Macrophage migration inhibitory factor (MIF) is necessary for progression of autoimmune diabetes mellitus.
Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine of the innate immune system that plays a major role in the induction of immunoinflammatory responses. To examine the role of endogenous MIF in the pathogenesis of type 1 diabetes (TID) we evaluated the effects of administration of neutralizing anti-MIF antibodies to NOD mice with accelerated forms of diabetes induced by injection of cyclophosphamide or by transfer of diabetogenic spleen cells. Both accelerated forms of diabetes were markedly reduced by anti-MIF antibody. Furthermore, MIF-deficient (MIF(-/-)) mice were less susceptible to the induction of immunoinflammatory diabetes, insulitis and apoptosis within the endocrine pancreas by multiple low doses of streptozotocin (MLD-STZ) than genetically matched wild type (WT) mice. MIF deficiency resulted in lower proliferation and lymphocyte adhesion, as well as reduced production from the spleens and peritoneal cells of a variety of inflammatory mediators typically associated with development of the disease including IL-12, IL-23, TNF-alpha, and IL-1beta. Furthermore, MIF deletion affected the production of IL-18, TNF-alpha, IL-1beta, and iNOS in the islets of Langerhans. These data, along with the higher expression of IL-4 and TGF-beta observed in the periphery and in the pancreas of MLD-STZ-challenged MIF(-/-) mice as compared to WT controls suggest that MIF deficiency has induced an immune deviation towards protective type 2/3 response. These results suggest that MIF participates in T1D by controlling the functional activity of monocytes/macrophages and T cells and modulating their secretory capacity of pro- and anti-inflammatory molecules.
Stosic-Grujicic
Stanislava
S
Department of Immunology, Institute for Biological Research Sinisa Stankovic, Belgrade, Serbia. duta@eunet.yu
Stojanovic
Ivana
I
Maksimovic-Ivanic
Danijela
D
Momcilovic
Miljana
M
Popadic
Dusan
D
Harhaji
Ljubica
L
Miljkovic
Djordje
D
Metz
Christine
C
Mangano
Katia
K
Papaccio
Gianpaolo
G
Al-Abed
Yousef
Y
Nicoletti
Ferdinando
F
D019264:Adoptive Transfer; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000494:pharmacology; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000473:pathology*; D003922:Diabetes Mellitus, Type 1 / Q000139:chemically induced / Q000473:pathology*; D018450:Disease Progression; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D019746:Intramolecular Oxidoreductases / Q000172:deficiency / Q000378:metabolism*; D007515:Islets of Langerhans / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D007963:Leukocytes, Mononuclear / Q000187:drug effects; D008263:Macrophage Migration-Inhibitory Factors / Q000172:deficiency / Q000378:metabolism*; D051379:Mice; D016688:Mice, Inbred NOD; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013154:Spleen / Q000187:drug effects / Q000473:pathology; D013311:Streptozocin; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
D000911:Antibodies, Monoclonal; D016207:Cytokines; D008263:Macrophage Migration-Inhibitory Factors; D012333:RNA, Messenger; D009569:Nitric Oxide; C002744:3-nitrotyrosine; D014443:Tyrosine; D013311:Streptozocin; D003520:Cyclophosphamide; D052247:Nitric Oxide Synthase Type II; D019746:Intramolecular Oxidoreductases; C076231:Mif protein, mouse