Immunoregulatory effects of Tripterygium wilfordii Hook F and its extracts in clinical practice

Abstract

Tripterygium wilfordii Hook F (TwHF) and its extracts have long been used for the treatment of rheumatoid arthritis, autoimmune diseases, and kidney disease due to their anti-inflammatory, immunoregulatory, and other pharmacological effects. However, the clinical immunoregulatory effects of TwHF and its extracts remain unclear, so we reviewed their effects for use in clinical practice. This review provides a comprehensive summary of the recent literature on the immunoregulatory effects of TwHF and its extracts in clinical studies. TwHF and its extracts affect the proliferation and activation of T and B cells; ratio of T cell subsets; inflammatory response of monocytes, macrophages, and immunoglobulins; and secretion of many cytokines. Together, these effects dictate immune function in a variety of diseases. TwHF and its extracts can be used alone or in combination with existing therapies against many immune disorders through immunomodulation.

Keywords

Tripterygium wilfordii Hook F / immunoregulation / clinical studies

Introduction

Immunomodulatory disorders include autoimmune diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Although immunomodulatory compounds, such as corticosteroids and immunosuppressants, have good clinical efficacy, some limitations cannot be ignored, including severe allergic reactions, infections, and anemia. Therefore, identifying safe and effective immunomodulatory drugs with minimal side effects is necessary.

Tripterygium wilfordii Hook F (TwHF) is a wood vine plant that is widely distributed in southern China as a traditional Chinese medicine. TwHF possesses immunoregulatory, anti-inflammatory, anti-tumor, anti-fertility, antibacterial, and other pharmacological properties, and it has been used for the treatment of RA [¹], SLE [²], nephritis [³], autoimmune diseases, and allergic skin diseases. Although some patients experience adverse effects with TwHF, including reproductive toxicity, adverse gastrointestinal complications, and hepatotoxicity, reasonable treatment and management strategies can help improve their tolerance for the plant [⁴]. Tripodine, triptonide, triptolide (TPT), and tripdiolide (TPO) are the main active ingredients of TwHF, and they have been used for many years to treat a range of inflammatory diseases in China with a certain degree of success. Clinical trials have been performed to study the immunomodulatory function of TwHF and its extracts. TwHF can be used as a routine drug for autoimmune diseases and is a highly effective alternative. Although studies have described the immunomodulatory effects of TwHF and its extracts, the molecular mechanisms responsible for these effects are not fully understood. This review aims to further describe the immunoregulatory effects of TwHF in clinical practice.

Immunoregulatory effects of TwHF and their mechanisms of action

The immunoregulatory effects of TwHF mainly target immune cells, immune molecules, and cell signal transduction. Given that T cells are a central part of the immune response, T cell-targeted immune interventions effectively control the immunopathology caused by these cells. TwHF exerts multidimensional regulation of T cells. In many autoimmune diseases, abnormalities in CD4⁺ and CD8⁺ T cells or an imbalance in Th17 and regulatory T cells (Tregs) can occur. The therapeutic effect of TwHF is related to the regulation of the ratio of CD4⁺ and CD8⁺ T cells, the immune balance of Th17 cells and Tregs, and dendritic cell differentiation [⁵–⁷]. B cells mainly produce antibodies, present antigens, and secrete cytokines involved in immune regulation and humoral immunity. An alcohol extract of TwHF known as T2 inhibits B lymphocyte proliferation and immunoglobulin production in immune responses [⁸]. Cytokines are proteins secreted by immune cells that can regulate cell function and the overall immune response. TwHF extracts mainly inhibit the expression of proinflammatory genes such as interleukin (IL)-2, inducible nitric oxide synthase, tumor necrosis factor-α (TNF-α), cyclooxygenase-2 (COX-2), and interferon (IFN)-γ [⁹]. Some extracts from TwHF can inhibit the inflammatory response by inhibiting the nuclear factor (NF)-κB signaling pathway [¹⁰] and regulating a variety of cytokines, such as the Th1/Th2 cytokine expression profile [¹¹].

