Article

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

Department of Medicine, Monash Medical Centre, Centre for Inflammatory Diseases, Monash University, Clayton, Victoria, Australia.
The Journal of Immunology (Impact Factor: 4.92). 07/2010; 185(2):1238-47. DOI: 10.4049/jimmunol.0904104
Source: PubMed

ABSTRACT

Macrophage migration inhibitory factor (MIF) has been shown to promote leukocyte-endothelial cell interactions, although whether this occurs via an effect on endothelial cell function remains unclear. Therefore, the aims of this study were to examine the ability of MIF expressed by endothelial cells to promote leukocyte adhesion and to investigate the effect of exogenous MIF on leukocyte-endothelial interactions. Using small interfering RNA to inhibit HUVEC MIF production, we found that MIF deficiency reduced the ability of TNF-stimulated HUVECs to support leukocyte rolling and adhesion under flow conditions. These reductions were associated with decreased expression of E-selectin, ICAM-1, VCAM-1, IL-8, and MCP-1. Inhibition of p38 MAPK had a similar effect on adhesion molecule expression, and p38 MAPK activation was reduced in MIF-deficient HUVECs, suggesting that MIF mediated these effects via promotion of p38 MAPK activation. In experiments examining the effect of exogenous MIF, application of MIF to resting HUVECs failed to induce leukocyte rolling and adhesion, whereas addition of MIF to TNF-treated HUVECs increased these interactions. This increase was independent of alterations in TNF-induced expression of E-selectin, VCAM-1, and ICAM-1. However, combined treatment with MIF and TNF induced de novo expression of P-selectin, which contributed to leukocyte rolling. In summary, these experiments reveal that endothelial cell-expressed MIF and exogenous MIF promote endothelial adhesive function via different pathways. Endogenous MIF promotes leukocyte recruitment via effects on endothelial expression of several adhesion molecules and chemokines, whereas exogenous MIF facilitates leukocyte recruitment induced by TNF by promoting endothelial P-selectin expression.

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Available from: Fernando Santos Santiago
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    • "Experiments using rodent showed that fibroblasts from skin wounds up-regulate MIF secretion that is chemotactic to keratinocytes which may facilitate wound healing (Abe et al., 2000; Zhao et al., 2005). It has been shown to promote expression of adhesion molecules and secretion of chemokines by human endothelial cells and increase leukocyte–endothelial cell interactions (Cheng et al., 2010). MIF is also found in organisms in other phyla including arthropods , helminths and protozoa and is found in a number of invertebrate parasites of mammals including ticks, hookworms, whipworms, roundworms, filarial worms, trypanosomes and coccidians . "

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    • "This occurs via upregulation of the pro-inflammatory adhesion molecules (E-selectin, VCAM-1 and ICAM-1), and cytokines and chemokines such as IL-6, CXCL8 and CCL2 (Ley et al., 2007). The expression of endothelial pro-inflammatory molecules is predominantly controlled by NF-κB and MAP kinase signaling pathways (Chen and Manning, 1995; Kuldo et al., 2005; Cheng et al., 2010). GC effects on the activation of human umbilical cord vein endothelial cells (HUVECs) require GR, as GR-deficient HUVECs show prolonged NF-κB activation (Goodwin et al., 2013). "
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    • "Experiments using rodent showed that fibroblasts from skin wounds up-regulate MIF secretion that is chemotactic to keratinocytes which may facilitate wound healing (Abe et al., 2000; Zhao et al., 2005). It has been shown to promote expression of adhesion molecules and secretion of chemokines by human endothelial cells and increase leukocyte–endothelial cell interactions (Cheng et al., 2010). MIF is also found in organisms in other phyla including arthropods , helminths and protozoa and is found in a number of invertebrate parasites of mammals including ticks, hookworms, whipworms, roundworms, filarial worms, trypanosomes and coccidians . "
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