Abstract
Rheumatoid arthritis (RA) is an autoimmune disease mainly characterized by chronic polyarthritis. Many types of cells play pivotal roles in the pathogenicity of RA, such as T cells, B cells, macrophages, dendritic cells (DCs), osteoclasts (OCs), and fibroblast-like synoviocytes (FLS). Tripterygium wilfordii Hook f. (TwHf) and its ingredients are able to control disease activity by regulating the functions of cells mentioned above, and the clinical studies have highlighted the importance of TwHf ingredients in RA treatment. They have been demonstrated to improve the RA symptoms of animal models and patients. In this review, we discussed the effect of TwHf ingredients on pathogenicity cells, including disease/cell phenotypes and molecular mechanisms. Here, we constructed a cell-cell interaction network to visualize the effect of TwHf ingredients. We found that TwHf ingredients could inhibit the differentiation and proliferation of the pathogenicity cells. Besides, the components could decrease the levels of pathogenicity cytokines [i.e., interleukin-6 (IL-6), interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α)]. Many signaling pathways are involved in the underlying mechanisms, such as PI3K, NF-κB, and MAPK signaling pathways.
Introduction
Rheumatoid arthritis (RA) is an autoimmune disease mainly characterized by chronic persistent synovitis, which causes the destruction of articular cartilage and bone, eventually leading to joint deformity and finally loss of function. The incidence of RA in mainland China is about 0.42%, and the disability rate of this disease course over 15 years is 61.3%. The clinical studies have shown that the effectiveness of the anchoring drug methotrexate is only 15%–25% (Lopez‐Olivo et al., 2014; Chinese Rheumatology Association, 2018). While the addition of Tripterygium wilfordii Hook. f. (TwHf) or Tripterygium hypoglaucum (Levl.) Hutch is able to control RA disease activity more effectively by regulating immune cell functions (Jun et al., 2016; Xiao-yue et al., 2019). In the separable components of TwHf and Levl. Hutch, there are many similar but different active component, such as Wilforlide, Celastrol (Cel), and Triptolide (TP) (Xianguang and Li, 2006; Chao, 2015; Chen-qiong et al., 2015). These active components can regulate the pathogenicity immune cells and connective tissue cells of RA. For example, they can reduce the secretion of inflammatory cytokines (such as TNF-α, IL-1β, and IL-6) of macrophages, the proliferation, and differentiation of pathogenic T cells, and the bone destruction which mediated by the fibroblast-like synoviocytes (FLS) and the osteoclasts (Peng et al., 2014; Wang et al., 2014; Te et al., 2019).
Tripterygium genus alleviates disease activity by regulating RA-related cells by multiple targeting approaches. Up to date, there is no literature review for TwHf or its active ingredients on RA-related cell dysfunction. Meanwhile, there are signal transduction interactions between various immune cells and connective tissue cells in the process of RA, which jointly promote the occurrence and development of RA. Therefore, we conducted a literature review (search strategy is available in Supplementary Materials 1) to summarize the effects of Tripterygium genus active ingredients on RA-related cells. Furthermore, we constructed signal pathways and cell-cell interaction networks to summarize their molecular mechanisms and to speculate the potential target cells and proteins.
The Functions of Tripterygium Ingredients on T Cells and the Molecule Mechanisms
T cells play a crucial role in various adaptive immune responses. During RA, T cells received antigens will be activated and proliferate (Smolen et al., 2018). Ho et al. (2013) found that PG27, one of the ingredients of TwHf, inhibited the T cell activation via targeting NF-κB and AP-1 pathways. PG27 can inhibit IKKα/IκBα/NF-κB and mitogen-activated protein kinase (MAPK)-AP-1 signaling pathways, while IKKβ activity was less sensitive for the inhibition of PG27. By contrast, the purified component of TwHf, PG490 (triptolide), similarly suppressed the above pathways. Similar results were demonstrated in RA animal models and patients but lacking molecule mechanisms. Triptolide reduced the numbers of CD4+ cells in the periphery and increased the numbers of CD8+ cells in Peyer’s patch (Zhou et al., 2006). When triptolide was used to treat T cell isolated from peripheral blood of RA patients, the percentage of CD4+ and CD8+T cells secreting IFN-γ, IL-2, and IL-4 was decreased, and the percentage of CD4+ and CD8+T cells expressing CD69 and CD25 was also reduced (Ming et al., 2014). Besides, Tripterygium active compounds have been demonstrated in vivo and in vitro to reduce T cell number by promoting T cell apoptosis as well as suppressing T cell proliferation and cytokine secretion, while the mechanism is unknown (Tao et al., 1991; Cascão et al., 2015b; Wang et al., 2018).
CD4+ T cells can activate and polarize into various T helper cell subsets, including T helper 1 (Th1), T helper 2 (Th2), regulatory T (Treg), T helper 9 (Th9), T follicular helper cells (Tfh), T helper 17 (Th17), or T helper 22 (Th22) cells. Th17 cell numbers were increased in the peripheral blood, inflamed synovial tissue, and synovial fluid of RA patients (Leipe et al., 2010; van Hamburg et al., 2011; Penatti et al., 2017). Th17 cells promote the development of RA through the secretion of various inflammatory cytokines and chemokines. TGF-β/SMADs/RORγt and IL-6/STAT3 pathways are involved in mediating Th17 cell differentiation and mediating the expression of IL-17A, IL-17F, and IL-21 (Ivanov et al., 2006; Nishihara et al., 2007; Yang et al., 2008). The Cel, one of the Tripterygium ingredients, has been proved to have anti-arthritic activity by inhibiting IL-6/STAT3 signal and finally reduce the secretion of Th17-related pro-inflammatory cytokines (Venkatesha et al., 2011). Moreover, Cel inhibits the activation of NF- κB, and caspase-1 in macrophages, resulting in the reduced release of IL-1β and TNF-α, and finally decreased the infiltration and proliferation of joint Th17 cells (Cascão et al., 2012) because IL-1β is able to promote the polarization of Th17 cells through inducing the expression of the transcription factors IFR4 and RORγ (Vallières et al., 2019). In addition, TP inhibits the expression of COX2 and the secretion of PGE2 in the co-culture models of RA synovial fibroblasts (RASFs) and RA CD4+ T cells, blocking the differentiation of Th17 cells in vitro (Peng et al., 2014).
Similar to Th17, Tfh cells also promote RA progression by secreting IL-21 (Vinuesa et al., 2016). However, there is less research on the effects of TwHf on Tfh. In patients with RA treated with TwHf, the number of tenderness joints, the number of swollen joints, and the evaluation score of overall RA in the experimental group were lower than those in the control group. Consistently, the levels of Tfh cells and IL-21 were lower than those in the control group, and the levels of Tfh cells and IL-21 were positively correlated with DAS28 score (Sun et al., 2016).
Treg cells act as protective cells during RA. Enhancing the function or improving the number of Treg cells has been proved to alleviate the RA activity in varying degrees (Cooles et al., 2013). So far, research focused on the effects of TwHf on Treg cells in RA were limited. In the co-culture system of bone marrow macrophages and Tregs, TP up-regulated IL-10 and TGF-β1 produced by Treg cells, resulting in the inhibition of osteoclast differentiation and bone resorption (Xu et al., 2016).
The role of tripterygium ingredients for T cells and the molecule mechanisms were summarized in Table 1. The molecule mechanisms of CD8+ cell and Th17 are available in Figures 1, 2 (Th1, Th2, Treg, and Tfh are not available because insufficient study describes their molecule mechanism).
Table 1
| Subtype | Component | Models | Molecular mechanism | Effects | Animal disease phenotype | Ref. |
|---|---|---|---|---|---|---|
| CD4+T cell | TP | CIA rats | NA | Reduce the number of CD4+ T cells in periphery blood | Ameliorate | (Zhou et al., 2006) |
| CD8+ T cell | TP | CIA rats | NA | Increase the number of CD8+ T cells in Peyer’s patch | Ameliorate | (Zhou et al., 2006) |
| CD4+T cell and CD8+T cell | TP | Peripheral blood T cells in RA patients | NA | Reduce the percentage of CD4+ and CD8+ T cells. Reduce the levels of IFN-γ, IL-2, IL-4. Decrease the expression of CD69 and CD25 | NA | (Ming et al., 2014) |
| Th17 | Cel | AIA Lewis rats | Prohibit the phosphorylation of STAT3 and ERK | Inhibit the differentiation of Th17; decrease the levels of cytokines (IL-17, IL-6, and IFN-γ) and antibodies (anti-Bhsp65 and anti-CCP) | Ameliorate | (Venkatesha et al., 2011) |
| Th17 | TP | Synovial fibroblasts from RA patients and Th17 cells co-cultured model | regulating cyclooxygenase-2/prostaglandin E2 axis | Inhibit Th17 differentiation | NA | (Peng et al., 2014) |
| Th17 | Cel | E. coli stimulated THP-1 macrophage-like cell line and AIA Wistar rats | Inhibiting activation of NF-κB and caspase-1 | Inhibit the release of IL-1β and TNF from macrophages, reducing joint the infiltration and proliferation of TH17 cells | Ameliorate | (Cascão et al., 2012) |
| Treg | TP | Co-cultures system of Tregs and BMMs | NA | Up-regulate IL-10 and TGF-β1, secreted by Treg. Inhibit the osteoclast differentiation and bone resorption caused by osteoclast | NA | (Xu et al., 2016) |
| TfH | Tripterygium glycosides tablets | Peripheral blood in patients with RA | NA | Decrease the numbers of TfH and the levels of IL-21 | Ameliorate | (Sun et al., 2016) |
| T cell | PG27 | Human peripheral blood T cells | Inhibiting activation of IKKα and AP-1 | Inhibit the activation of T cell | NA | (Ho et al., 2013) |
| T cell | TP | Human peripheral blood T cells | Inhibiting activation of IKKα, AP-1, and IKKβ | Inhibit the activation of T cell | NA | (Ho et al., 2013) |
| T cell | Cel | AIA rats | NA | Promote T cell apoptosis | Ameliorate | (Cascão et al., 2015b) |
| T cell | TP | TNF transgenic mice | NA | Promote T cell apoptosis | Ameliorate | (Wang et al., 2018) |
| T cell | Triptolide ethanol extraction | Human peripheral blood | NA | Inhibit antigen and mitogen stimulated T cell proliferation and the secretion of IL-2 | NA | (Tao et al., 1991) |
The effects of Tripterygium ingredients on T cells.
