Heat shock inhibits cytokine-induced nitric oxide synthase expression by rat and human islets

Endocrinology. 1998 Dec;139(12):5050-7. doi: 10.1210/endo.139.12.6366.


In this study the effects of heat shock on interleukin-1beta (IL-1)-induced inhibition of islet metabolic function were examined. Treatment of rat islets for 18 h with IL-1 results in a potent inhibition of glucose-stimulated insulin secretion. The inhibitory effects of IL-1 on insulin secretion are completely prevented if islets are pretreated for 60 min at 42 C before cytokine stimulation. Heat shock also prevents IL-1-induced inhibition of insulinoma RINm5F cell mitochondrial aconitase activity. The protective effects of heat shock on islet metabolic function are associated with the inhibition of IL-1-stimulated inducible nitric oxide synthase (iNOS or NOS II) expression. Islets heat shocked for 60 min at 42 C fail to express iNOS (messenger RNA or protein) or produce nitrite in response to IL-1. IL-1-induced iNOS expression by rat islets requires activation of the transcriptional regulator nuclear factor kappaB (NF-kappaB). Heat shock prevents IL-1-induced NF-kappaB nuclear localization by inhibiting inhibitory protein kappaB (IkappaB) degradation in rat islets. Similar to rat islets, heat shock (stimulated by 90 min incubation at 42 C) prevents IL-1 + interferon gamma-induced iNOS expression and NF-kappaB nuclear localization in human islets. IL-1 also stimulates heat-shock protein 70 (hsp 70) expression by rat islets, and hsp 70 expression is dependent on islet production of nitric oxide. Last, evidence is presented that implicates nitric oxide as a stimulus for the expression of proteins that participate in islet recovery from nitric oxide-mediated damage. These studies indicate that heat shock prevents cytokine-induced islet damage by inhibiting iNOS expression, and suggest that nitric oxide is one effector molecule that stimulates the expression of factors involved in beta-cell recovery from nitric oxide-mediated damage.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Aconitate Hydratase / metabolism
  • Animals
  • Cytokines / pharmacology*
  • DNA-Binding Proteins / metabolism
  • HSP70 Heat-Shock Proteins / metabolism
  • Hot Temperature*
  • Humans
  • Hydrazines / pharmacology
  • I-kappa B Proteins
  • Insulin / metabolism
  • Insulin Secretion
  • Interleukin-1 / pharmacology
  • Islets of Langerhans / enzymology*
  • Islets of Langerhans / metabolism
  • Male
  • Mitochondria / enzymology
  • NF-kappa B / metabolism
  • Nitric Oxide Synthase / antagonists & inhibitors*
  • Nitric Oxide Synthase / genetics
  • Nitric Oxide Synthase / metabolism
  • Nitric Oxide Synthase Type II
  • Nitrogen Oxides
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Shock / enzymology*


  • Cytokines
  • DNA-Binding Proteins
  • HSP70 Heat-Shock Proteins
  • Hydrazines
  • I-kappa B Proteins
  • Insulin
  • Interleukin-1
  • NF-kappa B
  • Nitrogen Oxides
  • RNA, Messenger
  • 1,1-diethyl-2-hydroxy-2-nitrosohydrazine
  • NOS2 protein, human
  • Nitric Oxide Synthase
  • Nitric Oxide Synthase Type II
  • Nos2 protein, rat
  • Aconitate Hydratase