Increased expression of beta-arrestin 1 and 2 in murine models of rheumatoid arthritis: Isoform specific regulation of inflammation

Pro-inflammatory cytokines and chemokines play critical roles in autoimmune diseases including rheumatoid arthritis (RA). Recently, it has been reported that beta-arrestin 1 and 2 are involved in the regulation of inflammation. We hypothesized that beta-arrestin 1 and 2 play critical roles in murine models of RA. Using a collagen-induced arthritis (CIA) and a human TNF alpha transgenic (TNFtg) mouse model, we demonstrated that beta-arrestin 1 and 2 expression are significantly increased in joint tissue of CIA mice and TNFtg mice. In fibroblast-like synoviocytes (FLS) isolated from hind knee joint of CIA mice, we observed an increase of beta-arrestin 1 and 2 protein and mRNA levels in the early stage of arthritis. In FLS, low molecular weight hyaluronan (HA)-induced TNF alpha and IL-6 production was increased by overexpression of beta-arrestin 1 but decreased by overexpression of beta-arrestin 2 demonstrating isoform specific regulation. TNF alpha and HA induced an increase of beta-arrestin 1 and 2 expression in FLS, while high mobility group box (HMGB)-1 only stimulated beta-arrestin 1 expression. TNF alpha- or HA-induced beta-arrestin 2 expression was blocked by a p38 inhibitor. To examine the in vivo role of beta-arrestin 2 in the pathogenesis of arthritis, WT and beta-arrestin 2 KO mice were subjected to collagen antibody-induced arthritis (CAIA). beta-Arrestin 2 KO mice exhibited more severe arthritis in CAIA. Thus p-arrestin 2 is anti-inflammatory in CAIA. These composite observations suggest that beta-arrestin 1 and 2 differentially regulate FLS inflammation and increased beta-arrestin 2 may reduce experimental arthritis severity. 0 2011 Elsevier Ltd. All rights reserved.