THE HARMONY OF THE SPHERES - INDUCIBLE NITRIC-OXIDE SYNTHASE AND RELATED GENES IN PANCREATIC BETA-CELLS

The radical nitric oxide (NO) is a possible mediator of pancreatic bet a-cell damage in insulin-dependent diabetes mellitus (IDDM). NO is pro duced by the enzyme nitric oxide synthase (NOS), in a reaction where a rginine is the main substrate. There are different isoforms of NOS, bu t in the context of immune mediated beta-cell damage the inducible for m of NOS (iNOS) is the most relevant. The beta-cell iNOS is similar an d encoded by the same gene on chromosome 17 as the iNOS expressed in m acrophages and other nucleated cells. iNOS activation depends on gene transcription and de novo enzyme synthesis, and NO seems to induce a n egative feedback on iNOS expression. While iNOS mRNA is induced by int erleukin-1 beta (IL-1 beta) alone in rodent insulin-producing cells, a combination of two (IL-1 beta + interferon gamma) (IFN-gamma) or thre e (IL-1 beta + IFN gamma + tumour necrosis factor alpha) cytokines is required for iNOS activation in human pancreatic islets. The promoter region of the murine iNOS gene has at least 25 binding sites for diffe rent transcription factors, and the nuclear transcription factor kappa B is necessary for cytokine-induced iNOS transcription in both rodent and human pancreatic islets. The nature of other transcription factor s relevant for iNOS regulation in these cells remains to be determined , Induction of iNOS is paralleled by induction of several other cytoki ne-dependent genes in beta cells, including argininosuccinate syntheta se, cyclooxygenase and manganese superoxide dismutase. Some of these g enes may contribute to beta-cell damage, while others are probably inv olved in beta-cell defence and/or repair. Regulation of iNOS and other related genes in beta cells is complex, and differs in several aspect s from that observed in macrophages. There are also important differen ces in iNOS regulation between rodent and human pancreatic islets. A d etailed knowledge of the molecular regulation of these genes in beta c ells may be instrumental in the development of new approaches to preve nt beta-cell destruction in early IDDM.