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* Centre for Inflammatory Diseases, Department of Medicine, Monash Institute of Medical Research, Monash University, Victoria, Australia; and
School of Molecular and Biomedical Science, University of Adelaide, Adelaide, Australia
Macrophage migration inhibitory factor (MIF) was originally identified for its ability to inhibit the random migration of macrophages in vitro. MIF is now recognized as an important mediator in a range of inflammatory disorders. We recently observed that the absence of MIF is associated with a reduction in leukocyte-endothelial cell interactions induced by a range of inflammatory mediators, suggesting that one mechanism whereby MIF acts during inflammatory responses is by promoting leukocyte recruitment. However, it is unknown whether MIF is capable of inducing leukocyte recruitment independently of additional inflammatory stimuli. In this study, we report that MIF is capable of inducing leukocyte adhesion and transmigration in postcapillary venules in vivo. Moreover, leukocytes recruited in response to MIF were predominantly CD68+ cells of the monocyte/macrophage lineage. Abs against the monocyte-selective chemokine CCL2 (JE/MCP-1) and its receptor CCR2, but not CCL3 and CXCL2, significantly inhibited MIF-induced monocyte adhesion and transmigration. CCL2–/– mice displayed a similar reduction in MIF-induced recruitment indicating a critical role of CCL2 in the MIF-induced response. This hypothesis was supported by findings that MIF induced CCL2 release from primary microvascular endothelial cells. These data demonstrate a previously unrecognized function of this pleiotropic cytokine: induction of monocyte migration into tissues. This function may be critical to the ability of MIF to promote diseases such as atherosclerosis and rheumatoid arthritis, in which macrophages are key participants.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by the National Health and Medical Research Council, Australia (Program Grant 334067 (to M.J.H. and E.F.M.) and Project Grant 349533 (to S.R.M.)) and the National Institutes of Health (Grant AR51807-01 (to M.J.H.)).
2 Address correspondence and reprint requests to Dr. Michael J. Hickey, Centre for Inflammatory Diseases, Department of Medicine, Monash University, Monash Medical Centre, 246 Clayton Road, Clayton, Victoria, 3168 Australia. E-mail address: michael.hickey{at}med.monash.edu.au
3 Abbreviations used in this paper: MIF, macrophage migration inhibitory factor; PTX, pertussis toxin.
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