Macrophage migration inhibitory factor (MIF) promotes fibroblast migration in scratch‐wounded monolayers in vitro

Abstract

MIF was recently redefined as an inflammatory cytokine, which functions as a critical mediator of diseases such as septic shock, rheumatoid arthritis, atherosclerosis, and cancer. MIF also regulates wound healing processes. Given that fibroblast migration is a central event in wound healing and that MIF was recently demonstrated to promote leukocyte migration through an interaction with G-protein-coupled receptors, we investigated the effect of MIF on fibroblast migration in wounded monolayers in vitro. Transient but not permanent exposure of primary mouse or human fibroblasts with MIF significantly promoted wound closure, a response that encompassed both a proliferative and a pro-migratory component. Importantly, MIF-induced fibroblast activation was accompanied by an induction of calcium signalling, whereas chronic exposure with MIF down-regulated the calcium transient, suggesting receptor desensitization as the underlying mechanism.

Macrophage Migration Inhibitory Factor Mediates Hypoxia-Induced Pulmonary Hypertension

“…Animal models indicate that the adventitia undergoes the earliest and most profound changes under hypoxic conditions (48,49) and in vitro, hypoxia induces fibroblast proliferation in the absence of any exogenous comitogen (50). In addition, several investigators have suggested that MIF can induce fibroblasts proliferation directly (12,(51)(52)(53)(54). Therefore, we chose cultures of lung fibroblasts, both a human cell line and primary mouse cells, to examine the inter-relationships between hypoxia, MIF and cell proliferation.…”

MIF Promotes B Cell Chemotaxis through the Receptors CXCR4 and CD74 and ZAP-70 Signaling

“…Of note, unlike neutralizing anti-CXCL1 or anti-CXCL12 strategies, Abs directed against MIF induced plaque regression in a mouse model of chronic atherosclerosis, suggesting that dual activation of the CXCR2 and CXCR4 axes is critical in atheroprogression in vivo (16). Moreover, MIF/CXCRmediated signaling mediates hepatic carcinoma cell migration (26), fibroblast migration (20), endothelial progenitor cell recruitment into hypoxic areas (27,28), and colon cancer cell metastasis (29).…”

“…MIF promotes monocyte and T cell chemotaxis and arrest through CXCR2 and CXCR4, respectively, whereas CXCR2/CD74 complexes are essential in neutrophil migratory responses (9,16,20,21).…”

Structural determinants of MIF functions in CXCR2-mediated inflammatory and atherogenic leukocyte recruitment

“…We have recently demonstrated that MIF, contrary to its historic and eponymous name, is a noncognate ligand of the CXC chemokine receptors CXCR2 and CXCR4. Importantly, through interaction with these receptors, MIF is instrumental in inflammatory leukocyte recruitment in atherosclerosis, targeting monocytes and neutrophils through CXCR2 and T cells through CXCR4 (15,16). MIF is strongly over-expressed in the arterial wall of human atherosclerotic tissue, and blockade or genetic deletion of MIF in animal models of both native and injury-induced atherogenesis leads to a marked reduction in arterial inflammation and lesion size, including regression of established plaques (14,17).…”