Adrenomedullin RegulatesIL-1βGene Expression in F4/80+ Macrophages during Synovial Inflammation

Abstract

Adrenomedullin (AM) plays an important role in the regulation of inflammatory processes; however, the role and expression of AM in synovial inflammation have not been determined. To investigate the expression and role of AM in inflamed synovial tissue (ST), the gene expression profiles of AM in the ST, including synovial macrophages and fibroblasts, of a murine patellar surgical dislocation model were characterized. In addition, the effects of interleukin-(IL-) 1βand AM in cultured synovial cells were also examined. CD11c+macrophages were found to be elevated in ST of the surgically dislocated patella. Higher gene expression ofCD11c,IL-1β,AM, receptor activity-modifying proteins 2(RAMP2), and 3(RAMP3)was also observed in ST obtained from the dislocated side.AMexpression was also significantly increased in synovial fibroblasts and macrophages in response to IL-1βtreatment. Synovial macrophages also highly expressedRAMP3compared to fibroblasts and this expression was further stimulated by exogenously added IL-1β. Further, the treatment of the F4/80-positive cell fraction obtained from ST with AM inhibitedIL-1βexpression. Taken together, these findings demonstrated that AM was produced by synovial fibroblasts and macrophages in inflamed ST and that increased levels of AM may exert anti-inflammatory effects on synovial macrophages.