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

Abstract

SummaryMacrophage migration inhibitory factor (MIF) is a pleiotropic proinflammatory 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.

Interactions of T helper cells with fibroblast‐like synoviocytes: Up‐regulation of matrix metalloproteinases by macrophage migration inhibitory factor from both Th1 and Th2 cells

“…We confirmed these results and showed clearly, using 2 Of note, T helper cells themselves have also been shown to express MMPs at a significant rate (44). As recently shown by Santos and colleagues (21), the reduction in arthritis in MIF-deficient mice was further associated with reduced T cell activation by down-regulation of ERK/MAP kinase phosphorylation (21). This mech- anism may therefore also play a role in our in vitro cocultivation system or in the interplay between T helper cells and FLS in vivo.…”

“…The importance of MIF in inflammatory joint diseases was further confirmed in several experimental animal models of RA. Murine collagen-induced arthritis (CIA) and murine antigen-induced arthritis (AIA), both of which are wellcharacterized T helper cell-dependent models of RA, are also partially dependent on MIF, as shown by the results of treatment with neutralizing anti-MIF antibodies and through the use of MIF-deficient mice (19)(20)(21)(22). The systemic application of recombinant MIF fully prevented the therapeutic effect of dexamethasone in murine AIA (20), confirming the notion that MIF antagonizes glucocorticoid action in RA (4).…”

Macrophage Migration Inhibitory Factor Increases Leukocyte–Endothelial Interactions in Human Endothelial Cells via Promotion of Expression of Adhesion Molecules

“…This is in agreement with recent studies that indicate that the MAPK pathway is a major target of MIF. Endogenous MIF has been found to facilitate MAPK activation in response to diverse stimuli, such as LPS, cytokines, or TCR activation (15,16,42). These effects of MIF have been shown to depend at least in part on permissive inhibition by MIF of MAPK phosphatase 1 (also known as DUSP1), a critical negative regulator of MAPK phosphorylation (16,43).…”

Suppression of Antigen-Specific T Cell Responses by the Kaposi's Sarcoma-Associated Herpesvirus Viral OX2 Protein and Its Cellular Orthologue, CD200

“…Suppressed ERK1/2 phosphorylation has been associated with reduced T cell responses by others. It was correlated with UV-induced inhibition of IFN-␥ production by ex vivo human cells (25) and reduced IFN-␥ production and rheumatoid arthritis severity in mice invoked by deleting the gene encoding macrophage migration inhibitory factor (MIF) (38). MIF enhances ERK1/2 phosphorylation.…”