 10.1016/j.fertnstert.2004.12.004
70. Zhang J, Zhao W, Zhou Y, Xi S, Xu X, Du X, et al. Pyroptotic T cell-derived active IL-16 has a driving function in ovarian endometriosis development. Cell Rep Med. (2024) 5:101476. doi: 10.1016/j.xcrm.2024.101476
71. Skundric DS, Cruikshank WW, Montgomery PC, Lisak RP, and Tse HY. Emerging role of IL-16 in cytokine-mediated regulation of multiple sclerosis. Cytokine. (2015) 75:234–48. doi: 10.1016/j.cyto.2015.01.005
72. Skundric DS, Cai J, Cruikshank WW, and Gveric D. Production of IL-16 correlates with CD4+ Th1 inflammation and phosphorylation of axonal cytoskeleton in multiple sclerosis lesions. J Neuroinflamm. (2006) 3:13. doi: 10.1186/1742-2094-3-13
73. Nischwitz S, Faber H, Sämann PG, Domingues HS, Krishnamoorthy G, Knop M, et al. Interferon β-1a reduces increased interleukin-16 levels in multiple sclerosis patients. Acta Neurol Scand. (2014) 130:46–52. doi: 10.1111/ane.12215
74. Skundric DS, Dai R, Zakarian VL, Bessert D, Skoff RP, Cruikshank WW, et al. Anti-IL-16 therapy reduces CD4+ T-cell infiltration and improves paralysis and histopathology of relapsing EAE. J Neurosci Res. (2005) 79:680–93. doi: 10.1002/jnr.20377
75. Powell TR, Gaspar H, Chung R, Keohane A, Gunasinghe C, Uher R, et al. Assessing 42 inflammatory markers in 321 control subjects and 887 major depressive disorder cases: BMI and other confounders and overall predictive ability for current depression. bioRxiv. (2018), 327239. doi: 10.1101/327239
76. Maes M, Almulla AF, Zhou B, Algon AAA, and Sodsai P. In major dysmood disorder, physiosomatic, chronic fatigue and fibromyalgia symptoms are driven by immune activation and increased immune-associated neurotoxicity. Sci Rep. (2024) 14:7344. doi: 10.1038/s41598-024-57350-1
77. González-Rodríguez S, Sordo-Bahamonde C, Álvarez-Artime A, Baamonde A, and Menéndez L. Hyperalgesic effect evoked by il-16 and its participation in inflammatory hypernociception in mice. (2024). doi: 10.21203/rs.3.rs-3917221/v1
78. Zhu X, Liu S, Tian L, Li X, Yao R, Zhao Y, et al. Spinal interleukin-16 mediates inflammatory pain via promoting glial activation. Int Immunopharmacol. (2024) 127:111411. doi: 10.1016/j.intimp.2023.111411
79. Yu H, Chen K, Sun Y, Carter M, Garey KW, Savidge TC, et al. Cytokines are markers of the clostridium difficile-induced inflammatory response and predict disease severity. Clin Vaccine Immunol. (2017) 24(8):e00037-17. doi: 10.1128/cvi.00037-17
80. Zhou P, Goldstein S, Devadas K, Tewari D, and Notkins AL. Human CD4+ cells transfected with IL-16 cDNA are resistant to HIV-1 infection: Inhibition of mRNA expression. Nat Med. (1997) 3:659–64. doi: 10.1038/nm0697-659
81. Tang X, Lu H, Tarwater PM, Silverberg DL, Schorl C, and Ramratnam B. Adeno-associated virus (AAV)-delivered exosomal TAT and biTE molecule CD4-αCD3 facilitate the elimination of CD4 T cells harboring latent HIV-1. Microorganisms. (2024) 12:1707. doi: 10.3390/microorganisms12081707
82. Huang C, Hu X, Wang D, Gong R, Wang Q, Ren F, et al. Multi-cohort study on cytokine and chemokine profiles in the progression of COVID-19. Sci Rep. (2024) 14:10324. doi: 10.1038/s41598-024-61133-z
83. Su H, Weng S, Luo L, Sun Q, Lin T, Ma H, et al. Mycobacterium tuberculosis hijacks host macrophages-derived interleukin 16 to block phagolysosome maturation for enhancing intracellular growth. Emerg Microbes Infect. (2024) 13:2322663. doi: 10.1080/22221751.2024.2322663
84. Zhang J, Yang Z, Liang Z, Wang M, Hu C, Chang C, et al. Anti-interleukin-16 neutralizing antibody treatment alleviates sepsis-induced cardiac injury and dysfunction via the nuclear factor erythroid-2 related factor 2 pathway in mice. Oxid Med Cell Longev. (2021) 2021:6616422. doi: 10.1155/2021/6616422
85. Behelgardi A, Hosseini SM, Mohebbi SR, Azimzadeh P, Derakhshani S, Karimi K, et al. A study on genetic association of interleukin-16 single nucleotide polymorphism (rs1131445) with chronic hepatitis B virus infection in Iranian patients. Jundishapur J Microbiol. (2015) 8:e23411. doi: 10.5812/jjm.23411
86. Zhu J, Qin C, Yan F, Wang M, Ding Q, Zhang Z, et al. IL-16 polymorphism and risk of renal cell carcinoma: association in a Chinese population. Int J Urol: Off J Jpn Urol Assoc. (2010) 17:700–7. doi: 10.1111/j.1442-2042.2010.02559.x
87. Zhang Y, Kornfeld H, Cruikshank WW, Kim S, Reardon CC, and Center DM. Nuclear translocation of the N-terminal prodomain of interleukin-16*. J Biol Chem. (2001) 276:1299–303. doi: 10.1074/jbc.m008513200
88. Richmond J, Tuzova M, Parks A, Adams N, Martin E, Tawa M, et al. Interleukin-16 as a marker of sézary syndrome onset and stage. J Clin Immunol. (2011) 31:39–50. doi: 10.1007/s10875-010-9464-8
89. Tuzova M, Richmond J, Wolpowitz D, Curiel-Lewandrowski C, Chaney K, Kupper T, et al. CCR4 + T cell recruitment to the skin in mycosis fungoides: potential contributions by thymic stromal lymphopoietin and interleukin-16. Leuk Lymphoma. (2015) 56:440–9. doi: 10.3109/10428194.2014.919634
90. Templin J, Luetkens T, and Atanackovic D. Cytokine interleukin-16 supports progression of multiple myeloma through different molecular mechanisms. Blood. (2013) 122:5367. doi: 10.1182/blood.v122.21.5367.5367
91. Krantz D, Mints M, Winerdal M, Riklund K, Rutishauser D, Zubarev R, et al. IL-16 processing in sentinel node regulatory T cells is a factor in bladder cancer immunity. Scand J Immunol. (2020) 92:e12926. doi: 10.1111/sji.12926
92. Tuzova M, Memari P, Mosaheb M, and Cruikshank W. Loss of nuclear Pro-IL-16 imparts resistance to apoptosis in CTCL T cells (47.5). J Immunol. (2012) 188:47.5–5. doi: 10.4049/jimmunol.188.supp.47.5
93. Blaschke S, Schulz H, Schwarz G, Blaschke V, Müller GA, and Reuss-Borst M. Interleukin 16 expression in relation to disease activity in rheumatoid arthritis. J Rheumatol. (2001) 28:12–21.