Cel, Celastrol; TP, Triptolide; STAT3, Signal Transduction and Transcription Activator Protein 3; SOCS, Cytokine Signal Negative Regulator; IL, Interleukin; IKK, IκB Kinase; AP-1, Activin 1; TfH, Follicular helper T cells; OC, Osteoclasts; TNF, Tumor necrosis factor.
Figure 1
Figure 2
The Effects of Tripterygium Ingredients on B Cells
B cells are also critical in the development of RA. B cells can be used as antigen-presenting cells (APC) to provide synergistic stimulation and then activate T cells. In addition, B cells are able to secrete autoantibodies, such as rheumatoid factor (RF) and anti-citrullinated protein antibody (ACPA) (Scherer et al., 2018; Smolen et al., 2018). ACPAs, RF, or their immune complexes interact with immune cells such as macrophages, neutrophils, and osteoclasts to promote joint inflammation of RA. The differentiation and activation of B cells could be mediated by BAFF/BAFF-R-ATK-mTOR, and TACI-NF-κB (Niiro and Clark, 2002; Schmidlin et al., 2009; Pieper et al., 2013). Many studies have demonstrated that Tripterygium ingredients could inhibit the proliferation and the antibody production of B cells while the molecular mechanisms remained unknown (Tao et al., 1991; Wang and Wu, 1994; Chang et al., 1997; Cascão et al., 2015b). Only one study revealed the molecular mechanisms. Pan etc. found Xinfeng capsule, a proprietary Chinese medicine mainly composed of TwHf, can up-regulate the PTEN level of B cells while down-regulate PDK1 and BAFF/BAFF-R to suppress the activation of PI3K/AKT/mTORC signal pathway and finally inhibit the proliferation and activation of B cells (Pan, 2018). Besides, the levels of related antibodies such as RF, anti-cyclic citrullinated peptide antibody (anti-CCP Ab), IgG, and IgM, were also inhibited. The effects of Tripterygium ingredients on B cells and the molecule mechanisms are summarized in Table 2. The molecule mechanisms of B cell are summarized in Figure 3.
Table 2
| Subtype | Component | Models | Molecular mechanism | Effects | Animal disease phenotype | Ref. | |
|---|---|---|---|---|---|---|---|
| CD19+ B cells | Cel | AIA rats | NA | Decrease the numbers of CD19+ cells | Ameliorate | (Cascão et al., 2015a) | |
| CD19+CD81+ and CD19+CD40+ B cells | Xinfeng capsule | RA patients | Inhibit PI3K/AKT/mTOR signaling pathway. Up-regulate PTEN; Down-regulate PDK1 and BAFF/BAFF-R | Inhibit B cells proliferation, and activation; Decrease the levels of antibodies, such as RF, anti-CCP Ab, IgG, and IgM | Ameliorate | (Pan, 2018) | |
| B cells | Tripterygium glycosides | B cells | NA | Inhibit the IgG levels secreted by B cell | NA | (Chang et al., 1997) | |
| B cells | Triptolide ethanol extraction | Human peripheral blood | NA | Inhibit B cell proliferation and decrease immunoglobulin levels | Ameliorate | (Tao et al., 1991) | |
| B cells | TwHf | RA patients | NA | Decrease the percentage of B cells | Ameliorate | (Wang and Wu, 1994) | |
The effects of Tripterygium ingredients on B cells.
PTEN, Phosphatase and tensin homolog; PDK1, 3-phosphoinositide-dependent protein kinase 1; BAFF, B cell activating factor; BAFF-R, B cell activating factor receptor; PI3K, Phosphatidyl muscle Alcohol-3-kinase; AKT, Serine protein kinase; mTORC, Rapamycin target protein complex; IL, Interleukin; IgG, Immunoglobulin; TwHf, Tripterygium wilfordii Hook f.
Figure 3
The Role of Tripterygium Ingredients on Macrophage and the Molecule Mechanism
Macrophages are mainly divided into classical activated M1 type and selective activated M2 type. The immuno-inflammatory reaction in RA patients directly affects the polarization of macrophages in peripheral blood, synovium, and synovial fluid, resulting in the continuous increase of M1-type macrophages and disrupting the balance of M1/M2 (Laria et al., 2016). Macrophages also promote RA and participate in the bone destruction of RA through antigen presentation. The degree of synovial macrophage infiltration was positively correlated with the bone destruction and clinical symptoms of RA (Gierut et al., 2010).
Tripterygium ingredients have been reported to inhibit the M1 polarization and promote the polarization of M2 type macrophages, resulting in the rebalance of the pro-inflammatory and anti-inflammatory cytokines (Feng, 2015; Liu, 2018). Besides, tripterygium ingredients could alleviate synovial macrophage infiltration. However, the molecular mechanism was not explained (Bao et al., 2007; Cascão et al., 2015a; Cascão et al., 2015b; Feng, 2015; Gan et al., 2015; Liu, 2018; Tong et al., 2018; Wang et al., 2018). M1 polarization is mediated by JAK-STAT1 signaling stimulated with IFNγ and characterized by increased iNOS, IL-1β, and TNF-α. Another M1 activated signaling pathway is the TLR4/NF-κB signaling pathway (Lawrence and Natoli, 2011). In the AIA rat model, Cel exerted the anti-inflammatory properties via down-regulating the NF-κB and the caspase-1 activation, leading to a decrease of IL-1β and TNF-α secretion in macrophages. Furthermore, the proliferation of Th17 was also inhibited because of lacking cytokines stimulation (Cascão et al., 2012). In addition, research has indicated that Cel blocked the binding of lipopolysaccharides (LPS) to a myeloid differentiation factor2 (MD2) and then inhibited the M1 activation, which was measured by the expression of inflammatory cytokines including TNF-α, IL-6, and IL-1β (Lee et al., 2015). Some researchers (Lin et al., 2001; Ping et al., 2015) also found that Tripterygium ingredients decreased the production of TNF-α, IL-1β, and IL-6 via inhibiting the expression of the TLR4, NF-κB, and prostaglandin E2 (PGE2). Besides, NO production and iNOS expression in macrophages were significantly inhibited by Tripterygium ingredients (Wang et al., 2004; Chen et al., 2018). Furthermore, TP inhibited the promoter activity of the iNOS gene and the inducible activity of iNOS transcriptional regulator Oct-1 (Wang et al., 2004). Pyroptosis is a unique and newly discovered mode of programmed cell death, which is triggered by the activation of Caspase-1 (Bergsbaken et al., 2009). It has been found that Cel can inhibit the pyroptosis induced by LPS and ATP via inhibiting the enzyme activities of cleaved-Caspase1 and Caspase-1, and finally blocking the secretion of IL-1β in macrophages (Xin et al., 2018). The effect of tripterygium ingredients on macrophages and the molecule mechanisms are summarized in Table 3. The figure for the molecule mechanism of macrophages is available in Figure 4.
Table 3
| Subtype | Component | Models | Molecular mechanism | Effects | Animal disease phenotype | Ref. |
|---|---|---|---|---|---|---|
| M1, M2 macrophages | Cel | Healthy mice | NA | Inhibit abdominal macrophages to M1 polarization. Promote M2 macrophages polarization | Alleviate | (Liu, 2018) |
| M1, M2 macrophages | TP | PBMCs, isolated from healthy people, cultured in different pH RPMI-1640 | NA | Decrease M1 macrophages level and promote M2 macrophages level | NA | (Feng, 2015) |
| CD68+ CD168+ synovial macrophage | Cel | AIA rats | NA | Inhibit the infiltration and proliferation of CD68+ CD168+ synovial macrophages in the synovial membrane | Alleviate | (Cascão et al., 2015a) |
| OCP | TP | TNF transgenic mice | NA | Promote the apoptosis of OCP. Inhibit OC proliferation, bone resorption and pro- inflammatory cytokines levels secreted by macrophages | Alleviate | (Wang et al., 2018) |
| BMDMs | Cel | LPS-induced BMDMs. | Inhibit TLR4 activation via prohibiting the binding of LPS to the TLR4/MD2 complex | Inhibit pro-inflammatory cytokine levels and TLR4 activation in macrophages | NA | (Lee et al., 2015) |
| Macrophage | Cel | E. coli stimulated THP-1 macrophage-like cell line and AIA Wistar rats | Inhibiting activation of NF-κB and caspase-1 | Inhibit the release of IL-1β and TNF from macrophages, reducing joint the infiltration and proliferation of TH17 cells | Alleviate | (Cascão et al., 2012) |
| Macrophage | TP | RAW 264.7 and U937 macrophage-like cell lines | Induce the degradation of Bcl-2 and the activation of caspase-3 | Promote macrophages apoptosis | NA | (Bao et al., 2007) |
| Macrophage | Cel | CIA DBA/1J mice and RANKL induced RAW264.7 cells | Decrease serum TRAP 5b and the expression of osteoclastic genes (Trap, Ctsk, Ctr, MMP-9) and transcriptional factors (c-Fos, c-Jun and NFATc1); Inhibit NF-κB and MAPK | Decrease the infiltration of osteoclast cells in joints. Decrease serum TRAP 5b and the expression of osteoclastic genes and transcriptional factors | Alleviate | (Gan et al., 2015) |
| Macrophage | Tripterygium glycosides | CFA-induced arthritis rat and LPS-induced RAW264.7 | NA | Ameliorate in paw swelling perimeter, arthritics score, and body weight loss. Reduce the levels of inflammatory cytokine (TNF-α, IL-6, and IL-1β) secreted by macrophages | Alleviate | (Tong et al., 2018) |
| Macrophage | Tripterygium glycosides | LPS-induced RAW264.7 | down-regulate the expression of TLR4and NF-κB p65 | Decrease the levels of TNF-α and IL-1β secreted by macrophages | NA | (Ping et al., 2015) |
| Macrophage | TP | LPS induced J774A.1 macrophage and IL-1α induced human synovial fibroblasts | Inhibit COX-2 in macrophages and pro-MMPs 1 and 3 in synovial fibroblasts. Up-regulate TIMPs 1 and 2 levels in synovial fibroblasts | Decrease PGE2 via inhibiting COX-2. Inhibit pro-MMPs and Up-regulate TIMPs | NA | (Lin et al., 2001) |
| Macrophage | Tripterygium wilfordii extraction | LPS-induced RAW264.7 | NA | Reduce the production of NO and iNOS mRNA in macrophages | NA | (Chen et al., 2018) |
| Macrophage | TP and TwHf ethyl acetate extraction | Peritoneal macrophages isolated from AIA C57BL/6J mice | Inhibit NO production and iNOS mRNA expression in macrophages. Inhibit the promoter activity of iNOS gene to regulate its transcript factor (Oct-1) activity | Inhibit the production of NO, iNOS, and the activity of Oct-1 | Alleviate | (Wang et al., 2004) |
| Macrophage | Cel | RAW264.7 | Decrease the expression of cleaved-caspase-1 and inhibit caspase-1 enzyme activity | Ameliorate cell pyroptosis | NA | (Xin et al., 2018) |
The role of Tripterygium ingredients on macrophages.
