Abstract
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.
MeSH terms
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Age Factors
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Animals
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Antigens, CD / biosynthesis
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Antigens, CD / genetics
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B7-2 Antigen
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Chemokine CXCL10
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Chemokines, CXC / biosynthesis
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Chemokines, CXC / genetics
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Cytokines / biosynthesis
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Diabetes Mellitus, Type 1 / epidemiology
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Diabetes Mellitus, Type 1 / immunology*
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Diabetes Mellitus, Type 1 / pathology*
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Diabetes Mellitus, Type 1 / physiopathology
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Female
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Genetic Vectors
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Glutamate Decarboxylase / metabolism
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Incidence
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Injections, Intramuscular
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Interferon-gamma / biosynthesis
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Interleukin-12 / biosynthesis
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Interleukin-12 / genetics
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Interleukin-12 Subunit p40
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Interleukin-18 / administration & dosage*
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Interleukin-18 / blood
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Interleukin-18 / genetics
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Islets of Langerhans / immunology
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Islets of Langerhans / pathology
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Lymphocyte Count
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Membrane Glycoproteins / biosynthesis
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Membrane Glycoproteins / genetics
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Mice
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Mice, Inbred NOD
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Pancreas / immunology
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Pancreas / metabolism
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Plasmids
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Protein Subunits / biosynthesis
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Protein Subunits / genetics
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RNA, Messenger / analysis
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RNA, Messenger / biosynthesis
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Reverse Transcriptase Polymerase Chain Reaction
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Severity of Illness Index
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Th1 Cells / enzymology
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Th1 Cells / immunology
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Th1 Cells / metabolism
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Up-Regulation / immunology
Substances
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Antigens, CD
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B7-2 Antigen
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Cd86 protein, mouse
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Chemokine CXCL10
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Chemokines, CXC
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Cytokines
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Interleukin-12 Subunit p40
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Interleukin-18
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Membrane Glycoproteins
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Protein Subunits
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RNA, Messenger
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Interleukin-12
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Interferon-gamma
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Glutamate Decarboxylase