Interleukin-12 gene expression is associated with rapid development of diabetes mellitus in non-obese diabetic mice.
A single dose of cyclophosphamide (250 mg/kg) is known to synchronize and accelerate development of diabetes in non-obese diabetic mice. We have reported previously that cyclophosphamide treatment of 10-week-old female non-obese diabetic mice induces a shift from T-helper type 2 to T-helper type 1 activity in islet lesions. We now show that this shift in regulatory T-cell function is preceded by the expression of interleukin-12 in the islets as well as in the spleen. In the spleen macrophages were identified as the interleukin-12 expressing cell type. At the same time there was little induction of tumour necrosis factor alpha gene expression by macrophages. Since interleukin-12 is well known to drive T-helper cell type 1 responses we assume that interleukin-12 released by macrophages mediates the accelerating effect of cyclophosphamide on islet inflammation in non-obese diabetic mice. mRNA expression of the p40 chain of interleukin-12 in response to cyclophosphamide was not seen in macrophages of Balb/c mice and thus represents an immune abnormality of non-obese diabetic mice favouring T-helper type 1 reactions.
Rothe
H
H
Diabetes Research Institute, Heinrich-Heine University, Düsseldorf, Germany.
Burkart
V
V
Faust
A
A
Kolb
H
H
D000818:Animals; D001483:Base Sequence; D003520:Cyclophosphamide / Q000494:pharmacology; D017931:DNA Primers; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology / Q000503:physiopathology*; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000494:pharmacology; D018664:Interleukin-12 / Q000096:biosynthesis*; D007700:Kinetics; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D008969:Molecular Sequence Data; D010179:Pancreas / Q000187:drug effects / Q000276:immunology; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis; D013154:Spleen / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology
D017931:DNA Primers; D007166:Immunosuppressive Agents; D012333:RNA, Messenger; D018664:Interleukin-12; D003520:Cyclophosphamide