TP, Triptolide; Cel, Celastrol; OC, Osteoclasts; TLR4, Toll-like receptor 4; NF-κB, Nuclear factor activated B cell kappa light chain enhancer; Caspase, Aspartic acid protease containing cysteine; NO, Nitric oxide; OCP, Osteoclast progenitor cells; MD2, Medullary differentiation factor2; PGE2, Prostaglandin E2: Cox, Cyclooxygenase; TIMPs, Metalloproteinases; proMMP, pro-matrix metalloproteinase; TRAP, Tartrate-resistant acid phosphatase; MAPK, Mitogen-activated protein kinases; BMDMs, Bone marrow-derived primary macrophages.
Figure 4
The Effects of Tripterygium Ingredients on Dendritic Cells (DCS)
TwHf is reported to inhibit DC development and induce DC apoptosis, finally decreasing the DC number, which resulted in the blocking of the naïve T cell activation and ultimately reduced the differentiation of the autoinflammatory T cells (Wang et al., 2001; Chen et al., 2006; Sun, 2017). Also, TP inhibits DC-related chemokines and reduces the sharing of DCs with MHC molecules and co-stimulatory factors of T and B cells, thereby blockade T and B cell activation. Antigenic peptide on MHC molecules, co-stimulatory molecules (CD80, CD86), and IL-12 of DCs promote the differentiation of Th1 cells, which produce IFN-γ and IL-2, required for cell-mediated immunity. Th1 cells directly modulate B cell differentiation into plasma cells. Besides, DCs also mediate the proliferation of these antibody-producing cells by producing BAFF (Khan et al., 2009). Unfortunately, the specific molecule mechanisms were not involved in these studies. Tripterygium ingredients for DCs are summarized in Table 4.
Table 4
| Component | Models | Molecular mechanism | Effects | Animal disease phenotype | Ref. |
|---|---|---|---|---|---|
| Duantengyimu decoction | GM-CSF and IL-4 stimulate PBMCs isolated from patients with RA | NA | Decrease the expression of CCR5 and CCR7, decrease the secretion of CXCL9 and CXCL10, and inhibit the migration of DC | NA | (Sun, 2017) |
| Tripterygium Wilfordii Saponins | GM-CSF, TNF-α, and IL-4 stimulate PBMCs | NA | Inhibit the expressions HLA-DR and CD80 on the membrane. Decrease the synthesis of IL-12 p40 subunit | NA | (Wang et al., 2001) |
| Tripterygium glycosides | DCs isolated from rats | NA | Reduce the expression of MHC-II, CD80, CD86, and CD40 on the membrane of DC | NA | (Chen et al., 2006) |
The role of Tripterygium ingredients for DCs.
TP, Triptolide; Caspase, Aspartic acid protease containing cysteine; CCR, Chemokine receptor; CXCL, C-X-C motif chemokine ligand; MAP, Mitogen activated protein; MHC, Major histocompatibility complex.
The Functions of Tripterygium Ingredients on Osteoclasts (OCS) and the Molecule Mechanism
OC-mediated bone resorption is one of the typical manifestations of RA. OCs, giant multinucleated cells derived from the monocyte lineage, are the only cells capable of resorbing bone (Teitelbaum and Ross, 2003). Receptor activator of nuclear factor kappa-B (RANK)/Receptor activator of nuclear factor kappa-B ligand (RANKL)/Osteoprotegerin (OPG) is the most crucial pathway of OC differentiation. Leibbrandt A etc. has demonstrated that RANKL is the critical mediator of OC activation and joint destruction; In a rat model of arthritis, osteoblasts and bone marrow stromal cells produce RANKL, which then triggers local development and activation of OCs. This finding has now become the basis for osteoimmunology (Leibbrandt and Penninger, 2009). Multiple studies have confirmed that Tripterygium ingredients can inhibit the expression of RANK and RANKL, thereby increasing the proportion of OPG, which can antagonize the function of RANK and finally inhibit the differentiation of OCs and reduce bone destruction (Nanjundaiah et al., 2012; Feng et al., 2013; Liu et al., 2013; Wang, 2015). Youn-Kwan Jung et al. (Jung et al., 2019) reviewed the roles of inflammatory signal pathways, including IL-1β/Myd88/TRAF6/NF-κB, TNF-α/TRADD/TRAF2/NF-κB, IL-6/STAT3/MAPK, and RANKL/RANK signal transduction. In these inflammatory pathways, TwHf or its active components impaired the release of cytokines/chemokines, reduced osteoclast differentiation, and activation, then finally blocked bone erosion in mice with collagen-induced arthritis through inhibiting the phosphorylation of NF- κB p65, MAPK (ERK, JNK, and p38) and reducing the expression of transcription factors c-Fos, c-Jun, and NFATcl (Gan, 2013; Qian et al., 2015). TwHf or its active components can also promote the apoptosis of OCs and osteoclast precursor (OCP) (Wang et al., 2018; Wang S. et al., 2019). The mechanism may be due to the inhibition of cIAP2 (the positive regulatory protein of TNF and NF-κB signaling pathway). Furthermore, TP has been reported to block OC differentiation by down-regulating the receptor for advanced glycation end-products (RAGE) and the high-mobility group box chromosomal protein 1 (HMGB1) (Wang et al., 2017). RAGE and its ligands (i.e., HMGB1) are necessary for the skeletal homeostasis and related-disease onset/progression (Plotkin et al., 2019). The elevated levels of RAGE and HMGB1 induce osteoblast apoptosis and OC differentiation/activity. Tripterygium ingredients on OC and the molecule mechanisms are summarized in Table 5. The figures for the molecule mechanism of OCs are available in Figure 5.
Table 5
| Component | Models | Molecular mechanism | Effects | Animal disease phenotype | Ref. |
|---|---|---|---|---|---|
| Cel | CIA mice | Reduce RANKL levels | Inhibiting OC differentiation | Alleviate | (Wang, 2015) |
| TP | CIA mice | Regulating the RANKL/RANK/OPG signaling pathway | Inhibiting OC differentiation | Alleviate | (Liu et al., 2013) |
| Cel | AIA Lewis rats and RANKL induced RAW264.7 | Decrease RANKL levels and regulate RANKL/OPG ratio | Reduce OC proliferation. Ameliorate bone destruction. Decrease levels of upstream pro-inflammatory cytokine (i.e., IL-6) and downstream effectors (i.e., MMP-9) | Alleviate | (Nanjundaiah et al., 2012) |
| Cel | IL-1β stimulated MH7A | Decrease RANKL levels and increase OPG levels | Inhibit OC differentiation and activation | NA | (Feng et al., 2013) |
| Cel | RANKL induced RAW264.7 and CIA mice | Inhibit the protein phosphorylation of RANK downstream signalings, such as NF-κB p65, MAPK (ERK, JNK, p38) and the expression of the relevant transcription factors (i.e., c-Fos, c-Jun, and NFATcl) | Inhibit OC differentiation and bone resorption | Alleviate | (Gan, 2013) |
| Cel | RANKL induced RAW264.7 | NA | Inhibit OC differentiation and chemokine CCl4 | NA | (Qian et al., 2015) |
| TP | C57BL/6 mice bone marrow mesenchymal stem cells induced by RANKL, M-CSF, and HMGB1 | Reduce the expression of RAGE mRNA to inhibit HMGB1 | Inhibit OC differentiation | NA | (Wang et al., 2017) |
| TP | Co-cultures system of Tregs and BMMs | NA | Increase the levels of IL-10 and TGF-β1 secreted by Treg to inhibit OC differentiation and bone resorption | NA | (Xu, 2016; Xu et al., 2016) |
| TP | TNF-Tg mice and spleen cells isolated and induced to differentiate into OCs by M-CSF | Down-regulate the cIAP2 | Promote OCP apoptosis and OC reduction | NA | (Wang S. et al., 2019) |
| TP | TNF-Tg mice | NA | Promote apoptosis rates of OCP and OC. Prohibit the bone erosion | Alleviate | (Wang et al., 2018) |
The function of Tripterygium ingredients on OC.
