TNF dependency of IL-17-induced joint pathology can be circumvented by Toll-like receptor-2 signaling
© The Author(s) 2003
Published: 12 September 2003
T-cell IL-17 is a proinflammatory cytokine present in the synovium of rheumatoid arthritis patients. Through the binding of IL-17 to its receptor (IL-17R) and the subsequent activation of a signaling pathway through TRAF-6 and NF-κB, IL-17 can induce other cytokines such as IL-1 and tumor necrosis factor (TNF). IL-17 can have both additive and synergistic effects on cytokine induction and tissue destruction with these cytokines, but may have direct pathological effects as well.
In the present study, we examined the relative dependency of TNF in the IL-17-induced joint inflammation and cartilage damage under naive and various arthritis conditions in vivo, including Toll-like receptor-2 (TLR-2)-dependent inflammation.
An adenoviral vector expressing murine IL-17 was used to intra-articularly overexpress IL-17 in the knee joints of control mice or mice deficient for IL-1 or TNF. Experiments were performed under naive conditions and during TLR-2-dependent streptococcal cell wall-induced arthritis (SCW) and passive immune complex-mediated arthritis (ICA) with lysozyme as an antigen.
IL-17 overexpression in the knee joint of naive mice resulted in joint inflammation and cartilage proteoglycan depletion, which gradually increased over time. No effects were noted with the same dose of control vector. IL-17 strongly upregulated IL-1 mRNA and protein levels in the synovium compared with the control group. However, no difference in IL-17-induced joint pathology was noted in IL-1-deficient mice (P = 0.39). Interestingly, when TNF-deficient mice were used, the IL-17-induced joint inflammation and cartilage damage were almost completely absent (P < 0.005). This indicates that, under naive conditions in vivo, the IL-17-induced joint inflammation and cartilage destruction are mediated by synergism with TNF and not with IL-1. Similar experiments were performed under SCW and ICA conditions. SCW arthritis runs through TLR-2, since arthritis was highly reduced in TLR-2-deficient mice, but not in TLR-4-/- mice. In addition, SCW arthritis is fully suppressed in mice deficient in the crucial Toll-like receptor signaling molecule Myd88. Overexpression of the T-cell cytokine IL-17 in the macrophage-mediated SCW model resulted in an elevation of joint inflammation and cartilage proteoglycan depletion compared with the control vector group (P < 0.005). Furthermore, IL-17 turned this acute model into a more chronic one. Remarkably, IL-17-enhanced SCW arthritis was not reduced in TNF-/- mice, identifying circumvention of TNF dependency in the presence of TLR-2 activation. Intriguingly, IL-17-induced enhancement of FcγR-mediated ICA still remained TNF dependent, since joint swelling was significantly reduced in TNF-deficient mice.
These data show TNF dependency of IL-17-induced joint pathology under naïve conditions and during ICA. However, this is lost during SCW arthritis. TLR-2 shares the same signaling pathway through TRAF-6 and NF-κB as the IL-17R. It suggests that TNF dependency can be bypassed by IL-17 in combination with TLR-2 triggers.