Macrophage migration inhibitory factor induces macrophage recruitment via CC chemokine ligand 2.
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.
Gregory
Julia L
JL
Centre for Inflammatory Diseases, Department of Medicine, Monash Institute of Medical Research, Monash University, 246 Clayton Road, Clayton, Victoria 3168, Australia.
Morand
Eric F
EF
McKeown
Sonja J
SJ
Ralph
Jennifer A
JA
Hall
Pamela
P
Yang
Yuan H
YH
McColl
Shaun R
SR
Hickey
Michael J
MJ
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D002448:Cell Adhesion / Q000276:immunology; D018932:Chemokine CCL2 / Q000276:immunology / Q000378:metabolism*; D002634:Chemotaxis, Leukocyte / Q000502:physiology*; D042783:Endothelial Cells / Q000378:metabolism; D007150:Immunohistochemistry; D008024:Ligands; D008263:Macrophage Migration-Inhibitory Factors / Q000276:immunology / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000097382:CD68 Molecule
D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D018932:Chemokine CCL2; D008024:Ligands; D008263:Macrophage Migration-Inhibitory Factors; D012333:RNA, Messenger; C067980:CD68 antigen, human; D000097382:CD68 Molecule