TP, Triptolide; Cel, Celastrol; RANKL, Nuclear factor kappa B ligand receptor activator; RANK, Nuclear factor receptor activator; OPG, Osteoprotegerin; NF-kappa B, Nuclear factor activated B cell κ light chain enhancer; MAPK, Mitogen activated protein kinase; ERK, Extracellular regulatory protein kinase; JNK, Jun N-terminal kinase; NFATcl, Osteoclast activated T nuclear factor 1; CCl4, C-C motif chemokine ligand 4; HMGB1, High mobility group protein B1; RAGE, Receptor for advanced glycation end products; OC, Osteoclasts.
Figure 5
The Role of Tripterygium Ingredients on FLS and the Molecule Mechanism
Synovial inflammation and synovial cell hyperplasia is a distinctive feature of RA. Synovial cells are composed of two types of cells, including type A and type B. Type A cells have a phagocytic function and are macrophage-like cells; type B cells are fibroblast-like, called FLS (Junqueira and Mescher, 2013). FLS is abundant in the endoplasmic reticulum and can secrete protein complexes (mucin) and hyaluronic acid in synovial fluid. FLS contributes mainly to the exacerbation of RA by attaching to, followed by invading into, and finally degrading cartilage and bone (Lefèvre et al., 2009). FLS are the primary cells leading to joint destruction in RA (Bartok and Firestein, 2010).
The molecular pathologic basis RA-FLS includes the MAPK and NF-κB pathways. These pathways are the most widely studied to mediate the aggressiveness of FLS in RA (Bottini and Firestein, 2013; Ganesan and Rasool, 2017). NF-κB pathway, a significant regulator of pro-inflammatory cytokine production, activates NF-κB kinase (IKK) subunit β (IKKβ) in the cytosol through IL-1β, TNF-α, and TLR signaling. The activation of IKKβ results in the NF-κB family inhibitor proteins (IκB) degradation, promoting NF-κB to migrate freely into the nucleus and initiate gene transcription (Bottini and Firestein, 2013). Cel inhibited the translocation of NF-κβ p65 and reduced the phosphorylation of IKBα and IKK in FLSs from patients with RA, resulting in the decreased expression of several chemokines (i.e., CCR2, CXCR4, CCL2, CXCL10, and CXCL12), cytokines (i.e., IL-6, IL-8, and MCP-1), and matrix metalloproteinase-9 (MMP-9) (Fang et al., 2017). Besides, HIF-1α binding to the CXCR4 promoter would increase the transcriptional activity of CXCR4, consequently leading to FLS migration and invasion. However, it could be reversed by Cel treatment (Li et al., 2013b). Guo et al. (Li et al., 2012) found that Cel inhibited IκBα phosphorylation and nuclear translocation of NF-κB. Cel also has been found to inhibit the expression of MMP-9 by suppressing the binding activity of NF-κB to the MMP-9 promoter (Li et al., 2012; Li et al., 2013a). Furthermore, MMP-9 suppression was also related to the inhibition of the TLR4/MyD88/NF-κB pathway (Li et al., 2013a). As a result, Cel changes the phenotype of FLS migration and invasion via the molecule mechanism mentioned above. RA-FLS releases important inflammatory cytokines (TNF-α, IL-1β, IL-6, IL-21, IL-22, and IL-32), chemokines (CXCL1, CXCL5, MCP-1, G-CSF, and IL-8) and Inflammatory mediators (TLR-2, TLR-3, TLR-4, iNOS, and COX-2), which promotes the infiltration of monocytes, macrophages, neutrophils, DCs, T cells, and B cells into joints and results in chronic inflammation and joint destruction (Bottini and Firestein, 2013; Ganesan and Rasool, 2017). Additionally, TP also was found to reduce the FLS migration and invasion by targeting JNK/MAPK signaling pathway (Yang et al., 2016). Moreover, LLDT-8, a Tripterygium derivative, decreased the secretion of chemokines in FLS (Ping et al., 2016; Jia et al., 2017).
Many studies showed the Tripterygium ingredients have the properties to promote FLS apoptosis and cell cycle arrest and inhibit FLS autophagy (Xu, 2013; Xu et al., 2013; Lei et al., 2015; Su et al., 2017; Wong et al., 2019). It may be relevant to the increased expression of Bax/Bcl-2, Caspase-3, Caspase-9, and regulating by Ca2+/calmodulin-dependent protein kinases beta (CaMKK)-AMPK-mTOR signaling pathway. Tripterygium ingredients for FLS and the molecule mechanism are summarized in Table 6. The figures for the molecule mechanism of FLS are available in Figure 6.
Table 6
| Component | Models | Molecular mechanism | Effects | Animal disease phenotype | Ref. |
|---|---|---|---|---|---|
| Cel | FLSs from patients with RA | Reduce the phosphorylation of IKK and IKBα, and inhibit the translocation of NF-κβ p65 from the cytoplasm to the nucleus | Inhibit FLS proliferation and invasion. Reduce the levels of FLS pro-inflammatory cytokines (i.e., IL-6, IL-8, MCP, and MMP9) and chemokines (i.e., CCL2, CXCL10, CXCL12, CCR2, and CXCR4) | NA | (Fang et al., 2017) |
| Cel | AIA model | Inhibited the transcriptional activity of MMP-9 by suppression of the binding activity of NF-κB in the MMP-9 promoter, and inhibited IκBα phosphorylation and nuclear translocation of NF-κB | Suppressed the IL-17A-induced migration and invasion abilities of FLS | Alleviate | (Li et al., 2012) |
| Cel | FLSs isolated from the synovium of active RA patients | Inhibit the transcriptional activity of MMP-9 and TLR4/MyD88/NF-κB signaling pathway | Inhibit FLS invasion and migration | NA | (Li et al., 2013a) |
| TP | FLSs isolated from active RA patients and CIA DBA/1 mice | Inhibit JNK/MAPK signaling pathway | Inhibit FLS invasion and migration | Alleviate | (Yang et al., 2016) |
| Cel | FLSs isolated from active RA patients | Inhibit the binding activity of HIF-1α in the CXCR4 promoter to inhibit the transcription activity of CXCR4 | Inhibit FLS invasion and migration | NA | (Li et al., 2013b) |
| TP | MH7A cell line | NA | Promote MH7A cell apoptosis; Decrease the levels of IL-1β, IL-6, and IL-8; Induce membrane ultrastructural changes | NA | (Su et al., 2017) |
| Cel | Human fibroblast-like synoviocytes-rheumatoid arthritis cells | Increase the expression of Bax/Bcl-2 and promote proteolytic cleavage of Caspase-3, Caspase-9, and PARP | Lead to FLS DNA damage and cycle arrest; Promote FLS apoptosis | NA | (Xu, 2013; Xu et al., 2013) |
| Cel | Immortalized wild-type and Bax-Bak double-knockout mouse embryonic fibroblasts; RASFs isolated from RA patients; AIA rats | Inhibit SERCA to induce autophagy-dependent cytotoxicity in RASFs/RAFLS via Ca2+/calmodulin-dependent kinase kinase-β-AMP-activated protein kinase-mTOR pathway | Induce autophagic FLS death in RASFs/RAFLS | Alleviate | (Wong et al., 2019) |
| TP | MH7A cell line | NA | Inhibit angiogenesis | NA | (Zhang et al., 2008; Mao et al., 2009) |
| TP | FLSs isolated from RA patients | NA | Lead to FLS cycle arrest and promote FLS apoptosis | NA | (Lei et al., 2015) |
| LLDT-8 | FLSs isolated from RA patients | NA | Inhibit FLS cytokines and chemokines (i.e., IL-6, CCL3, and CCL5) | NA | (Ping et al., 2016; Jia et al., 2017) |
The function of Tripterygium ingredients on FLS.
TP, Triptolide; Cel, Celastrol; NF-κB, Nuclear factor activated B cell kappa light chain enhancer; Caspase, Aspartic acid protease containing cysteine; TLR4, Toll-like receptor 4; JNK, Jun N-terminal kinase; MAPK, Mitogen activated protein kinase; mTOR, Rapamycin target protein; MMP-9, Matrix metalloproteinase-9; IL, Interleukin; AMPK, AMP-dependent protein kinase.
Figure 6
Discussion
We systematically summarized the role of tripterygium ingredients in the RA treatment as well as explained the therapeutic mechanism (Figure 7). The NF-κB pathway is a common pathway involved in TwHf-treated RA. It has been involved in mediating multiple genes, such as the genes of cytokines (i.e., IL-6, IL-17, and TNF-α), chemokines (i.e., CCL2 and CXCL5), growth factors (i.e., GM-CSF and M-CSF), regulators of apoptosis (i.e., Bcl-2) and transcription factors (i.e., HIF-1α), to regulate cell function, cell death and survival, and proliferation (Mitchell and Carmody, 2018). Experimental inhibitors targeted the IKK kinases to inhibit the activation of NF-κB, but they failed due to toxicity in genetic models (Mitchell and Carmody, 2018). The failure indicated that a broad blockade of NF-κB activation maybe an impracticable approach. Thus, some drugs focus on the non-canonical NF-κB pathway in RA, such as BAFF/NF-κB, RANK/NF-κB signaling (Noort et al., 2015). A phase II trial showed that belimumab [a biologics target B lymphocyte stimulator (BLyS)] was efficacy and well-tolerated in patients with RA (Stohl et al., 2013). Denosumab is a monoclonal antibody neutralizing RANKL. Up to date, many clinical studies have demonstrated that denosumab could inhibit the progression of joint destruction and increase bone mineral density, including a double-blind, placebo-controlled phase 3 trial (Deodhar et al., 2010; Dore et al., 2010; Sharp et al., 2010; Takeuchi et al., 2016; Yue et al., 2017; Takeuchi et al., 2019). However, none of the studies reported there is any benefit in improving disease activity. It is also regrettable that none of the studies test the expression of cytokines, chemokines, and RA-related pathogenicity cells. NF-κB pathways, including canonical and non-canonical pathways, are critical targets of tripterygium ingredients. In the experimental and clinical dimensions, these could explain why tripterygium ingredients could reduce the levels of many chemokines, cytokines, and growth factors in different cells to improve disease activity as well as inhibit the progression of joint destruction. TwHf and its ingredients could be regarded as one of DMARDs. Thus, they are widely used in treating RA in China. The last 24 weeks, open-label, multicentre, randomized controlled trial demonstrated MTX+TwHF was better than MTX monotherapy (Lv et al., 2015). Furthermore, three meta-analyses (the trial mentioned above included) showed that MTX+TwHF had advantages in improving the laboratory index (CRP, RF, ESR), clinical symptoms, and clinical efficacy, compared with MTX alone (assessed in ACR20, ACR50, and ACR70) (Li et al., 2019; Wang X. et al., 2019; Chen et al., 2020). Another small sample meta-analyses showed that TwHF could decrease bone destruction scores (Zhu et al., 2019).
