Gadd45γ alleviates collagen-induced arthritis by increasing IL-10 level and suppressing JNK activity

It has been shown that Gadd45β alleviated K/BxN serum-induced arthritis, but in collagen-induced arthritis (CIA), it exacerbated joint inflammatory response, clinical signs, and symptoms. So far, the function of Gadd45γ in arthritis remains to be explored. This study aimed to investigate the role and immune regulatory mechanism of Gadd45γ in arthritis by intra-articular injection of a lentiviral vector encoding the Gadd45γ gene (LV-Gadd45γ) or lentiviral vectors (LV). The experiments showed that CIA increased the level of Gadd45γ, overexpression of Gadd45γ inhibited the symptoms and articular destruction of CIA, reduced the pro-inflammatory cytokine IL-1β, IL-6, and matrix metalloproteinases-13 (MMP-13), and increased the anti-inflammatory cytokine IL-10. In turn, high levels of IL-10 elevated Gadd45γ in CIA mice, human rheumatoid synovial fibroblasts (HRSF), and RAW cell lines. Furthermore, the increasing expression of Gadd45γ dramatically raised IL-10 and diminished the phosphorylation of c-Jun N-terminal kinase (JNK) in CIA mice and HRSF. Mechanistic analysis showed that the attenuating effect of Gadd45γ on CIA may be attributed to the mutual enhancement of the expression of Gadd45γ and IL-10 and the inhibition of JNK activity through downregulating IL-1β and IL-6. The results indicate that Gadd45γ can act as an inflammatory suppressor and joint damage attenuator in CIA mice. Increased IL-10 levels through a positive feedback circuit between Gadd45γ and IL-10 and the inhibitory effect of Gadd45γ on JNK activity endows this protein with the ability to inhibit CIA.