Clinical immunoregulatory effects of TwHF

Immune diseases can be caused by the imbalance of immune regulation that affects the body’s immune response. Numerous clinical trials have demonstrated the immunoregulatory effects of TwHF. Table 1 and Fig. 1 summarize the molecular targets that mediate the immunoregulatory activities of TwHF and its bioactive components.

TwHF immunoregulation in RA

RA is a chronic, systemic inflammatory disease associated with swollen joints, pain, and related dysfunction. Clinical and experimental studies have shown that sustained-release TwHF has significant anti-inflammatory, analgesic, and immunosuppressive effects and significantly reduced toxic effects [¹²]. Tripterygium wilfordii polyglycoside (TWP) inhibits the immune response at multiple levels by reducing the serum levels of TNF-α, IL-6, and other cytokines in the treatment of RA [¹³,¹⁴]. Treatment with TWP and leflunomide reduces the serum levels of IL-1, IL-6, IL-10, TNF-α and soluble intercellular adhesion molecule-1 (sICAM-1) in patients with RA, and the changes in IL-1, TNF-α, IL-10, and sICAM-1 are significantly reduced compared with those of the monotherapy group, demonstrating the enhanced anti-inflammatory effects of combined treatment [¹⁵,¹⁶]. TWP combined with tocilizumab demonstrates obvious clinical efficacy in the treatment of RA, with significantly reduced serum levels of IL-1, IL-6, IL-8, and TNF-α; decreased Th1 cell ratio; and increased Treg cell ratio compared with tocilizumab alone [¹⁷]. The regulation of Th1 and Th2 cytokine secretion may be one of the mechanisms by which TWP improves the inflammatory injury of RA.

TwHF not only regulates Th1 and Th2 cytokines but also has varying degrees of impact on other cytokines. TPT is the main active monomer of TwHF in the treatment of RA. Synovial fibroblasts (SFs) treated with TPT were cocultured with CD4⁺ T cells from healthy volunteers, and TPT was found to inhibit COX-2 level by downregulating prostaglandin E (PGE) 2 secreted by SFs, thereby inhibiting Th17 cell differentiation [¹⁸]. Meanwhile, miR-155 can promote inflammatory cell recruitment to aggravate RA synovial inflammation [¹⁹]. TPT also inhibits the expression of TNF-α, IL-6, and miR-155 in peripheral blood mononuclear cells (PBMCs) of patients with RA stimulated by lipopolysaccharide, whereas the overexpression of miR-155 significantly reverses the inhibition of proinflammatory cytokine expression. Moreover, TPT upregulates the suppressor of cytokine signaling-1 (SOCS1) and SH2-inositol phosphatase 1 (SHIP-1) expression in PBMCs of patients, whereas the overexpression of miR-155 reverses the upregulation of SHIP-1 without affecting SOCS1 expression [²⁰]. TPT treatment reduces the activation of matrix metalloproteinase (MMP)-9 and the TNF-α-induced expression of phosphorylated c-Jun N-terminal kinases, which may also explain the therapeutic effects of TPT on the aggressive behavior of RA SFs [²¹].

Neutrophil extracellular traps (NETs) play a pivotal role in autoimmune diseases with inflammation-mediated organ damage. TPO, one of the main active components in TwHF, completely inhibits neutrophil oxidative burst and NET formation induced by the IgG purified from sera of a patient with RA via downregulation of the spleen tyrosine kinase-mitogen-activated protein kinase kinase-extracellular-signal-regulated kinase-NF-κB signaling cascade, further providing a potential mechanism for the decrease in autoantibody production in RA [²²]. Besides, chemokine (C–C motif) ligand (CCL) 5 plays an important role in RA and is overproduced in RA bone marrow, which may contribute to the accumulation of T cells observed in RA bone marrow. Tripterygium glucoside treatment can reduce the level of CCL5 in patients with RA [²³].

TwHF immunoregulation in immune thrombocytopenia (ITP)

ITP is an autoimmune hemorrhagic disease with many immune dysfunctions, including a low percentage of CD4⁺ T cells and a high percentage of CD8⁺ T cells [²⁴]. Multigly-TwHF combined with recombinant human IL-11 (rhIL-11) increases the ratio of CD4⁺ T cells in peripheral blood from 21.03% to 34.49% after 2 months of treatment for ITP. Thereafter, the ratio of CD8⁺ T cells in the peripheral blood decreases from 26.35% to 20.18%. Multigly-TwHF can also correct T cell dysfunction and shorten the treatment period when combined with rhIL-11. With few side effects, this combination may be safe and effective for the treatment of ITP [²⁵].