Figure 7
Our previous research using a bioinformatics approach demonstrated that Kunxian Capsule (a Traditional Chinese Medicine (TCM) patent prescription mainly comprises Levl. Hutch) could target at PI3K/AKT/mTOR signaling pathway (Tang et al., 2020). Therefore, we speculate that some proteins in the PI3K-AKT-mTOR signal pathway are the most likely direct targets of tripterygium ingredients. The signaling pathway is an intracellular signaling pathway and performs multiple physiological functions, such as regulating the cell cycle, survival, and growth (Yap et al., 2008; Ersahin et al., 2015). By far, no clinical study has reported PI3K inhibitors approved by the FDA (idelalisib, copanlisib, duvelisib, and alpelisib) in treating RA. Some drugs were demonstrated they were effective in treating RA models via PI3K signaling pathway in vivo and in vitro, including one PI3K inhibitor (Boyle et al., 2014; Feng and Qiu, 2018; Qi et al., 2019).
The two pathways mentioned above have a variety of biological functions. Both of them control cell death, survival, and proliferation. We found that the therapeutic effects of tripterygium ingredients are mostly related to the reduction of the absolute number of cells. At the same time, there are some differences in stimulating signals, signal receptors, and transcription factors required for cascade reactions in different cells, which is related to the multi-target of TwHf. Considering the adverse effects (AEs) of these drugs, a variety of healthy cells in multiple systems (i.e., liver cells) are also be affected. Therefore, the AEs of tripterygium ingredients could be due to the inhibition of NF-κB and PI3K pathways. Ameliorating AEs through drug matching may be a feasible strategy (Tang et al., 2020). For example, some Chinese researchers matched the TwHf with Cistanche deserticola Ma or Cuscuta chinensis Lam, to reduce the reproductive toxicity of TwHf (Dong et al., 2009; Jing and He, 2013). Nevertheless, whether drug matching would impair the curative effect, still needed to be discovered.
There are many deficiencies in this review. The studies on the drugs/ingredients are all indirect mechanism studies, even with only cell phenotypes but no specific molecular mechanism. Besides, most of them are normal phenotypes in this field, such as inhibition of the apoptosis and differentiation of T cells or impaired proliferation, migration, and invasion of FLS. Moreover, none of the studies analyzed the direct interaction between the drugs and proteins via bioinformatics and mass spectrometry approaches. For example, computer simulation and electrospray mass spectrometry (ESI-MS) were used to explore the inhibitory effect of paclitaxel and aryl ether ketone on farpentine diphosphate synthetase by binding to isoprene diphosphate site (Liu et al., 2014), and explain the anticancer and anti-infective drug mechanism of paclitaxel and aryl et her ketone in the direct interaction mechanism. Therefore, we could follow the methods which were used in the study, as mentioned above. For example, we could use bioinformatics to identify whether TP and Cel could bind to some sites of PI3K, ATK, and NF-κB. Subsequently, we could use ESI-MS to validate it.
Funding
Research was funded by National Key R&D Program of China (2018YFC1705500) to CW, National Natural Science Foundation of Zhejiang Province (No.LY20H270007), TCM Science and Technology Plan of Zhejiang Province (No.2020ZQ012) to YZ, and National Natural Science Foundation of China (81673623) to ZX.
Statements
Author contributions
YT: evidence collection, manuscript preparation and write the central part of the manuscript. QL: evidence collection and manuscript editing. FY: evidence collection and write the minor part of the manuscript. YiZ: evidence collection, figures preparation. XZ: gave many professional suggestions and project funding. CW: ideas, reviewed the manuscript, and project funding. YuZ: critically reviewed the manuscript, study initiation, and project funding. All authors contributed to the article and approved the submitted version.
Acknowledgments
We thank Yujie Tang for the modification of the figures.
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.
Supplementary material
The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fphar.2020.583171/full#supplementary-material
References
1
BaoX.CuiJ.WuY.HanX.GaoC.HuaZ.et al. (2007). The roles of endogenous reactive oxygen species and nitric oxide in triptolide-induced apoptotic cell death in macrophages. J. Mol. Med. (Berl)85 (1), 85–98. doi: 10.1007/s00109-006-0113-x
2
BartokB.FiresteinG. S. (2010). Fibroblast-like synoviocytes: key effector cells in rheumatoid arthritis. Immunol. Rev.233 (1), 233–255. doi: 10.1111/j.0105-2896.2009.00859.x
3
BergsbakenT.FinkS. L.CooksonB. T. (2009). Pyroptosis: host cell death and inflammation. Nat. Rev. Microbiol.7 (2), 99–109. doi: 10.1038/nrmicro2070
4
BottiniN.FiresteinG. S. (2013). Duality of fibroblast-like synoviocytes in RA: passive responders and imprinted aggressors. Nat. Rev. Rheumatol.9 (1), 24. doi: 10.1038/nrrheum.2012.190
5
BoyleD. L.KimH. R.TopolewskiK.BartokB.FiresteinG. S. (2014). Novel phosphoinositide 3-kinase δ,γ inhibitor: potent anti-inflammatory effects and joint protection in models of rheumatoid arthritis. J. Pharmacol. Exp. Ther.348 (2), 271–280. doi: 10.1124/jpet.113.205955
6
CascãoR.VidalB.RaquelH.Neves-CostaA.FigueiredoN.GuptaV.et al. (2012). Effective treatment of rat adjuvant-induced arthritis by celastrol. Autoimmun. Rev.11 (12), 856–862. doi: 10.1016/j.autrev.2012.02.022
7
CascãoR.VidalB.LopesI. P.PaisanaE.RinoJ.MoitaL. F.et al. (2015a). Decrease of CD68 Synovial Macrophages in Celastrol Treated Arthritic Rats. PloS One10 (12), e0142448. doi: 10.1371/journal.pone.0142448
8
CascãoR.VidalB.LopesI. P.PaisanaE.RinoJ.MoitaL. F.et al. (2015b). Decrease of CD68 synovial macrophages in celastrol treated arthritic rats. PloS One10 (12), e0142448. doi: 10.1371/journal.pone.0142448
9
ChangD. M.ChangW. Y.KuoS. Y.ChangM. L. (1997). The effects of traditional antirheumatic herbal medicines on immune response cells. J. Rheumatol.24 (3), 436–441.
10
ChaoL. (2015). Study on the differences between Tripterygium wilfordii Hook.f. and Tripterygium Hypoglaucum (Level) Hutch Based on Genetics and chemical methods (China Academy of Chinese Medical Sciences: Dissertation).
11
ChenT.XuH.WangH.JiM.WuW. (2006). Single and conjoined effects of tripterygium wilfordii and IL-10 on the immuna function of rat dendritic cells in vitro. Acta Universit. Med. Nanjing (Natural Sci.)07), 520–522. doi: 10.1007/s11664-006-0095-z
12
ChenX.-L.LiuF.XiaoX.-R.YangX.-W.LiF. (2018). Anti-inflammatory abietanes diterpenoids isolated from Tripterygium hypoglaucum. Phytochemistry156, 167–175. doi: 10.1016/j.phytochem.2018.10.001
13
ChenW.LiT.WangX.XueZ.LvC.LiH.et al. (2020). Meta-analysis of RCT studies on clinical efficacy of single administration of Tripterygium Glycosides Tablets or combined administration with methotrexate against rheumatoid arthritis. China J. Chin. Mater. Med.45 (04), 791–797. doi: 10.19540/j.cnki.cjcmm.20191115.503
14
Chen-qiongX.PingZ.XiangL.Jian-weiC. (2015). Research progress on chemical constituents, pharmacological effects, and clinical application of Tripterygium hypoglaucum. Chin. Tradit. Herbal Drugs46 (13), 1996–2010. doi: 10.7501/j.issn.0253-2670.2015.13.024
15
Chinese Rheumatology Association (2018). 2018 Chinese rheumatoid arthritis diagnosis and treatment guide. Clin. Res. Pract.57 (4), 242–251. doi: 10.3760/cma.j.issn.0578-1426.2018.04.004
16
CoolesF. A.IsaacsJ. D.AndersonA. E. (2013). Treg cells in rheumatoid arthritis: an update. Curr. Rheumatol. Rep.15 (9), 352. doi: 10.1007/s11926-013-0352-0
17
DeodharA.DoreR. K.MandelD.SchechtmanJ.ShergyW.TrappR.et al. (2010). Denosumab-mediated increase in hand bone mineral density associated with decreased progression of bone erosion in rheumatoid arthritis patients. Arthritis Care Res. (Hoboken)62 (4), 569–574. doi: 10.1002/acr.20004
18
DongF.LiJ.HuangD.HeL. (2009). Effects of Glycosides of Tripterygium Wilfordii on Reproduction Capacity and Its Intervention by Caulis Cistanchi in Male Mice. Shanghai J. Tradit. Chin. Med.43 (08), 64–66. doi: 10.16305/j.1007-1334.2009.08.025
19
DoreR. K.CohenS. B.LaneN. E.PalmerW.ShergyW.ZhouL.et al. (2010). Effects of denosumab on bone mineral density and bone turnover in patients with rheumatoid arthritis receiving concurrent glucocorticoids or bisphosphonates. Ann. Rheum Dis.69 (5), 872–875. doi: 10.1136/ard.2009.112920
20
ErsahinT.TuncbagN.Cetin-AtalayR. (2015). The PI3K/AKT/mTOR interactive pathway. Mol. Biosyst.11 (7), 1946–1954. doi: 10.1039/c5mb00101c
21
FangZ.HeD.YuB.LiuF.ZuoJ.LiY.et al. (2017). High-Throughput Study of the Effects of Celastrol on Activated Fibroblast-Like Synoviocytes from Patients with Rheumatoid Arthritis. Genes (Basel)8 (9), 221. doi: 10.3390/genes8090221
22
FengF. B.QiuH. Y. (2018). Effects of Artesunate on chondrocyte proliferation, apoptosis and autophagy through the PI3K/AKT/mTOR signaling pathway in rat models with rheumatoid arthritis. BioMed. Pharmacother.102, 1209–1220. doi: 10.1016/j.biopha.2018.03.142
23
FengX.TanW.WanF.GanK.ZhangM.ZhangQ. (2013). The effect of Celastrol on the expressions of RANKL, OPG, IL-6, TNF-α and IL-8 in human rheumatoid synoviocyte MH7A. Acta Universit. Med. Nanjing (Natural Sci.)33 (06), 759–765. doi: 10.7655/NYDXBNS20130609
24
FengH. (2015). Influence of Acid-microenvironment on Monocyte-macrophages, Tca8113 Cells and the Role of Triptolide. dissertation (Guizhou: Guizhou Medical University).