94. Pritchard J, Tsui S, Horst N, Cruikshank WW, and Smith TJ. Synovial fibroblasts from patients with rheumatoid arthritis, like fibroblasts from graves’ Disease, express high levels of IL-16 when treated with igs against insulin-like growth factor-1 receptor. J Immunol. (2004) 173:3564–9. doi: 10.4049/jimmunol.173.5.3564
95. Lee S, Kaneko H, Sekigawa I, Tokano Y, Takasaki Y, and Hashimoto H. Circulating interleukin-16 in systemic lupus erythematosus. Br J Rheumatol. (1998) 37:1334–7. doi: 10.1093/rheumatology/37.12.1334
96. Niewold TB, Meves A, Lehman JS, Popovic-Silwerfeldt K, Häyry A, Söderlund-Matell T, et al. Proteome study of cutaneous lupus erythematosus (CLE) and dermatomyositis skin lesions reveals IL-16 is differentially upregulated in CLE. (2021). doi: 10.21203/rs.3.rs-145148/v1
97. Pritchard J, Horst N, Cruikshank W, and Smith TJ. Igs from patients with graves’ Disease induce the expression of T cell chemoattractants in their fibroblasts. J Immunol. (2002) 168:942–50. doi: 10.4049/jimmunol.168.2.942
98. Vendrame F, Cataldo D, Ciarlo L, Umland O, Misasi R, and Dotta F. In type 1 diabetes immunocompetent cells are defective in IL-16 secretion. Scand J Immunol. (2012) 75:127–8. doi: 10.1111/j.1365-3083.2011.02630.x
99. Yang S-J, Chang S-T, Chang K-C, Lin B-W, Chang K-Y, Liu Y-W, et al. Neutralizing IL-16 enhances the efficacy of targeting Aurora-A therapy in colorectal cancer with high lymphocyte infiltration through restoring anti-tumor immunity. Cell Death Dis. (2024) 15:103. doi: 10.1038/s41419-023-06381-z
100. You R, He X, Zeng Z, Zhan Y, Xiao Y, and Xiao R. Pyroptosis and its role in autoimmune disease: A potential therapeutic target. Front Immunol. (2022) 13:841732. doi: 10.3389/fimmu.2022.841732
101. Liao X-X, Dai Y-Z, Zhao Y-Z, and Nie K. Gasdermin E: A prospective target for therapy of diseases. Front Pharmacol. (2022) 13:855828. doi: 10.3389/fphar.2022.855828
102. Lu X, Guo T, and Zhang X. Pyroptosis in cancer: friend or foe? Cancers. (2021) 13:3620. doi: 10.3390/cancers13143620
103. de Souza VH, de Alencar JB, Tiyo BT, Alves HV, Vendramini ECL, Sell AM, et al. Association of functional IL16 polymorphisms with cancer and cardiovascular disease: a meta-analysis. Oncotarget. (2020) 11:3405–17. doi: 10.18632/oncotarget.27715
104. Mo C-J, Peng Q-L, He Y, Wang J, Xie L, Li T-J, et al. Positive association between IL-16 rs11556218 T/G polymorphism and cancer risk: a meta-analysis. Asian Pac J Cancer Prev. (2014) 15:4697–703. doi: 10.7314/apjcp.2014.15.11.4697
Keywords: cytokine - immunological terms, interleukin-16, inflammation, infection, cancer, tumor
Citation: Niewold TB, Lehman JS, Gunnarsson I, Meves A and Oke V (2025) Role of interleukin-16 in human diseases: a novel potential therapeutic target. Front. Immunol. 16:1524026. doi: 10.3389/fimmu.2025.1524026
Received: 06 November 2024; Accepted: 13 May 2025;
Published: 02 June 2025.
Edited by:
Sheela Ramanathan, Université de Sherbrooke, CanadaReviewed by:
Sanchari Chatterjee, National Cancer Institute at Frederick (NIH), United StatesIbrahim AlZaim, Aarhus University, Denmark
Copyright © 2025 Niewold, Lehman, Gunnarsson, Meves and Oke. 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: Vilija Oke, VmlsaWphLm9rZUBraS5zZQ==