TwHF immunoregulation in ophthalmology diseases

Graves’ ophthalmopathy (GO) is an organ-specific autoimmune disease associated with the elevation of multiple serum Th1 cytokines (including TNF-α, IL-2, and IFN-γ) [²⁶]. The levels of TNF-α, IL-2, and IFN-γ in peripheral blood significantly decrease in patients with moderate to severe acute GO treated with TWP, whereas the concentration of IL-10 significantly increases compared with that of prednisone, with a total clinical efficacy of 88.10% for the treatment group [²⁷]. In vitro, TPT can inhibit the IFN-γ-induced activation of cultured retro-ocular fibroblasts derived from patients with GO [²⁸]. In addition, TWP can significantly inhibit the levels of IL-2 and TNF-α in patients with acute anterior uveitis (AAU), thereby providing a reliable therapeutic effect on AAU [²⁹].

TwHF immunoregulation in Crohn’s disease (CD)

Tregs expressing Forkhead box P3 (Foxp3) play an important role in maintaining intestinal homeostasis by secreting IL-10 and transforming growth factor (TGF)-β. Many studies have found a correlation between Foxp3⁺ Tregs and CD. TWP has been shown to be clinically effective in inducing CD remission due to the relief of the pathological inflammation of CD. Specifically, the levels of Foxp3⁺ Tregs and IL-10 in the mucosa of patients with CD significantly increase, whereas TNF-α is downregulated after TWP treatment [³⁰]. TWP may exert a therapeutic effect on mildly or moderately active CD by reducing the serum levels of TNF-α and IL-1β [³¹].

TwHF immunoregulation in myasthenia gravis (MG)

MG is a rare autoimmune disease associated with failure of neuromuscular transmission. In the treatment of MG, TWP combined with prednisone can significantly reduce serum IL-6 and peripheral blood B lymphocyte levels compared with prednisone alone [³²]. In addition, TWP with prednisone is superior to prednisone alone in the treatment of MG and exhibits a strong immunosuppressive effect [³²].

TwHF immunoregulation in asthma

The balance between the Th1 and Th2 responses maintains normal cellular and humoral immunity. In the treatment of patients with asthma, TWP reduces the number of CD4⁺ T cells and increases the number of CD8⁺ T cells for regulating the balance between T lymphocyte subsets [³³]. This treatment also reduces the serum levels of IL-2, IL-4, and IL-5 [³⁴]. TPT also reduces the abovementioned cytokines secreted by the PBMCs of patients [³⁴].

After TWP treatment, sputum IL-5 and soluble interleukin-2 receptor (sIL-2R) significantly decrease [³⁵]. In addition, IL-4, sIL-2R, and sCD23 in the supernatants of PBMCs from patients with asthma are significantly lower than those in the control group, whereas the IFN-γ content significantly increases [³⁶]. The inhibition of T and B cell activation, correction of the Th1 and Th2 cytokine imbalance, and reduction in basophils may be some of the important mechanisms for the anti-inflammatory and anti-asthmatic effects of TWP [³⁵,³⁶].

TwHF immunoregulation in Guillain–Barre syndrome (GBS)

The biological function of IL-6 is to promote B lymphocyte proliferation and differentiation, which is necessary to produce antibodies. sIL-2R provides an important signal to the immune system for cellular activation. In GBS treatment, TWP inhibits the immune response to adrenal corticosteroid abnormalities, and the clinical improvement rate and levels of IL-6, sIL-2R, and IgG are significantly better with TWP treatment compared with hormone therapy [³⁷,³⁸]. Thus, TWP inhibits the abnormal immune response in patients with GBS better than hormones.

