Inhibition of tumour necrosis factor and IL-17 production by leflunomide involves the JAK/STAT pathway

Abstract

Objective:To study the effects of different disease-modifying antirheumatic drugs (DMARD) on different events mediated by IL-15-activated lymphocytes.Methods:Peripheral blood lymphocytes (PBL) were isolated from healthy donors and activated with IL-15 after exposure to different DMARD: leflunomide, cyclosporin A, methotrexate, mycophenolic acid, FK-506, sulphasalazine and sodium aurothiomalate. The expression of different surface molecules on the PBL was then determined by flow cytometry. Cells were also co-cultured with the monocytic cell line THP-1 and the tumour necrosis factor (TNF) concentration in the supernatant was measured after 24 h using an immunoenzyme assay. The effect of the aforementioned drugs on IL-17 production by IL-15-activated PBL was also studied.Results:Treatment of PBL with leflunomide, cyclosporin A and FK-506 inhibited the IL-15-induced expression of both CD54 and CD69 by PBL, as well as TNF production in co-cultures of activated PBL and THP-1 cells. The downregulation of CD54 and CD69 in PBL was correlated with the inhibition of TNF production. Likewise, leflunomide, cyclosporin A and FK-506 all inhibited IL-17 production in IL-15-activated PBL. Interestingly, the effect of leflunomide was not reverted by the presence of uridine in the medium. In addition, leflunomide inhibited the phosphorylation of STAT6 in vitro.Conclusion:Inhibition of the JAK/STAT pathway may represent an additional effect of leflunomide in chronic polyarthritis because it impairs certain events that control proinflammatory TNF and IL-17 cytokine production.

4SC-101, a novel immunosuppressive drug, inhibits IL-17 and attenuates colitis in two murine models of inflammatory bowel disease†

“…In that study, both TNF-a and IL-17 were inhibited by leflunomide. 28 However, we found specific inhibition of IL-17 by 4SC-101 when cells were stimulated with PHA. The different TNF-a inhibition results described here could be due to the involvement of specific intracellular signaling pathways (JAK/STAT or NF-jB, respectively) in these two studies when utilizing either IL-15 or PHA stimulation.…”

“…24,25 Recently, IL-17 has also gained increasing attention as a key mediator in the pathogenesis of intestinal inflammation. 11,17,18,[26][27][28] Of some relevance, leflunomide can inhibit IL-15 induced cytokine production by lymphocytes. 28 Our results (Fig.…”

“…11,17,18,[26][27][28] Of some relevance, leflunomide can inhibit IL-15 induced cytokine production by lymphocytes. 28 Our results (Fig. 1B) show that 4SC-101 inhibited PHA stimulated IL-17 production.…”

Leflunomide Induces Apoptosis in Fludarabine-Resistant and Clinically Refractory CLL Cells

“…This results in depletion of intracellular pyrimidines which can be reversed by addition of uridine. However, it has also been reported that A771726 can inhibit the JAK/STAT pathway induced by cytokines (31,32,55). Accordingly in our hands, this compound induced uridine-reversible inhibition of CD40L/IL-4-stimulated CLL proliferation at low levels (3-5mg/mL) without interfering with STAT phosphorylation.…”

Emerging oral immunomodulating agents – focus on teriflunomide for the treatment of multiple sclerosis

“…In vitro experiments in murine cell lines have shown that teriflunomide inhibits protein tyrosine-kinase (PTK) activity via inhibition of interleukin 2(IL-2)-induced tyrosine phosphorylation. [36][37][38] Specifically, teriflunomide inhibits the janus tyrosine kinases jak1 and jak3 in an IL-2 dependent murine cytotoxic T cell line. Several effects result from the inhibition of PTK activity including reduced T-cell proliferation, reduced production of IL-2, inhibition of calcium mobilization, and a blockage of immunoglobulin G1 production.…”