ABSTRACT
Objectives: 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.
ACKNOWLEDGEMENTS
This study was supported by a Program Grant from the National Health and Medical Research Council (NHMRC) Australia (#334067) and an RO1 grant from the National Institutes of Health (NIH; Bethesda, Maryland, USA) (#AR51807-01). MJH is an NHMRC Senior Research Fellow. EFM is an inventor on patents for methods of MIF inhibition, and co-founder of Cortical Pty Ltd, a biotech company developing this technology.
The authors would like to thank ,Dr.. Gunter Fingerle-Rowson MD, Ph.D. (University Hospital Cologne, Cologne, Germany) for his generous provision of the C57BL/6 background MIF−/− mice.
EFM and MJH contributed equally to this study.
Declaration of interest: The authors report no financial conflicts of interest. The authors alone are responsible for the content and writing of this paper.