TwHF immunoregulation in islet transplantation (IT)

IT is an important therapeutic mean to cure insulin-dependent diabetes mellitus (IDDM), but immune tolerance is crucial for long-term efficacy after transplantation. In patients with IT, TWP inhibits the number and function of T lymphocyte subsets such as CD2, CD4, and CD8 and normalizes the CD4⁺/CD8⁺ ratio. TWP also prolongs the survival time of patients with IT and IDDM by inhibiting immune rejection [³⁹].

TwHF immunoregulation in ankylosing spondylitis (AS)

IL-17 is also an inflammatory cytokine that is closely correlated with erythrocyte sedimentation rate and C-reactive protein levels contributing to the development of AS. In the treatment of AS, Tripterygium glycoside (TGG) exerts an anti-inflammatory effect by regulating the levels of IL-17, PGE2, and MMP-3 [⁴⁰]. Tregs can suppress immune reaction, and their absence in the blood of patients with AS may contribute to the pathogenesis of AS. The ratio of CD4⁺CD25⁺CD127^low Tregs in patients with AS significantly increases. TGG is efficient for the treatment of patients with AS, and its mechanism of action may be correlated with the upregulation of CD4⁺CD25⁺CD127^low Tregs and the downregulation of IL-17 in the peripheral blood [⁴¹].

TwHF immunoregulation in psoriasis

Psoriasis is a chronic relapsing inflammatory skin disease involving a variety of immune cells, factors, and inflammatory mediators. Aside from lowering the psoriasis area and severity index in patients with psoriasis vulgaris, TWP treatment for 8 weeks can reduce the serum levels of IL-6, IL-17, and IL-23 [⁴²]. These results also explain that TWP can regulate Th17 lymphocyte immune function in the treatment of psoriasis.

TwHF immunoregulation in human immunodeficiency virus (HIV)

Immune activation plays a crucial role in 20% of patients infected with HIV who are unable to achieve adequate immunologic recovery. TwHF extract has immunomodulatory effects that may help CD4 cell recovery. In the treatment of patients with HIV via combined antiretroviral therapy, the use of TwHF extract is correlated with reduced T cell immune activation and CD4 cell recovery [⁴³].

TwHF Immunoregulation in SLE

After treatment with TwHF, NF-κB activity in patients with SLE significantly decreases, reaching a level similar to that in patients with inactive SLE. The pathogenesis of SLE is complex, and TwHF may inhibit the expression of NF-κB to exert its immunosuppressive effect on SLE [⁴⁴].

TwHF Immunoregulation in nephropathy

IL-18 is a cytokine with multiple biological functions. TWP inhibits the production of plasma IL-18 to control lupus nephritis activity [⁴⁵]. TwHF treatment can improve the renal function and reduce proteinuria in patients with diabetic kidney disease (DKD), which is caused by reduced urinary excretion of monocyte chemotactic protein-1 to inhibit the inflammatory response [⁴⁶]. The pro-inflammatory factors of connective tissue growth factor (CTGF) and TGF-β1 are associated with DKD pathogenesis and contribute to podocyte impairment. TwHF treatment can prevent DKD development by reducing the urinary levels of CTGF and TGF-β1 [⁴⁷]. TWP can also improve the immunity imbalance of patients with DKD by inhibiting the expression of CD4⁺, CD4⁺/CD8⁺, and TNF-α [⁴⁸].

In addition, TWP may have a therapeutic effect in children with recurrent nephrotic syndrome, which is closely related to the reduction in cytokine levels of IL-2, TNF-α, IL-13, IL-6, and IL-4 from Th1 and Th2 in peripheral blood [⁴⁹]. TNF-α is an inflammatory mediator produced by activated mononuclear cells and macrophages that stimulate glomerular cells, neutrophils, and vascular endothelial cells, and its levels are elevated in patients with chronic glomerulonephritis (CGN). IL-6 is an important inflammatory cytokine that plays a role in the immune pathogenesis of CGN and glomerular sclerosis. TwHF treatment can reduce the expression of TNF-α, IL-6, and other inflammatory cytokines, indicating that it regulates the balance of cell-mediated immunity and humoral immunity to inhibit inflammatory reactions. Therefore, the therapeutic effect of TwHF on kidney function and improvement in clinical symptoms are related to its inhibition of the expression of TNF-α and IL-6 [⁵⁰].

