Background IL-6-mediated STAT3 signaling which is essential to Th17 differentiation plays the central role in the pathogenesis of rheumatoid arthritis.
Objectives To investigate the molecular mechanism underlying the anti-rheumatic effects and the T cell regulatory effects of STAT3 inhibition, we studied the effects of JAK2 inhibitor, AG490, on Th17/Treg balance and osteoclastogenesis.
Methods AG490, inhibitor of Jak2, was administered via intraperitoneal injection in collagen-induced arthritis (CIA) model and the in vivo effects of AG490 were determined. The differential expressions of proinflammatory cytokines including IL-17, IL-1β and IL-6 were analyzed by immunohistochemistry. The levels of phosphorylated STAT3 and STAT5, the differentiation of Th17 and Treg after the treatment of AG490 in CIA model were analyzed by immunostaining. In vitro development of Th17 and Treg was analyzed by flowcytometry and real-time polymerase chain reaction.
Results AG490 administration ameliorated the arthritic phenotype of CIA and increased the proportion of Foxp3-positive Treg cells. In contrast, the proportion of IL-17-producing T cells and the levels of inflammatory markers were reduced in AG490-treated group. The pSTAT3-positive CD4 T cells were reduced, whereas pSTAT5-positve CD4 T cells were elevated with treatment of AG490. Further, AG490 markedly enhanced the expression of molecules associated with Treg development (ICOS, PD-1, ICAM-1 and CD103) as well as Foxp3. The development and the function of osteoclast were also suppressed with AG490 treatment.
Conclusions Our results suggest that AG490 which specifically regulates JAK2/STAT3 pathway may be the promising treatment strategy for rheumatoid arthritis.
Disclosure of Interest None Declared