IL-17 induces production of IL-6 and IL-8 in rheumatoid arthritis synovial fibroblasts via NF-κB- and PI3-kinase/Akt-dependent pathways

Abstract

Recent studies of the pathogenesis of rheumatoid arthritis (RA) have revealed that both synovial fibroblasts and T cells participate in the perpetuation of joint inflammation as dynamic partners in a mutual activation feedback, via secretion of cytokines and chemokines that stimulate each other. In this study, we investigated the role of IL-17, a major Th1 cytokine produced by activated T cells, in the activation of RA synovial fibroblasts. Transcripts of IL-17R (IL-17 receptor) and IL-17RB (IL-17 receptor B) were present in fibroblast-like synoviocytes (FLS) of RA patients. IL-17R responded with increased expression upon in vitro stimulation with IL-17, while the level of IL-17RB did not change. IL-17 enhanced the production of IL-6 and IL-8 in FLS, as previously shown, but did not affect the synthesis of IL-15. IL-17 appears to be a stronger inducer of IL-6 and IL-8 than IL-15, and even exerted activation comparable to that of IL-1β in RA FLS. IL-17-mediated induction of IL-6 and IL-8 was transduced via activation of phosphatidylinositol 3-kinase/Akt and NF-κB, while CD40 ligation and p38 MAPK (mitogen-activated protein kinase) are not likely to partake in the process. Together these results suggest that IL-17 is capable of more than accessory roles in the activation of RA FLS and provide grounds for targeting IL-17-associated pathways in therapeutic modulation of arthritis inflammation.

Interleukin-6 (IL-6) and IL-17 Synergistically Promote Viral Persistence by Inhibiting Cellular Apoptosis and Cytotoxic T Cell Function

“…These results are consistent with previous reports indicating that both IL-6 and IL-17 activate STAT3 and NF-B (27,29,41). In addition, it was previously shown that the activation of both STAT3 and NF-B leads to the upregulation of Bcl-2 and Bcl-xL expression (26,42).…”

“…The upregulation of prosurvival molecules in turn inhibited the apoptotic cell death of virus-infected cells and the destruction of virus epitope-bearing target cells by virus-specific CD8 ϩ T cells. The common signals involved in the upregulation caused by IL-6 and IL-17 were the activation of STAT3 and NF-B, although the signaling pathways for the activation are different between IL-6 and IL-17 (20,24,25,(27)(28)(29). These synergistic effects appear to be operational in TMEV-infected mice, as viral persistence in the CNS is partially enhanced after IL-17 administration and reduced after anti-IL-17 antibody treatment.…”

“…The TMEV antigen-specific cytokine production by T cells was determined with in vitro recall responses as previously described (5). To measure the levels of IL-17 and IFN-␥, CNS-infiltrating mononuclear cells were restimulated with different doses of UV-TMEV or mixed major histocompatibility complex (MHC) class II-restricted epitopes (VP4 [25][26][27][28][29][30][31][32][33][34][35][36][37][38] and VP2 206-220 ) for 48 h. The culture supernatants were then assessed for the cytokines using cytokinespecific enzyme-linked immunosorbent assays (ELISAs) for IL-17A (R&D Systems kit) and IFN-␥ (OptEIA kit; BD). To determine intracellular levels of the cytokines, CNS-infiltrating mononuclear cells or splenocytes from virus-infected mice were restimulated with 50 ng/ml phorbol myristate acetate (PMA) and 1 g/ml ionomycin (both from Sigma-Aldrich), or 2 M mixed epitope peptides, for 6 h and then were stained with anti-IL-17-PE, anti-IFN-␥-APC, and anti-CD4-fluorescein isothiocyanate (FITC) (all from BD).…”

“…To understand the mechanisms underlying the synergistic function of IL-6 and IL-17 in combination, we first explored the possible involvement of the signal transducer and activator of transcription 3 (STAT3), which is phosphorylated when cells are treated with IL-6 (24) or IL-17 (20,26,27,29,32). Flow-cytometric assessment of phosphorylated intracellular STAT3 indicated that a high concentration (100 ng/ml) of IL-6 or IL-17, but not low concentrations (10 and 20 ng/ml), induced STAT3 activation in IL-6-deficient BM cells (Fig.…”

siRNA-Act1 Inhibits the Function of IL-17 on Lung Fibroblasts via the NF-κB Pathway

“…IL-17A directly modulates fibroblast inflammatory functions by increasing IL-6, IL-8, G-CSF and matrix metalloproteinase production [14,15,16]. In vitro studies have also shown that rIL-17A did or did not upregulate the proliferation and collagen expression of cardiac or skin fibroblasts, respectively [17,18].…”