Conclusions

The immunomodulatory and anti-inflammatory properties of TwHF make it an attractive drug for the treatment of autoimmune diseases. Combining TwHF with other drugs or altering the use of ingredients or methods may reduce its adverse effects. TwHF and its extracts exert a regulatory effect on immune function by regulating the proliferation and activation of T and B cells, proportion of T cell subsets, inflammatory response of monocyte and macrophage, production of immunoglobulin and a variety of cytokines, and other complex mechanisms. However, the molecular mechanisms responsible for these effects need to be studied further, including the signaling pathways of cells and molecules. The immunosuppressive effects of this compound mainly focus on TWP, and the immune promotion of TwHF has not been considered. Formulations with minimal side effects and the identification of the precise immunomodulatory functions of TwHF should be determined prior to use in clinical applications. Further studies on the immunoregulatory effects of TwHF and its extracts may explain their function and modes of action, and TwHF has great potential as an effective immunomodulatory drug.

References

[1] Wang X, Zu Y, Huang L, Yu J, Zhao H, Wen C, Chen Z, Xu Z. Treatment of rheumatoid arthritis with combination of methotrexate and Tripterygium wilfordii: a meta-analysis. Life Sci 2017; 171: 45–50

[2] Patavino T, Brady DM. Natural medicine and nutritional therapy as an alternative treatment in systemic lupus erythematosus. Altern Med Rev 2001; 6(5): 460–471

[3] Mao SJ, Huang XM. Tripterygium wilfordii Hook F is efficacious in the treatment of Henoch-Schönlein purpura nephritis in children. World J Pediatr 2016; 12(3): 375–376

[4] Zhang C, Sun PP, Guo HT, Liu Y, Li J, He XJ, Lu AP. Corrigendum: Safety profiles of Tripterygium wilfordii Hook F: a systematic review and meta-analysis. Front Pharmacol 2017; 8: 59

[5] Chen F, Ma YL, Ding H, Chen BP. Effects of Tripterygium wilfordii glycosides on regulatory T cells and Th17 in an IgA nephropathy rat model. Genet Mol Res 2015; 14(4): 14900–14907

[6] Chen P, Han R, Zhou Q, Cheng H, Zhu K. Modulatory effect of triptolide on differentiation of human Th17 cells. Chin J Chin Mater Med (Zhongguo Zhong Yao Za Zhi) 2011; 36(11): 1499–1502 (in Chinese)

[7] Yan YH, Shang PZ, Lu QJ, Wu X. Triptolide regulates T cell-mediated immunity via induction of CD11c^low dendritic cell differentiation. Food Chem Toxicol 2012; 50(7): 2560–2564

[8] Tao X, Davis LS, Lipsky PE. Effect of an extract of the Chinese herbal remedy Tripterygium wilfordii Hook F on human immune responsiveness. Arthritis Rheum 1991; 34(10): 1274–1281

[9] Brinker AM, Ma J, Lipsky PE, Raskin I. Medicinal chemistry and pharmacology of genus Tripterygium (Celastraceae). Phytochemistry 2007; 68(6): 732–766

[10] Zhou Y, Hong Y, Huang H. Triptolide attenuates inflammatory response in membranous glomerulo-nephritis rat via downregulation of NF-kB signaling pathway. Kidney Blood Press Res 2016; 41(6): 901–910

[11] Abdin AA, Hasby EA. Modulatory effect of celastrol on Th1/Th2 cytokines profile, TLR2 and CD3⁺ T-lymphocyte expression in a relapsing-remitting model of multiple sclerosis in rats. Eur J Pharmacol 2014; 742: 102–112

[12] Li RL, Liu PL, Wu XC. Clinical and experimental study on sustained release tablet of Tripterygium wilfordii in treating rheumatoid arthritis. Chin J Integr Tradit West Med (Zhongguo Zhong Xi Yi Jie He Za Zhi) 1996; 16(1): 10–13 (in Chinese)

[13] Li LL. Effects of Tripterygium wilfordii polyglycoside on plasma TNF-α and IL-6 in patients with rheumatoid arthritis. Acta Acad Med Guangxi (Guangxi Yi Ke Da Xue Xue Bao) 2005; 22(5): 33–35 (in Chinese)