25
GanK.XuL.FengX.ZhangQ.WangF.ZhangM.et al. (2015). Celastrol attenuates bone erosion in collagen-Induced arthritis mice and inhibits osteoclast differentiation and function in RANKL-induced RAW264. 7. Int. Immunopharmacol.24 (2), 239–246. doi: 10.1016/j.intimp.2014.12.012
26
GanK. (2013). The role of Celastrol on osteoclastogenesis and bone erosion in collagen-induced arthritis doctor (Nanjing: Nanjing University of Chinese Medicine).
27
GanesanR.RasoolM. (2017). Fibroblast-like synoviocytes-dependent effector molecules as a critical mediator for rheumatoid arthritis: Current status and future directions. Int. Rev. Immunol.36 (1), 20–30. doi: 10.1080/08830185.2016.1269175
28
GierutA.PerlmanH.PopeR. M. (2010). Innate immunity and rheumatoid arthritis. Rheumatic Dis. Clinics36 (2), 271–296. doi: 10.1016/j.rdc.2010.03.004
29
HoL. J.ChangW. L.ChenA.ChaoP.LaiJ. H. (2013). Differential immunomodulatory effects by Tripterygium wilfordii Hook f-derived refined extract PG27 and its purified component PG490 (triptolide) in human peripheral blood T cells: potential therapeutics for arthritis and possible mechanisms explaining in part Chinese herbal theory “Junn-Chenn-Zuou-SS”. J. Transl. Med.11:294. doi: 10.1186/1479-5876-11-294
30
IvanovI. I.McKenzieB. S.ZhouL.TadokoroC. E.LepelleyA.LafailleJ. J.et al. (2006). The orphan nuclear receptor RORγt directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell126 (6), 1121–1133. doi: 10.1016/j.cell.2006.07.035
31
JiaL.PingT.DongyiH. (2017). Effects of (5R) -5-Hydroxytriptolide (LLDT-8) on Gene Expressions in Fibroblast-like Synoviocytes of Rheumatoid Arthritis. Acta Universit. Tradit. Med. Sinensis Pharmacol. Shanghai31 (06), 70–75. doi: 10.16306/j.1008-861x.2017.06.017
32
JingX.HeL. (2013). Effects of GTW on expression of EGF and the intervention effect of Tusizi flavones in male juvenile rats. China J. Tradit. Chin. Med. Pharm.28 (06), 1884–1886.
33
JunZ.WeiX.RuiW.XiaoleS. (2016). Effectiveness and Safety of Kunxian Capsule for Rueumatoid Arthritis:A Systematic Review. J. Liaoning Univ. Tradit. Chin. Med.18 (10), 122–126. doi: 10.13194/j.issn.1673-842x.2016.10.037
34
JungY.-K.KangY.-M.HanS. (2019). Osteoclasts in the inflammatory arthritis: Implications for pathologic osteolysis. Immune Netw.19 (1), e2. doi: 10.4110/in.2019.19.e2
35
JunqueiraL. C.MescherA. L. (2013). Junqueira’s basic histology: text & atlas/Anthony L. Mescher (New York [etc.]: McGraw-Hill Medical).
36
KhanS.GreenbergJ. D.BhardwajN. (2009). Dendritic cells as targets for therapy in rheumatoid arthritis. Nat. Rev. Rheumatol.5 (10), 566. doi: 10.1038/nrrheum.2009.185
37
LariaA.LuratiA.MarrazzaM.MazzocchiD.ReK. A.ScarpelliniM. (2016). The macrophages in rheumatic diseases. J. Inflammation Res.9, 1–11. doi: 10.2147/JIR.S82320
38
LawrenceT.NatoliG. (2011). Transcriptional regulation of macrophage polarization: enabling diversity with identity. Nat. Rev. Immunol.11 (11), 750–761. doi: 10.1038/nri3088
39
LeeJ. Y.LeeB. H.KimN. D.LeeJ. Y. (2015). Celastrol blocks binding of lipopolysaccharides to a Toll-like receptor4/myeloid differentiation factor2 complex in a thiol-dependent manner. J. Ethnopharmacol.172, 254–260. doi: 10.1016/j.jep.2015.06.028
40
LefèvreS.KnedlaA.TennieC.KampmannA.WunrauC.DinserR.et al. (2009). Synovial fibroblasts spread rheumatoid arthritis to unaffected joints. Nat. Med.15 (12), 1414–1420. doi: 10.1038/nm.2050
41
LeiY.ShuangJ.WenpingP. (2015). Study on Inhibitory Effects of Triptolide on the Proliferation of Fibroblast-like Synovial Cells from Patients with Rheumatoid Arthritis in vitro. China Pharm.26 (31), 4357–4359. doi: 10.6039/j.issn.1001-0408.2015.31.13
42
LeibbrandtA.PenningerJ. M. (2009). RANKL/RANK as key factors for osteoclast development and bone loss in arthropathies. Adv. Exp. Med. Biol.649, 100–113. doi: 10.1007/978-1-4419-0298-6_7
43
LeipeJ.GrunkeM.DechantC.ReindlC.KerzendorfU.Schulze-KoopsH.et al. (2010). Role of Th17 cells in human autoimmune arthritis. Arthritis Rheumatism62 (10), 2876–2885. doi: 10.1002/art.27622
44
LiX.HeL. (2006). Pharmacological Control Study between Tripterygium. J. Kunming Med. Coll.02), 107–110.
