Suppression of collagen-induced arthritis in growth arrest and DNA damage-inducible protein 45β-deficient mice.

Rheumatoid arthritis (RA) is a chronic inflammatory disease marked by synovial lining hyperplasia, chronic synovitis and progressive matrix damage (1). The mitogen-activated protein (MAP) kinases are thought to play a role in the disease by virtue of their ability to regulate cytokines and matrix metalloproteinases (2–4). c-Jun N-terminal kinase (JNK), which is one of the MAP kinases, is a potential therapeutic target and selective inhibitors suppress synovitis and joint destruction in rat adjuvant arthritis (5). More recently, JNK1 was shown to be the responsible for inflammation in murine arthritis by virtue of its critical role in mast cell degranulation (6). Of the upstream kinases involved in the JNK pathway, MKK7 is especially important and is primarily responsible for phosphorylating JNK in cultured fibroblast-like synoviocytes (7). Based on the role of MKK7 and JNK in arthritis, we recently evaluated the role of anendogenous MKK7 inhibitor, namely Growth Arrest and DNA Damage inducible genes-s (Gadd45β) in the passive K/BxN serum transfer model of arthritis (8). Gadd45β deficiency markedly increased JNK activation and clinical arthritis, suggesting that strategies to enhance Gadd45β expression might be beneficial in RA. Gadd45β also regulates T cell differentiation and activation (9–11). For instance, Gadd45β contributes to initiating Th1 cell differentiation by enhancing the expression of T-bet and also affects persistent p38 activation mediated by T cell receptor ligation (12, 13). An overall suppressive role of Gadd45β in adaptive immunity was demonstrated in studies using Gadd45β deficient mice, which have increased disease severity in murine experimental allergic encephalomyelitis (EAE)(11). To understand the role of Gadd45β in an adaptive immunity model of RA, we studied collagen-induced arthritis (CIA) in Gadd45β deficient mice. Based on the results in EAE and the passive K/BxN model, we predicted that the mice would have increased disease severity. Surprisingly, Gadd45β−/− mice had significantly lower arthritis scores and decreased joint destruction compared with wild type (WT) mice. The mechanism was associated with decreased production of IL-17, increased expression of the suppressive cytokine IL-10, and increased numbers of regulatory T cells (Tregs). These unexpected findings suggest that Gadd45β can have the diametrically opposing effects in inflammation and autoimmunity models depending on the relative contributions of innate and adaptive immunity.