CYCLOPHOSPHAMIDE TREATMENT OF FEMALE NONOBESE DIABETIC MICE CAUSES ENHANCED EXPRESSION OF INDUCIBLE NITRIC-OXIDE SYNTHASE AND INTERFERON-GAMMA, BUT NOT OF INTERLEUKIN-4

In pancreatic lesions of non-obese diabetic (NOD) mice the expression of inducible nitric oxide synthase (iNOS) and of the cytokines interfe ron-gamma and interleukin-4 were studied. Strong iNOS expression as de termined at the level of transcription, translation and of enzyme acti vity was associated with destructive insulitis as seen 8-10 days after cyclophosphamide treatment of 70- to 80-day-old female NOD mice. Immu nohistochemistry showed iNOS associated with infiltrating macrophages but not in endocrine cells. The enhancement of iNOS after cyclophospha mide correlated with an increase of T-helper type 1 (Th1) associated i nterferon-gamma expression while T-helper type 2 (Th2) associated inte rleukin-4 was the dominant cytokine prior to cyclophosphamide and afte r diabetes onset. We conclude that insulitis in young NOD mice is carr ied by Th2 cells while cyclophosphamide enhanced insulitis is determin ed by Th1 cells. Macrophages show two different functional states in i nsulitis; strong iNOS expression in macrophages is associated with des tructive insulitis.