Role of Jak3-Stat6 and effect of Jak inhibitor on dendritic cells and its involvement in rheumatoid arthritis

• Published in: Nihon Rinsho Men'eki Gakkai Sokai Shorokushu Vol. 37; p. 167
• Main Authors: 前島, 圭佑, 鈴木, 克典, 尾下, 浩一, 山岡, 邦宏, 齋藤, 和義, 田中, 良哉
• Format: Journal Article
• Language: Japanese
• Published: 日本臨床免疫学会 2009; The Japan Society for Clinical Immunology
• Subjects: IL-10; Jak3; Stat6; 樹状細胞
• ISSN: 1880-3296
• DOI: 10.14906/jscisho.37.0.167.0

Recently a Jak inhibitor possessing specificity on Jak3 has been reported to have high clinical efficacy on rheumatoid arthritis (RA). We have previously reported that Jak3-/- bone marrow-derived DCs (BMDCs) exhibit enhanced IL-10 production. To investigate the role of Jak3-Stat6 in RA, effects of Jak inhibitor on DCs and DCs from Stat6-/- mice were analyzed. Stat6-/- DCs developed and matured normally both in vitro and in vivo. Surprisingly, IL-10 production from the mice was increased while there was no difference in TNF-α and IL-6 production in response to TLR ligands. Such a profile of differential regulation of cytokine production was also seen in Jak3-/- DCs. Culture condition (GM-CSF and IL-4 vs. GM-CSF) or the genetic background of the mice (C57BL/6 vs. Balb/c) did not affect IL-10 overproduction. Jak inhibitor on human monocyte-derived DCs showed normal TNF-α and IL-6 production, but IL-10 production was decreased. In summary, Jak3 and Stat6 are not essential for DC development, but play an important role in regulating IL-10 production from DCs, which leads to inflammation in mouse. In contrast, a new Jak inhibitor, CP-690,550 had minimum effect on human DCs, but it rather decreased IL-10. The discrepancy in IL-10 production via the Jak3 pathway was observed between human and mouse, possibly due to its low specificity, and effects of Jak inhibitor warrant further investigation.