Activation of the JNK signalling pathway by macrophage migration inhibitory factor (MIF) and dependence on CXCR4 and CD74

Abstract

C-Jun N-terminal kinase (JNK) is a member of the mitogen-activated protein kinase (MAPK) family and controls essential processes such as inflammation, cell differentiation, and apoptosis. JNK signalling is triggered by extracellular signals such as cytokines and environmental stresses. Macrophage migration inhibitory factor (MIF) is a pleiotropic pro-inflammatory cytokine with chemokine-like functions in leukocyte recruitment and atherosclerosis. MIF promotes MAPK signalling through ERK1/2, while it can either activate or inhibit JNK phosphorylation, depending on the cell type and underlying stimulation context. MIF activities are mediated by non-cognate interactions with the CXC chemokine receptors CXCR2 and CXCR4 or by ligation of CD74, which is the cell surface expressed form of the class II invariant chain. ERK1/2 signalling stimulated by MIF is dependent on CD74, but the receptor pathway involved in MIF activation of the JNK pathway is unknown. Here we comprehensively characterize the stimulatory effect of MIF on the canonical JNK/c-Jun/AP-1 pathway in fibroblasts and T cell lines and identify the upstream signalling components. Physiological concentrations of recombinant MIF triggered the phosphorylation of JNK and c-Jun and rapidly activated AP-1. In T cells, MIF-mediated activation of the JNK pathway led to upregulated gene expression of the inflammatory chemokine CXCL8. Activation of JNK signalling by MIF involved the upstream kinases PI3K and SRC and was found to be dependent on CXCR4 and CD74. Together, these data show that the CXCR4/CD74/SRC/PI3K axis mediates rapid and transient activation of the JNK pathway as triggered by the inflammatory cytokine MIF in T cells and fibroblasts.

High expression levels of macrophage migration inhibitory factor sustain the innate immune responses of neonates

“…Alternative mechanisms through which exogenous and endogenous MIF may influence cell responses comprise its binding to the cell surface receptors CD74, CXCR2, and CXCR4 to initiate intracellular signaling (16,17); intracellular interaction with p53, JAB-1/CSN5, or RPS19 (18)(19)(20); and inhibition of MKP-1 (21). In primary newborn monocytes, MIF sustains MAPK activation by microbial products, in line with previous observations in mice and immortalized cell lines showing that MIF activates the p38, ERK1/2, and JNK pathways to mediate prosurvival, proproliferative, and proinflammatory activities (35,36,(56)(57)(58).…”

Insights into the role of macrophage migration inhibitory factor in obesity and insulin resistance

“…MIF can exert its chemotactic properties via CXCR2 and CXCR4 in macrophages and T-cells, respectively (114) . Binding of MIF to CXCR4 on the surface of fibroblasts and T-cells induced JNK propagating CXCL8 secretion (115) . Intriguingly, an alternative MIF receptor CD74, traditionally involved in the activation of mitogen-activated protein kinases pathway, has recently been demonstrated to also mediate macrophage chemotactic responses (116) .…”

Macrophage Migration Inhibitory Factor Limits Activation-Induced Apoptosis of Platelets via CXCR7-Dependent Akt Signaling

“…9,[19][20][21][22] Both CXCR2-CXCR4 can form functional complexes with the single-pass transmembrane-receptor CD74. 9 CD74 is essential for MIF-dependent Erk1/2 phosphorylation 19 after CXCR4 ligation.…”