Cytokines and nitric oxide in islet inflammation and diabetes.
Cytokines released by both T lymphocytes and activated macrophages, in particular interleukin-1 (IL-1), have been implicated as immunological effector molecules that both inhibit insulin secretion from the pancreatic beta cell and induce beta-cell destruction. Recent findings have demonstrated that production of the free radical nitric oxide (NO), resulting from the expression of the cytokine-inducible isoform of NO synthase (iNOS), mediates these deleterious effects. The cellular mechanism responsible for inhibition of beta-cell function and destruction by NO involves, in part, inactivation of enzymes specifically localized to the beta-cell mitochondria that contain iron- sulfur centers or clusters. Intraislet release of IL-1 also inhibits beta-cell function by this same cellular mechanism involving the overproduction of NO. In addition, the cytokine, IL-1, induces the co-expression of both iNOS and the cytokine-inducible isoform of cyclooxygenase, COX-2. The expression of COX-2 results in the overproduction of the proinflammatory prostaglandins and thromboxanes. Furthermore, NO produced by iNOS directly stimulates the activities of both constitutive and inducible isoforms of COX, further augmenting the overproduction of these proinflammatory mediators, NO and prostaglandins, which may be important in initiating or maintaining the inflammatory response and destruction of the beta cell associated with autoimmune diabetes.
McDaniel
M L
ML
Department of Pathology, Washington University School of Medicine, St. Louis, Missouri 63110-1010, USA.
Kwon
G
G
Hill
J R
JR
Marshall
C A
CA
Corbett
J A
JA
D000818:Animals; D016207:Cytokines / Q000502:physiology*; D003922:Diabetes Mellitus, Type 1 / Q000209:etiology*; D006801:Humans; D007249:Inflammation / Q000209:etiology*; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007375:Interleukin-1 / Q000494:pharmacology; D007515:Islets of Langerhans / Q000201:enzymology; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism
D016207:Cytokines; D007328:Insulin; D007375:Interleukin-1; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D011451:Prostaglandin-Endoperoxide Synthases