title: Interferon gamma suppresses collagen-induced arthritis by regulation of Th17 through the induction of indoleamine-2,3-deoxygenase.
abstract: C57BL/6 mice are known to be resistant to the development of collagen-induced arthritis (CIA). However, they show a severe arthritic phenotype when the Ifng gene is deleted. Although it has been proposed that IFN-γ suppresses inflammation in CIA via suppressing Th17 which is involved in the pathogenesis of CIA, the exact molecular mechanism of the Th17 regulation by IFN-γ is poorly understood. This study was conducted to 1) clarify that arthritogenic condition of IFN-γ knockout (KO) mice is dependent on the disinhibition of Th17 and 2) demonstrate that IFN-γ-induced indoleamine-2,3-dioxgenase (IDO) is engaged in the regulation of Th17. The results showed that the IFN-γ KO mice displayed increased levels of IL-17 producing T cells and the exacerbation of arthritis. Also, production of IL-17 by the splenocytes of the IFN-γ KO mice was increased when cultured with type II collagen. When Il17 was deleted from the IFN-γ KO mice, only mild arthritis developed without any progression of the arthritis score. The proportion of CD44(high)CD62L(low) memory-like T cells were elevated in the spleen, draining lymph node and mesenteric lymph node of IFN-γ KO CIA mice. Meanwhile, CD44(low)CD62L(high) naïve T cells were increased in IFN-γ and IL-17 double KO CIA mice. When Th17 polarized CD4+ T cells of IFN-γ KO mice were co-cultured with their own antigen presenting cells (APCs), a greater increase in IL-17 production was observed than in co-culture of the cells from wild type mice. In contrast, when APCs from IFN-γ KO mice were pretreated with IFN-γ, there was a significant reduction in IL-17 in the co-culture system. Of note, pretreatment of 1-methyl-DL- tryptophan, a specific inhibitor of IDO, abolished the inhibitory effects of IFN-γ. Given that IFN-γ is a potent inducer of IDO in APCs, these results suggest that IDO is involved in the regulation of IL-17 by IFN-γ.
authors.affiliation: The Rheumatism Research Center, Catholic Research Institute of Medical Science, The Catholic University of Korea, Seoul, South Korea.
authors.forename: Jaeseon
authors.initials: J
authors.lastname: Lee
authors.forename: Jennifer
authors.initials: J
authors.lastname: Lee
authors.forename: Mi-Kyung
authors.initials: MK
authors.lastname: Park
authors.forename: Mi-Ae
authors.initials: MA
authors.lastname: Lim
authors.forename: Eun-Mi
authors.initials: EM
authors.lastname: Park
authors.forename: Eun-Kyung
authors.initials: EK
authors.lastname: Kim
authors.forename: Eun-Ji
authors.initials: EJ
authors.lastname: Yang
authors.forename: Seon-Yeong
authors.initials: SY
authors.lastname: Lee
authors.forename: Joo-Yeon
authors.initials: JY
authors.lastname: Jhun
authors.forename: Sung-Hwan
authors.initials: SH
authors.lastname: Park
authors.forename: Ho-Youn
authors.initials: HY
authors.lastname: Kim
authors.forename: Mi-La
authors.initials: ML
authors.lastname: Cho
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics / Q000378:metabolism*; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism*; D020381:Interleukin-17 / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D020381:Interleukin-17; D007371:Interferon-gamma