45
LiG. Q.ZhangY.LiuD.QianY. Y.ZhangH.GuoS. Y.et al. (2012). Celastrol inhibits interleukin-17A-stimulated rheumatoid fibroblast-like synoviocyte migration and invasion through suppression of NF-kappaB-mediated matrix metalloproteinase-9 expression. Int. Immunopharmacol.14 (4), 422–431. doi: 10.1016/j.intimp.2012.08.016
46
LiG.LiuD.ZhangY.QianY.ZhangH.GuoS.et al. (2013a). Celastrol inhibits lipopolysaccharide-stimulated rheumatoid fibroblast-like synoviocyte invasion through suppression of TLR4/NF-kappaB-mediated matrix metalloproteinase-9 expression. PloS One8 (7), e68905. doi: 10.1371/journal.pone.0068905
47
LiG. Q.LiuD.ZhangY.QianY. Y.ZhuY. D.GuoS. Y.et al. (2013b). Anti-invasive effects of celastrol in hypoxia-induced fibroblast-like synoviocyte through suppressing of HIF-1alpha/CXCR4 signaling pathway. Int. Immunopharmacol.17 (4), 1028–1036. doi: 10.1016/j.intimp.2013.10.006
48
LiT.WangX.XueZ.LvC.LiH.FanY.et al. (2019). Meta-analysis of laboratory index of Tripterygium Glycosides Tablets in treatment of rheumatoid arthritis. China J. Chin. Mater. Med.44 (16), 3542–3550. doi: 10.19540/j.cnki.cjcmm.20190612.503
49
LinN.SatoT.ItoA. (2001). Triptolide, a novel diterpenoid triepoxide from Tripterygium wilfordii Hook. f., suppresses the production and gene expression of pro-matrix metalloproteinases 1 and 3 and augments those of tissue inhibitors of metalloproteinases 1 and 2 in human synovial fibroblasts. Arthritis Rheum44 (9), 2193–2200. doi: 10.1002/1529-0131(200109)44:9<2193::aid-art373>3.0.co;2-5
50
LiuC.ZhangY.KongX.ZhuL.PangJ.XuY.et al. (2013). Triptolide prevents bone destruction in the collagen-induced arthritis model of rheumatoid arthritis by targeting RANKL/RANK/OPG signal pathway. Evidence-Based Complement. Altern. Med.2013, 626038. doi: 10.1155/2013/626038
51
LiuY. L.LindertS.ZhuW.WangK.McCammonJ. A.OldfieldE. (2014). Taxodione and arenarone inhibit farnesyl diphosphate synthase by binding to the isopentenyl diphosphate site. Proc. Natl. Acad. Sci. U.S.A.111 (25), E2530–E2539. doi: 10.1073/pnas.1409061111
52
LiuX. (2018). Impact of celastrol on polarization of mouse peritoneal macrophage. Basic Clin. Med.38 (05), 643–648. doi: 10.16352/j.issn.1001-6325.2018.05.011
53
Lopez-OlivoM. A.SiddhanamathaH. R.SheaB.TugwellP.WellsG. A.Suarez-AlmazorM. E. (2014). Methotrexate for treating rheumatoid arthritis. Cochrane Database Systemat. Rev.2014 (6), CD000957. doi: 10.1002/14651858.CD000957.pub2
54
LvQ. W.ZhangW.ShiQ.ZhengW. J.LiX.ChenH.et al. (2015). Comparison of Tripterygium wilfordii Hook F with methotrexate in the treatment of active rheumatoid arthritis (TRIFRA): a randomised, controlled clinical trial. Ann. Rheum Dis.74 (6), 1078–1086. doi: 10.1136/annrheumdis-2013-204807
55
MaoX.SunS.PeiZ.ZhangL. (2009). Inhibitory effect of triptolide on interleukin-18 and its receptor in rheumatoid arthritis synovial fibroblasts. Chin. J. Cell. Mol. Immunol.25 (07), 606–608+611. doi: 10.1007/s00011-007-7128-9
56
MingZ.LihuaM.YingC.JunX. (2014). Inhibitory Effects of Triptolide on Immune Function of Peripheral Blood T Cells in Rheumatoid Arthritis Patients. China Pharm.25 (47), 4441–4443. doi: 10.6039/j.issn.1001-0408.2014.47.08
57
MitchellJ. P.CarmodyR. J. (2018). NF-κB and the Transcriptional Control of Inflammation. Int. Rev. Cell Mol. Biol.335, 41–84. doi: 10.1016/bs.ircmb.2017.07.007
58
NanjundaiahS. M.VenkateshaS. H.YuH.TongL.StainsJ. P.MoudgilK. D. (2012). Celastrus and its bioactive celastrol protect against bone damage in autoimmune arthritis by modulating osteoimmune cross-talk. J. Biol. Chem.287 (26), 22216–22226. doi: 10.1074/jbc.M112.356816
59
NiiroH.ClarkE. A. (2002). Regulation of B-cell fate by antigen-receptor signals. Nat. Rev. Immunol.2 (12), 945–956. doi: 10.1038/nri955
60
NishiharaM.OguraH.UedaN.TsuruokaM.KitabayashiC.TsujiF.et al. (2007). IL-6–gp130–STAT3 in T cells directs the development of IL-17+ Th with a minimum effect on that of Treg in the steady state. Int. Immunol.19 (6), 695–702. doi: 10.1093/intimm/dxm045
61
NoortA. R.TakP. P.TasS. W. (2015). Non-canonical NF-κB signaling in rheumatoid arthritis: Dr Jekyll and Mr Hyde? Arthritis Res. Ther.17 (1):15. doi: 10.1186/s13075-015-0527-3
62
PanH. (2018). Mechanism Research of Xinfeng Capsule on rheumatoid arthritis by PI3K / AKT / mTOR signal pathway mediated by BAFF / BAFF-R. master (Hefei: Anhui University of Chinese Medicine).
63
PenattiA.FacciottiF.De MatteisR.LarghiP.ParoniM.MurgoA.et al. (2017). Differences in serum and synovial CD4+ T cells and cytokine profiles to stratify patients with inflammatory osteoarthritis and rheumatoid arthritis. Arthritis Res. Ther.19 (1), 103. doi: 10.1186/s13075-017-1305-1
64
PengA.WangX.ZhuangJ. (2014). Triptolide inhibites Th17 cell differentiation via regulating cyclooxygenase-2/prostaglandin E2 axis in synovial fibroblasts from rheumatoid arthritis. China J. Chin. Mater. Med.39 (3), 536–539. doi: 10.4268/cjcmm20140334
65
PieperK.GrimbacherB.EibelH. (2013). B-cell biology and development. J. Allergy Clin. Immunol.131 (4), 959–971. doi: 10.1016/j.jaci.2013.01.046
66
PingQ.ZhouY.ZhangS.CaoJ.XuL.FangG.et al. (2015). Study on effects of Tripterygium wilfordii polycoride in resisting macrophage inflammation and regulating inflammation via TLR4/NF-κB. China J. Chin. Mater. Med.40 (16), 3256–3261. doi: 10.4268/cjcmm20151626
67
PingT.JiaL.DongyiH. (2016). Effect of (5R)-5-hydroxytriptolide(LLDT-8) on chemotactic factor in fibroblast-like synoviocytes. Curr. Immunol.36 (06), 448–454.
68
PlotkinL. I.EssexA. L.DavisH. M. (2019). RAGE Signaling in Skeletal Biology. Curr. Osteoporos Rep.17 (1), 16–25. doi: 10.1007/s11914-019-00499-w
69
QiW.LinC.FanK.ChenZ.LiuL.FengX.et al. (2019). Hesperidin inhibits synovial cell inflammation and macrophage polarization through suppression of the PI3K/AKT pathway in complete Freund’s adjuvant-induced arthritis in mice. Chem. Biol. Interact.306, 19–28. doi: 10.1016/j.cbi.2019.04.002
70
QianC.PengL.FengX.TanW.ZhangQ. (2015). Celastrol Inhibiting Osteoclast Formation by Reducing Chemokine CCl4. Liaoning J. Tradit. Chin. Med.42 (02), 415–417+447. doi: 10.13192/j.issn.1000-1719.2015.02.078
71
SchererH. U.HuizingaT. W.KrönkeG.SchettG.ToesR. E. (2018). The B cell response to citrullinated antigens in the development of rheumatoid arthritis. Nat. Rev. Rheumatol.14 (3), 157. doi: 10.1038/nrrheum.2018.10
72
SchmidlinH.DiehlS. A.BlomB. (2009). New insights into the regulation of human B-cell differentiation. Trends Immunol.30 (6), 277–285. doi: 10.1016/j.it.2009.03.008
73
SharpJ. T.TsujiW.OryP.Harper-BarekC.WangH.NewmarkR. (2010). Denosumab prevents metacarpal shaft cortical bone loss in patients with erosive rheumatoid arthritis. Arthritis Care Res. (Hoboken)62 (4), 537–544. doi: 10.1002/acr.20172
74
SmolenJ. S.AletahaD.BartonA.BurmesterG. R.EmeryP.FiresteinG. S.et al. (2018). Rheumatoid arthritis. Nat. Rev. Dis. Primers4, 18001. doi: 10.1038/nrdp.2018.1
75
StohlW.MerrillJ. T.McKayJ. D.LisseJ. R.ZhongZ. J.FreimuthW. W.et al. (2013). Efficacy and safety of belimumab in patients with rheumatoid arthritis: a phase II, randomized, double-blind, placebo-controlled, dose-ranging Study. J. Rheumatol.40 (5), 579–589. doi: 10.3899/jrheum.120886
76
SuZ.SunH.AoM.ZhaoC. (2017). Atomic Force Microscopy Study of the Anti-inflammatory Effects of Triptolide on Rheumatoid Arthritis Fibroblast-like Synoviocytes. Microsc. Microanal.23 (5), 1002–1012. doi: 10.1017/s1431927617012399
77
SunF.JiangS.PingL.FengH.DaiL. (2016). Effect of Tripterygium Wilfordii on Follicular Helper T Cells and IL-21 of Rheumatoid Arthritis Patients. Med. Recapitulate22 (03), 566–569. doi: 10.3969/j.issn.1006-2084.2016.03.044
78
SunJ. (2017). The effects of Duantengyimu decoction on the expression of chemokine receptor and secretion of chemokine in dendritic cells of patients with rheumatoid arthritis. dissertation (Guangzhou: Guangzhou University of Chinese Medicine).
79
TakeuchiT.TanakaY.IshiguroN.YamanakaH.YonedaT.OhiraT.et al. (2016). Effect of denosumab on Japanese patients with rheumatoid arthritis: a dose-response study of AMG 162 (Denosumab) in patients with RheumatoId arthritis on methotrexate to Validate inhibitory effect on bone Erosion (DRIVE)-a 12-month, multicentre, randomised, double-blind, placebo-controlled, phase II clinical trial. Ann. Rheum Dis.75 (6), 983–990. doi: 10.1136/annrheumdis-2015-208052
80
TakeuchiT.TanakaY.SoenS.YamanakaH.YonedaT.TanakaS.et al. (2019). Effects of the anti-RANKL antibody denosumab on joint structural damage in patients with rheumatoid arthritis treated with conventional synthetic disease-modifying antirheumatic drugs (DESIRABLE study): a randomised, double-blind, placebo-controlled phase 3 trial. Ann. Rheum Dis.78 (7), 899–907. doi: 10.1136/annrheumdis-2018-214827
81
TangY.ZhangY.LiL.XieZ.WenC.HuangL. (2020). Kunxian Capsule for Rheumatoid Arthritis: Inhibition of Inflammatory Network and Reducing Adverse Reactions Through Drug Matching. Front. Pharmacol.11, 485. doi: 10.3389/fphar.2020.00485
82
TaoX.DavisL. S.LipskyP. E. (1991). Effect of an extract of the Chinese herbal remedy Tripterygium wilfordii Hook F on human immune responsiveness. Arthritis Rheum34 (10), 1274–1281. doi: 10.1002/art.1780341011
83
TeW.Zhao-fuL.TaoL.Xiao-youY.Li-pingZ. (2019). Research Progress on the Mechanism of Kunmingshanhaitang in the Treatment of Rheumatoid Arthritis. Rheumatism Arthritis08), 60–63. doi: 10.3969/j.issn.2095-4174.2019.08.014
84
TeitelbaumS. L.RossF. P. (2003). Genetic regulation of osteoclast development and function. Nat. Rev. Genet.4 (8), 638. doi: 10.1038/nrg1122
85
TongZ.ChengL.SongJ.WangM.YuanJ.LiX.et al. (2018). Therapeutic effects of Caesalpinia minax Hance on complete Freund’s adjuvant (CFA)-induced arthritis and the anti-inflammatory activity of cassane diterpenes as main active components. J. Ethnopharmacol.226, 90–96. doi: 10.1016/j.jep.2018.08.011
86
VallièresF.DurocherI.GirardD. (2019). Biological activities of interleukin (IL)-21 in human monocytes and macrophages. Cell. Immunol.337, 62–70. doi: 10.1016/j.cellimm.2019.02.002
87
van HamburgJ. P.AsmawidjajaP.DavelaarN.MusA.ColinE.HazesJ.et al. (2011). Th17 cells, but not Th1 cells, from patients with early rheumatoid arthritis are potent inducers of matrix metalloproteinases and proinflammatory cytokines upon synovial fibroblast interaction, including autocrine interleukin-17A production. Arthritis Rheumatism63 (1), 73–83. doi: 10.1002/art.30093
88
VenkateshaS. H.YuH.RajaiahR.TongL.MoudgilK. D. (2011). Celastrus-derived celastrol suppresses autoimmune arthritis by modulating antigen-induced cellular and humoral effector responses. J. Biol. Chem.286 (17), 15138–15146. doi: 10.1074/jbc.M111.226365
89
VinuesaC. G.LintermanM. A.YuD.MacLennanI. C. (2016). Follicular Helper T Cells. Annu. Rev. Immunol.34, 335–368. doi: 10.1146/annurev-immunol-041015-055605
90
WangG.WuD. (1994). Effect of tripterygium wilfordii on lymphocyte subsets in patients with rheumatoid arthritis. Chin. J. Internal Med.01), 41–42.