[14] Goldbach-Mansky R, Wilson M, Fleischmann R, Olsen N, Silverfield J, Kempf P, Kivitz A, Sherrer Y, Pucino F, Csako G, Costello R, Pham TH, Snyder C, van der Heijde D, Tao X, Wesley R, Lipsky PE. Comparison of Tripterygium wilfordii Hook F versus sulfasalazine in the treatment of rheumatoid arthritis: a randomized trial. Ann Intern Med 2009; 151(4): 229–240, W49–51

[15] Min J, Jing YP, Gu ZH. Effects of Tripterygium wilfordii polyglycoside combined with leflunomide on elderly rheumatoid arthritis and interleukin-1, interleukin-6 and tumor necrosis factor-α. Pharmacol Clin Chin Mater Clin Med (Zhong Yao Yao Li Yu Lin Chuang) 2013; 29(3): 185–186 (in Chinese)

[16] Cui YX, Yang L. Effects of Tripterygium wilfordii polyglycoside combined with leflunomide on C-reactive protein, interleukin-10, soluble cell adhesion molecule 1 levels of elderly patients with active rheumatoid arthritis. Chin J Gerontol (Zhongguo Lao Nian Xue Za zhi) 2016; 36(19): 4878–4880 (in Chinese)

[17] Li YJ, Zhang T, Zhu XF, Tu JX, Jin Y, Xia XR. Clinical analysis of Tripterygium wilfordii polyglycoside combined with tocilizumab in the treatment of rheumatoid arthritis. Chin Med Mat (Zhong Yao Cai) 2015; 38(8): 1775–1777 (in Chinese)

[18] Peng AP, Wang XY, Zhuang JH. Effect of triptolide on COX2/PGE2 axis to inhibit Th17 cell differentiation. Chin J Chin Mater Med (Zhongguo Zhong Yao Za Zhi) 2014, 39(3): 536–539 (in Chinese)

[19] Elmesmari A, Fraser AR, Wood C, Gilchrist D, Vaughan D, Stewart L, McSharry C, McInnes IB, Kurowska-Stolarska M. MicroRNA-155 regulates monocyte chemokine and chemokine receptor expression in rheumatoid arthritis. Rheumatology (Oxford) 2016; 55(11): 2056–2065

[20] Peng A, Huang X, Liu R, Wang X, Zhuang J. Triptolide inhibits the inflammatory response of monocytes from rheumatoid arthritis patients by regulating miR-155. Cell Mol Immunol (Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi) 2014; 30(6): 635–638 (in Chinese)

[21] Yang Y, Ye Y, Qiu Q, Xiao Y, Huang M, Shi M, Liang L, Yang X, Xu H. Triptolide inhibits the migration and invasion of rheumatoid fibroblast-like synoviocytes by blocking the activation of the JNK MAPK pathway. Int Immunopharmacol 2016; 41: 8–16

[22] Yu Y, Koehn CD, Yue Y, Li S, Thiele GM, Hearth-Holmes MP, Mikuls TR, O’Dell JR, Klassen LW, Zhang Z, Su K. Celastrol inhibits inflammatory stimuli-induced neutrophil extracellular trap formation. Curr Mol Med 2015; 15(4): 401–410

[23] Yang MH, Wu FX, Xie CM, Qing YF, Wang GR, Guo XL, Tang Z, Zhou JG, Yuan GH. Expression of CC chemokine ligand 5 in patients with rheumatoid arthritis and its correlation with disease activity and medication. Chin Med Sci J 2009; 24(1): 50–54

[24] Li W, Wang X, Li J, Liu M, Feng J. A study of immunocyte subsets and serum cytokine profiles before and after immunal suppression treatment in patients with immune thrombocytopenia. Chin J Intern Med (Zhonghua Nei Ke Za Zhi) 2016; 55(2): 111–115 (in Chinese)

[25] Yu XQ, Chen HM, Sun JH, Luo M, Lu YL. Therapeutic efficacy of multigly-cosidorum Tripterygium combined with rhIL-11 for immune thrombocytopenia. J Exp Hematol (Zhongguo Shi Yan Xue Ye Xue Za Zhi) 2015; 23(5): 1400–1403 (in Chinese)

