Independent roles of macrophage migration inhibitory factor and endogenous, but not exogenous glucocorticoids in regulating leukocyte trafficking.
OBJECTIVE
Macrophage migration inhibitory factor (MIF) promotes leukocyte recruitment and antagonizes the anti-inflammatory effects of glucocorticoids (GC). The aim of this study was to examine whether interaction between MIF and GC underlies the ability of MIF to promote leukocyte-endothelial cell (EC) interactions.


METHODS
Intravital microscopy was used to assess leukocyte-EC interactions in wild-type and MIF(-/-) mice following treatment with lipopolysaccharide (LPS), the GC dexamethasone, and inhibition of endogenous GC, using the GC-receptor antagonist, RU486.


RESULTS
Dexamethasone reduced LPS-induced leukocyte interactions in wild-type mice to levels similar to those observed in MIF(-/-) mice not treated with dexamethasone, whereas in MIF(-/-) mice, leukocyte interactions were not further inhibited by dexamethasone. RU486 increased LPS-induced leukocyte adhesion and emigration to a similar extent in both wild-type and MIF(-/-) mice, indicating that endogenous GC exert a similar inhibitory effect on leukocyte trafficking in wild-type and MIF(-/-) mice. Both MIF deficiency and RU486 treatment reduced VCAM-1 expression, while neither treatment modulated expression of ICAM-1 or chemokines CCL2, KC, and MIP-2.


CONCLUSIONS
These results suggest that endogenous MIF and GC regulate leukocyte-EC interactions in vivo reciprocally but through predominantly independent mechanisms, and that the anti-inflammatory effect of MIF deficiency is comparable to that of exogenous GC.
Gregory
Julia L
JL
Monash University Department of Medicine, Monash Medical Center, Clayton, Victoria, Australia.
Hall
Pam
P
Leech
Michelle
M
Morand
Eric F
EF
Hickey
Michael J
MJ
D000818:Animals; D002448:Cell Adhesion; D002634:Chemotaxis, Leukocyte; D003907:Dexamethasone / Q000494:pharmacology; D042783:Endothelial Cells; D004730:Endothelium, Vascular; D005938:Glucocorticoids / Q000494:pharmacology*; D018836:Inflammation Mediators; D007962:Leukocytes; D008070:Lipopolysaccharides / Q000494:pharmacology; D008263:Macrophage Migration-Inhibitory Factors / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout
D005938:Glucocorticoids; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D008263:Macrophage Migration-Inhibitory Factors; D003907:Dexamethasone