Macrophage migration inhibitory factor promotes resistance to glucocorticoid treatment in EAE.
OBJECTIVE
Glucocorticoids (GCs) are used as standard treatment for acute attacks of multiple sclerosis (MS). However, GCs eventually lose efficacy and do not prevent disease progression. Macrophage migration inhibitory factor (MIF) is the only known proinflammatory cytokine induced by GCs that inhibits their anti-inflammatory effects. Therefore, we investigated whether MIF plays a role in resistance to GC treatment in experimental autoimmune encephalomyelitis (EAE), an animal model of MS.


METHODS
EAE was induced in wild-type (Wt) and MIF knockout (MIF(-/-)) mice followed by treatment with dexamethasone (Dex) before or upon disease onset. Splenocytes and brain mononuclear cells were harvested for cytokine ELISPOT assay and flow cytometry analysis.


RESULTS
Treatment of EAE with Dex was substantially more efficacious in MIF(-/-) mice than Wt mice. Dex treatment decreased MOG35-55-induced cytokine production by Wt or MIF(-/-) CD4(+) T cells only at the onset of EAE but inhibited upregulation of T-bet during acute and chronic phases of disease, particularly in MIF(-/-) mice. Furthermore, passive EAE induced by adoptive transfer of T cells showed that Dex was highly effective in ameliorating disease induced by MIF(-/-) CD4(+) T cells but not by Wt CD4(+) T cells. The expression of T-bet and VLA-4 was decreased in CD4(+) T cells in MIF(-/-) mice compared with Wt mice.


CONCLUSIONS
Our data establish MIF as a key molecule in resistance of pathogenic CD4(+) T cells to GC treatment in EAE and as a potential target to enhance the effectiveness of steroid treatment in neuroinflammatory disorders.
Department of Biology (N.J., M.N.G., T.G.F.), University of Texas at San Antonio; Department of Pathology (A.K.), Frederick Memorial Hospital, Frederick, MD; and Clinic I of Internal Medicine and Center of Integrative Oncology Cologne-Bonn (G.F.-R.), Cologne, Germany.
Niannian
N
Ji
Department of Biology (N.J., M.N.G., T.G.F.), University of Texas at San Antonio; Department of Pathology (A.K.), Frederick Memorial Hospital, Frederick, MD; and Clinic I of Internal Medicine and Center of Integrative Oncology Cologne-Bonn (G.F.-R.), Cologne, Germany.
Andra
A
Kovalovsky
Department of Biology (N.J., M.N.G., T.G.F.), University of Texas at San Antonio; Department of Pathology (A.K.), Frederick Memorial Hospital, Frederick, MD; and Clinic I of Internal Medicine and Center of Integrative Oncology Cologne-Bonn (G.F.-R.), Cologne, Germany.
Günter
G
Fingerle-Rowson
Department of Biology (N.J., M.N.G., T.G.F.), University of Texas at San Antonio; Department of Pathology (A.K.), Frederick Memorial Hospital, Frederick, MD; and Clinic I of Internal Medicine and Center of Integrative Oncology Cologne-Bonn (G.F.-R.), Cologne, Germany.
M Neal
MN
Guentzel
Department of Biology (N.J., M.N.G., T.G.F.), University of Texas at San Antonio; Department of Pathology (A.K.), Frederick Memorial Hospital, Frederick, MD; and Clinic I of Internal Medicine and Center of Integrative Oncology Cologne-Bonn (G.F.-R.), Cologne, Germany.
Thomas G
TG
Forsthuber