91
WangS. J.YaoK.XieF. D.JiX. H. (2001). Effects of Tripterygium wilfordii saponins and interleukin-10 on dendritic cells from human peripheral blood. Acta Pharmacol. Sin.22 (8).
92
WangB.MaL.TaoX.LipskyP. (2004). Triptolide, an active component of the Chinese herbal remedy Tripterygium wilfordii Hook F, inhibits production of nitric oxide by decreasing inducible nitric oxide synthase gene transcription. Arthritis Rheumatism: Off. J. Am. Coll. Rheumatol.50 (9), 2995–3003. doi: 10.1002/art.20459
93
WangX.ZhangL.DuanW.LiuB.GongP.DingY.et al. (2014). Anti−inflammatory effects of triptolide by inhibiting the NF−κB signalling pathway in LPS−induced acute lung injury in a murine model. Mol. Med. Rep.10 (1), 447–452. doi: 10.3892/mmr.2014.2191
94
WangG.GuoM.XuH.HuangJ.LvS.ZhaoH.et al. (2017). The effect of triptolide on differentiation of osteoclasts induced by HMGB1. J. China-Japan Friendship Hosp.31 (02), 102–106+130. doi: 10.3969/j.issn.1001-0025.2017.02.010
95
WangS.ZuoS.LiuZ.JiX.YaoZ.WangX. (2018). Study on the efficacy and mechanism of triptolide on treating TNF transgenic mice with rheumatoid arthritis. BioMed. Pharmacother.106, 813–820. doi: 10.1016/j.biopha.2018.07.021
96
WangS.LiuZ.WangJ.WangY.LiuJ.JiX.et al. (2019). The triptolide-induced apoptosis of osteoclast precursor by degradation of cIAP2 and treatment of rheumatoid arthritis of TNF-transgenic mice. Phytother. Res.33 (2), 342–349. doi: 10.1002/ptr.6224
97
WangX.LiT.XueZ.LvC.LiH.FanY.et al. (2019). Clinical symptoms effect of Tripterygium Glycosides Tablets alone or combined with methotrexate in treatment of rheumatoid arthritis: a Meta-analysis. China J. Chin. Mater. Med.44 (16), 3533–3541. doi: 10.19540/j.cnki.cjcmm.20190605.501
98
WangX. (2015). Effects of Triptolide on RANKL Expression in the Epidermal Microenvironment of CIA Mice. dissertation (Nanjing: Nanjing Medical University).
99
WongV. K. W.QiuC.XuS. W.LawB. Y. K.ZengW.WangH.et al. (2019). Ca(2+) signalling plays a role in celastrol-mediated suppression of synovial fibroblasts of rheumatoid arthritis patients and experimental arthritis in rats. Br. J. Pharmacol.176 (16), 2922–2944. doi: 10.1111/bph.14718
100
Xiao-yueW.Tai-xianL.Zhi-pengX.ChengL.Hui-zhenL.Yuan-fangF.et al. (2019). Clinical symptoms effect of Tripterygium Glycosides Tablets Tablets alone or combined with methotrexate in treatment of rheumatoid arthritis: a Meta-analysis. China J. Chin. Mater. Med.44 (16), 3533–3541. doi: 10.19540/j.cnki.cjcmm.20190605.501
101
XinW.WeiZ.ZhangY.SunY.ZhangD. (2018). Effect of celastrol on pyroptosis of macrophages RAW264.7. Chin. Tradit. Herbal Drugs49 (05), 1087–1091. doi: 10.7501/j.issn.0253-2670.2018.05.015
102
XuZ.WuG.WeiX.ChenX.WangY.ChenL. (2013). Celastrol induced DNA damage, cell cycle arrest, and apoptosis in human rheumatoid fibroblast-like synovial cells. Am. J. Chin. Med.41 (3), 615–628. doi: 10.1142/s0192415x13500432
103
XuH.ZhaoH.LuC.QiuQ.WangG.HuangJ.et al. (2016). Triptolide Inhibits Osteoclast Differentiation and Bone Resorption In Vitro via Enhancing the Production of IL-10 and TGF-β1 by Regulatory T Cells. Mediators Inflammation2016, 8048170. doi: 10.1155/2016/8048170
104
XuZ. (2013). Celastrol-Introduced Apoptosis, cell Cycle arrest and DNA Damage in Rheumatoid Arthritis Fibroblast-like synovial dissertation (Fuzhou: Fujian University of Traditional Chinese Medicine).
105
XuH. (2016). Effects of Triptolide on OC Differentiation and Bone Resorption in Tregs-OC Co-culture System. dissertation (Beijing: Beijing University of Chinese Medicine).
106
YangX. O.PappuB. P.NurievaR.AkimzhanovA.KangH. S.ChungY.et al. (2008). T helper 17 lineage differentiation is programmed by orphan nuclear receptors RORα and RORγ. Immunity28 (1), 29–39. doi: 10.1016/j.immuni.2007.11.016
107
YangY.YeY.QiuQ.XiaoY.HuangM.ShiM.et al. (2016). Triptolide inhibits the migration and invasion of rheumatoid fibroblast-like synoviocytes by blocking the activation of the JNK MAPK pathway. Int. Immunopharmacol.41, 8–16. doi: 10.1016/j.intimp.2016.10.005
108
YapT. A.GarrettM. D.WaltonM. I.RaynaudF.de BonoJ. S.WorkmanP. (2008). Targeting the PI3K-AKT-mTOR pathway: progress, pitfalls, and promises. Curr. Opin. Pharmacol.8 (4), 393–412. doi: 10.1016/j.coph.2008.08.004
109
YueJ.GriffithJ. F.XiaoF.ShiL.WangD.ShenJ.et al. (2017). Repair of Bone Erosion in Rheumatoid Arthritis by Denosumab: A High-Resolution Peripheral Quantitative Computed Tomography Study. Arthritis Care Res. (Hoboken)69 (8), 1156–1163. doi: 10.1002/acr.23133
110
ZhangQ.ShiY.TanW.WangF. (2008). Effect of triptolide on the changes of VEGF and MMP-9 levels in the rheumatoid arthritis fibroblast-like synoviocyte line, MH7A. Acta Universit. Med. Nanjing (Natural Sci.)07), 902–905. doi: 10.3724/SP.J.1141.2008.00459
111
ZhouJ.XiaoC.ZhaoL.JiaH.ZhaoN.LuC.et al. (2006). The effect of triptolide on CD4+ and CD8+ cells in Peyer’s patch of SD rats with collagen induced arthritis. Int. Immunopharmacol.6 (2), 198–203. doi: 10.1016/j.intimp.2005.08.011
112
ZhuG.HanX.WangH.YuzhengY.GaoY.WangH. (2019). Effect of Tripterygium Glycosides Tablets in treating rheumatoid arthritis:a systematic review and Meta-analysis. China J. Chin. Mater. Med.44 (15), 3358–3364. doi: 10.19540/j.cnki.cjcmm.20190305.004
Summary
Keywords
Tripterygium wilfordii Hook f., rheumatoid arthritis, immune cell, mechanism, review
Citation
Tang Y, Liu Q, Feng Y, Zhang Y, Xu Z, Wen C and Zhang Y (2020) Tripterygium Ingredients for Pathogenicity Cells in Rheumatoid Arthritis. Front. Pharmacol. 11:583171. doi: 10.3389/fphar.2020.583171
Received
14 July 2020
Accepted
03 September 2020
Published
02 October 2020
Volume
11 - 2020
Edited by
Yanqiong Zhang, China Academy of Chinese Medical Sciences, China
Reviewed by
Jinxia Zhao, Peking University Third Hospital, China; Ganesan Ramamoorthi, Moffitt Cancer Center, United States
Updates
Copyright
© 2020 Tang, Liu, Feng, Zhang, Xu, Wen and Zhang.
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: Chengping Wen, wengcp@163.com; Yun Zhang, zhangyun@zcmu.edu.cn
This article was submitted to Ethnopharmacology, a section of the journal Frontiers in Pharmacology
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