[26] Shen J, Li Z, Li W, Ge Y, Xie M, Lv M, Fan Y, Chen Z, Zhao D, Han Y. Th1, Th2, and Th17 cytokine involvement in thyroid associated ophthalmopathy. Dis Markers 2015; 2015: 609593

[27] Xu JP, Xu JP, Xu C, Chen J, Jin ZH, Zheng HF, Zhu J. Peripheral blood cell factors of Graves ophthalmopathy and effect of intervention with Tripterygium glycosides. Chin J Chin Mater Med (Zhongguo Zhong Yao Za Zhi) 2014; 39(3): 544–547 (in Chinese)

[28] Yan SX, Wang Y. Inhibitory effects of triptolide on interferon-γ-induced human leucocyte antigen-DR, intercellular adhesion molecule-1, CD40 expression on retro-ocular fibroblasts derived from patients with Graves’ ophthalmopathy. Clin Experiment Ophthalmol 2006; 34(3): 265–271

[29] Huang QS, Zhang ZL, Liu YM. Effect of Tripterygium wilfordii polyglycoside on serum IL-2 and TNF-α in patients with acute anterior U-veitis. Chin J Integr Tradit West Med (Zhongguo Zhong Xi Yi Jie He Za Zhi) 2002; 22(6): 432–434 (in Chinese)

[30] Li G, Ren J, Wang G, Gu G, Hu D, Ren H, Hong Z, Wu X, Liu S, Li J. T2 enhances in situ level of Foxp3⁺ regulatory cells and modulates inflammatory cytokines in Crohn’s disease. Int Immunopharmacol 2014; 18(2): 244–248

[31] Ren J, Tao Q, Wang X, Wang Z, Li J. Efficacy of T2 in active Crohn’s disease: a prospective study report. Dig Dis Sci 2007; 52(8): 1790–1797

[32] Li ZX, Tan H, Xiong XJ. Clinical effect of Tripterygiitotorum combined with prednisone and its effect on serum IL-6 level in treating patients with myasthenia gravis. Chin J Integr Tradit West Med (Zhongguo Zhong Xi Yi Jie He Za Zhi) 2002; 22(3): 175–177 (in Chinese)

[33] Wang XH, Zhang ZY. Effect of Tripterygium polyglucoside on T-lymphocyte subsets and serum interleukin-5 level in asthma patients. Chin J Integr Tradit West Med (Zhongguo Zhong Xi Yi Jie He Za Zhi) 2001; 21(1): 25–27 (in Chinese)

[34] Lin KX, Wang CZ, Qian GS. Effect of Tripterygium wilfordii on Th1, Th2 cytokines production in asthma patients. Chin J Integr Tradit West Med (Zhongguo Zhong Xi Yi Jie He Za Zhi) 2001; 21(1): 22–24 (in Chinese)

[35] Xu JY, Jiang FX, Qiu YJ. Effects of Tripterygium polyglucosideo (TP) on cytokines and eosinophil apoptosis in asthmatic patients in sputum. Chin J Microbiol Immunol (Zhong hua Wei Sheng Wu Xue He Mian Yi Xue Za Zhi) 2004; 24(2): 57–59 (in Chinese)

[36] Shen QJ, Wang LM, Wang JH, Xu YP, Zhu LJ. Modulatory effect of glucosidorum Tripterygii tororum (GTT) on TH1/TH2 cytokine balance state of asthmatic patients. Chin J Microbiol Immunol (Zhong hua Wei Sheng Wu Xue He Mian Yi Xue Za Zhi) 2002; 22(3): 96–98 (in Chinese)

[37] Zhang X, Xia J, Ye H. Effect of Tripterygium polyglycoside on interleukin-6 in patients with Guillain-Barre syndrome. Chin J Integr Tradit West Med (Zhongguo Zhong Xi Yi Jie He Za Zhi) 2000; 20(5): 332–334(in Chinese)

