Abstract
IntroductionInterleukin (IL)-17 is a pro-inflammatory cytokine in rheumatoid arthritis (RA) and collagen-induced arthritis (CIA). Since interferon (IFN)-γ inhibits Th17 cell development, IFN-γ receptor knockout (IFN-γR KO) mice develop CIA more readily. We took advantage of this model to analyse the mechanisms of action of IL-17 in arthritis. The role of IFN-γ on the effector mechanisms of IL-17 in an in vitro system was also investigated.MethodsIFN-γR KO mice induced for CIA were treated with anti-IL-17 or control antibody. The collagen type II (CII)-specific humoral and cellular autoimmune responses, myelopoiesis, osteoclastogenesis, and systemic cytokine production were determined. Mouse embryo fibroblasts (MEF) were stimulated with IL-17, tumor necrosis factor (TNF)-α and the expression of cytokines and chemokines were determined.ResultsA preventive anti-IL-17 antibody treatment inhibited CIA in IFNγR KO mice. In the joints of anti-IL-17-treated mice, neutrophil influx and bone destruction were absent. Treatment reduced the cellular autoimmune response as well as the splenic expansion of CD11b+ cells, and production of myelopoietic cytokines such as granulocyte macrophage colony-stimulating factor (GM-CSF) and IL-6. IL-17 and TNF-α synergistically induced granulocyte chemotactic protein-2 (GCP-2), IL-6 and receptor activator of NFκB ligand (RANKL) in MEF. This induction was profoundly inhibited by IFN-γ in a STAT-1 (signal transducer and activator of transcription-1)-dependent way.ConclusionsIn the absence of IFN-γ, IL-17 mediates its pro-inflammatory effects mainly through stimulatory effects on granulopoiesis, neutrophil infiltration and bone destruction. In vitro IFN-γ profoundly inhibits the effector function of IL-17. Thus, aside from the well-known inhibition of the development of Th17 cells by IFN-γ, this may be an additional mechanism through which IFN-γ attenuates autoimmune diseases.
Highlights
Interleukin (IL)-17 is a pro-inflammatory cytokine in rheumatoid arthritis (RA) and collagen-induced arthritis (CIA)
Increased levels of IL-17 in collagen type II (CII)/complete Freund's adjuvant (CFA)-immunized IFN-γR knock out (KO) mice IFN-γR KO mice develop CIA more readily than wild-type controls: symptoms of arthritis usually appear in IFN-γR KO mice from day 16 onwards compared with day 30 in wild-type animals [30]
To exclude that IFN-γ non- inhibits cytokine production, we tested the effect of IFN-γ on the production of keratinocyte-derived chemokine (KC), macrophage inflammatory protein (MIP)-2, IP-10, Regulated upon Activation, Normal T-cell Expressed, and Secreted (RANTES), monocyte chemotactic protein (MCP)-1, interferon-inducible T cell alpha chemoattractant (ITAC), and monokine induced by gamma interferon (MIG)
Summary
Interleukin (IL)-17 is a pro-inflammatory cytokine in rheumatoid arthritis (RA) and collagen-induced arthritis (CIA). Since interferon (IFN)-γ inhibits Th17 cell development, IFN-γ receptor knockout (IFN-γR KO) mice develop CIA more readily. IL-17 promotes inflammation by enhancing production of cytokines such as IL-1β, TNF-α, IL-6 and receptor activator of nuclear factor-κB ligand (RANKL), as well as chemokines such as macrophage inflammatory protein (MIP) and IL-8 [4,5,6]. Interferon (IFN)-γ, as a contrast, strongly inhibits development of Th17 cells both in vitro and in vivo [1,3,8]. Anti-IFN-γ added during in vitro Th17 differentiation causes increased IL-17 expression, and treated cells display increased expression of the IL-23 receptor (R) [3]. This, together with the observation that IFN-γ decreases the expression of IL-23R in IFN-γ-deficient CD4+ T cells differentiated towards a Th17 phenotype, indicates that IFN-γ is able to inhibit expression of the IL-23R. IFN-γ-deficient mice have increased numbers of IL-17-producing T cells following mycobacterial infection as compared with wild-type mice, and exogenous IFN-γ reduces the frequency of IL-17producing T cells in IFN-γ-deficient mice [9]
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