PLoS One. 2013 Apr 16;8(4):e60900. doi: 10.1371/journal.pone.0060900. Print 2013.
Interferon Gamma Suppresses Collagen-Induced Arthritis by Regulation of Th17 through the Induction of Indoleamine-2,3-Deoxygenase.
Lee J, Lee J, Park MK, Lim MA, Park EM, Kim EK, Yang EJ, Lee SY, Jhun JY, Park SH, Kim HY, Cho ML.
The Rheumatism Research Center, Catholic Research Institute of Medical Science, The Catholic University of Korea, Seoul, South Korea.
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-? 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-? is poorly understood. This study was conducted to 1) clarify that arthritogenic condition of IFN-? knockout (KO) mice is dependent on the disinhibition of Th17 and 2) demonstrate that IFN-?-induced indoleamine2,3dioxgenase (IDO) is engaged in the regulation of Th17. The results showed that the IFN-? 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-? KO mice was increased when cultured with type II collagen. When Il17 was deleted from the IFN-? 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-? KO CIA mice. Meanwhile, CD44(low)CD62L(high) naïve T cells were increased in IFN-? and IL-17 double KO CIA mice. When Th17 polarized CD4+ T cells of IFN-? 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-? KO mice were pretreated with IFN-?, 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-?. Given that IFN-? is a potent inducer of IDO in APCs, these results suggest that IDO is involved in the regulation of IL-17 by IFN-?. |
