Systemic administration of IL-18 promotes diabetes development in young nonobese diabetic mice.
IL-18 is now identified as a pleiotropic cytokine that acts as a cofactor for both Th1 and Th2 cell development. Type 1 diabetes is considered a Th1-type autoimmune disease, and to date, the suppressive effect of exogenous IL-18 on the development of diabetes has been reported in 10-wk-old nonobese diabetic (NOD) mice. In the present study we administered exogenous IL-18 systemically in 4-wk-old NOD mice using i.m. injection of the IL-18 expression plasmid DNA (pCAGGS-IL-18) with electroporation. Contrary to previous reports, the incidence of diabetes development was significantly increased in NOD mice injected with pCAGGS-IL-18 compared with that in control mice. Systemic and pancreatic cytokine profiles deviated to a Th1-dominant state, and the the frequency of glutamic acid decarboxylase-reactive IFN-gamma-producing CD4(+) cells was also high in the IL-18 group. Moreover, it was suggested that the promoting effect of IL-18 might be associated with increased peripheral IL-12, CD86, and pancreatic IFN-inducible protein-10 mRNA expression levels. In conclusion, we demonstrate here that IL-18 plays a promoting role as an enhancer of Th1-type immune responses in diabetes development early in the spontaneous disease process, which may contribute to elucidating the pathogenesis of type 1 diabetes.
Oikawa
Yoichi
Y
Department of Internal Medicine, Keio University School of Medicine, Department of Internal Medicine, Tokyo Denryoku Hospital, Japan.
Shimada
Akira
A
Kasuga
Akira
A
Morimoto
Jiro
J
Osaki
Tadashi
T
Tahara
Hideaki
H
Miyazaki
Tatsushi
T
Tashiro
Fumi
F
Yamato
Eiji
E
Miyazaki
Jun-Ichi
J
Saruta
Takao
T
D000367:Age Factors; D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis / Q000235:genetics; D051940:B7-2 Antigen; D054357:Chemokine CXCL10; D019743:Chemokines, CXC / Q000096:biosynthesis / Q000235:genetics; D016207:Cytokines / Q000096:biosynthesis; D003922:Diabetes Mellitus, Type 1 / Q000453:epidemiology / Q000276:immunology* / Q000473:pathology* / Q000503:physiopathology; D005260:Female; D005822:Genetic Vectors; D005968:Glutamate Decarboxylase / Q000378:metabolism; D015994:Incidence; D007273:Injections, Intramuscular; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000096:biosynthesis / Q000235:genetics; D053762:Interleukin-12 Subunit p40; D020382:Interleukin-18 / Q000008:administration & dosage* / Q000097:blood / Q000235:genetics; D007515:Islets of Langerhans / Q000276:immunology / Q000473:pathology; D018655:Lymphocyte Count; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D016688:Mice, Inbred NOD; D010179:Pancreas / Q000276:immunology / Q000378:metabolism; D010957:Plasmids; D021122:Protein Subunits / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012720:Severity of Illness Index; D018417:Th1 Cells / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D015854:Up-Regulation / Q000276:immunology
D015703:Antigens, CD; D051940:B7-2 Antigen; C497965:Cd86 protein, mouse; D054357:Chemokine CXCL10; D019743:Chemokines, CXC; D016207:Cytokines; D053762:Interleukin-12 Subunit p40; D020382:Interleukin-18; D008562:Membrane Glycoproteins; D021122:Protein Subunits; D012333:RNA, Messenger; D018664:Interleukin-12; D007371:Interferon-gamma; D005968:Glutamate Decarboxylase