Reduced arthritis in MIF deficient mice is associated with reduced T cell activation: down-regulation of ERK MAP kinase phosphorylation

Abstract

Macrophage migration inhibitory factor (MIF) is a pleiotropic pro-inflammatory cytokine with many cellular targets in rheumatoid arthritis (RA). MIF has been reported to activate cells via mitogen-activated protein kinase and serine/threonine kinase (AKT or protein kinase B)-dependent signal transduction pathways. Its contribution to T cell activation and signalling in RA is not known. Using MIF -/- mice and a T cell-mediated model of RA, antigen-induced arthritis, we investigated the role of MIF in T cell activation and signalling. Arthritis severity was significantly reduced in MIF -/- mice compared with wildtype mice. This reduction was associated with decreased T cell activation parameters including footpad delayed type hypersensitivity, antigen-induced splenocyte proliferation and cytokine production. Splenocyte proliferation required extracellular signal-regulated kinase (ERK)1/2 phosphorylation, and decreased T cell activation in MIF -/- mice was associated with decreased phosphorylation of ERK1/2 but not AKT. Collectively, these data suggest that MIF promotes antigen-specific immune responses via regulation of ERK phosphorylation in T cells.