[38] Zhang X, Xia JH, Ye HH. Effect of Tripterygium wilfordii polyglycoside on IL-6 and sIL-2R in serum and cerebrospinal fluid of patients with Guillain-Barré syndrome. Chin J Immunol (Zhongguo Mian Yi Xue Za Zhi) 2001; 17(1): 53–54 (in Chinese)

[39] Zhang XZ, Li S, Wu XZ. Effects of Tripterygiitotorum in the treatment of insulin dependent diabetes mellitus with islet transplantation. Chin J Integr Tradit West Med (Zhongguo Zhong Xi Yi Jie He Za Zhi) 1994; 14(8): 451–453 (in Chinese)

[40] Ji W, Chen Y, Zhao X, Guo Y, Zhong L, Li H, Wang D, Song Y. Beneficial effects of Tripterygium glycosides tablet on biomarkers in patients with ankylosing spondylitis. Mol Med Rep 2015; 12(1): 684–690

[41] Ji W, Li H, Gao F, Chen Y, Zhong L, Wang D. Effects of Tripterygium glycosides on interleukin-17 and CD4⁺CD25⁺ CD127^low regulatory T-cell expression in the peripheral blood of patients with ankylosing spondylitis. Biomed Rep 2014; 2(4): 517–520

[42] Lan SH, Ye J, Zou X, Wang HZ, Zhao LJ. Effect of Tripterygium wilfordii on serum levels of IL-6, IL-17 and IL-23 in patients with psoriasis vulgaris. J Clin Dermatol (Lin Chuang Pi Fu Ke Za Zhi) 2017; 46(12): 877–879 (in Chinese)

[43] Li T, Xie J, Li Y, Routy JP, Li Y, Han Y, Qiu Z, Lv W, Song X, Sun M, Zhang X, Wang F, Jiang H. Tripterygium wilfordii Hook F extract in cART-treated HIV patients with poor immune response: a pilot study to assess its immunomodulatory effects and safety. HIV Clin Trials 2015; 16(2): 49–56

[44] Peng XB, Wang N, Zeng K. Effect of Tripterygium wilforddi Hook on the expression of nuclear factor-kB in peripheral blood mononuclear cells in patients with systemic lupus erythematosus. Chin J Derm Venereol (Zhongguo Pi Fu Xing Bing Xue Za Zhi) 2006; 20(6): 336–337 (in Chinese)

[45] Jin CY, Hu GH, Zheng BZ, Wang DL. Study on effect of Tripterygium on plasma IL-18 content in patients with lupus nephritis. Chin J Chin Mater Med (Zhongguo Zhong Yao Za Zhi) 2008; 33(9): 1075–1077 (in Chinese)

[46] Song HX, Gong J, Chen W. Effect of triptolide on urinary monocyte chemoattractant protein-1 in patients with diabetic nephropathy. Chin J Integr Tradit West Med (Zhongguo Zhong Xi Yi Jie He Za Zhi) 2005; 25(5): 416–418 (in Chinese)

[47] Ma R, Xu Y, Jiang W, Zhang W. Combination of Tripterygium wilfordii Hook F and angiotensin receptor blocker synergistically reduces excretion of urinary podocytes in patients with type 2 diabetic kidney disease. Biotechnol Biotechnol Equip 2015; 29(1): 139–146

[48] Xu GB, Chen DJ, Chen WZ. Effect of Tripterygium wilfordii polyglycoside on inflammatory factor level in patients with diabetic nephropathy. Chin Arch J Tradit Chin Med (Zhonghua Zhong Yi Yao Xue Kan) 2017; 35(8): 2206–2208 (in Chinese)

[49] Hu GH, Yi ZW, Wang JH, Yao JC. Effect of Triptergium wilfordii polyglycosidium on content of Th1 and Th2 in child recurrent nephrotic syndrome. Chin J Chin Mater Med (Zhongguo Zhong Yao Za Zhi) 2008; 33(4): 441–443 (in Chinese)

[50] Pei WY, Yang CH, Zhang XL. Effects and mechanism of Tripterygium wilfordii on chronic glomerulo nephritis. Genet Mol Res 2016; 15(1): 1–7

RIGHTS & PERMISSIONS

Higher Education Press and Springer-Verlag GmbH Germany, part of Springer Nature