IL-10 increases tissue injury after selective intestinal ischemia/reperfusion

Ann Surg. 2003 Jul;238(1):49-58. doi: 10.1097/01.sla.0000074962.26074.d3.

Abstract

OBJECTIVE This study focused on the effect of immunoregulatory cytokines on tissue injury after intestinal ischemia/reperfusion (IR). Furthermore, the role of nitric oxide, heme oxygenase-1 (HO-1) and the transcription factor NF-kappaB/Rel in the disease process was evaluated.SUMMARY BACKGROUND DATA Oxidative stress and inflammatory gene products contribute to ischemia/reperfusion injury (IRI). However, expression of stress proteins such as the inducible nitric oxide synthase (NOS-2) and HO-1 might also provide protection against IRI. METHODS IR was achieved in Lewis rats by selective clamping of the superior mesenteric artery. IL-2 or IL-10 was administered intravenously before reperfusion. Animals were killed 1 hour, 4 hours, and 24 hours after reperfusion. Tissue destruction was assessed by hyaluronic acid (HA) and aminoaspartate-transaminase (AST) serum levels, whereas reduction of glutathione (GSH) tissue levels was used as a marker for oxidative stress. Furthermore, the activation of NF-kappaB/Rel and the expression of NOS-2 and HO-1 were analyzed.RESULTS IR resulted in tissue destruction and significantly reduced GSH tissue levels in the intestines and liver. In addition, NF-kappaB/Rel activation and increased NOS-2 and HO-1 mRNA expression were detected in both organs after IR. IL-2 administration resulted in clinical improvement of the animals and was associated with increased NF-kappaB/Rel activation and enhanced NOS-2 and HO-1 mRNA expression. In contrast, IL-10 resulted in increased tissue destruction in both organs and sustained reduction of GSH levels in the intestines. Furthermore, IL-10 administration failed to enhance NF-kappaB/Rel activity, NOS-2 mRNA, or HO-1 mRNA expression after IR. CONCLUSION IL-10 resulted in increased tissue damage after intestinal IR. This detrimental effect of IL-10 might have been the result of reduced NOS-2 and HO-1 mRNA expression. In contrast, the beneficial effect of IL-2 might have relied on increased HO-1 expression and NOS-2 activity. These controversial effects of IL-2 and IL-10 might have been mediated through transcriptional regulation of NOS-2 and HO-1 gene expression.

Publication types

  • Evaluation Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Gene Expression / drug effects
  • Glutathione / metabolism
  • Heme Oxygenase (Decyclizing) / biosynthesis
  • Heme Oxygenase-1
  • Interleukin-10 / pharmacology*
  • Interleukin-2 / pharmacology
  • Intestinal Mucosa / metabolism*
  • Liver / metabolism*
  • Male
  • Models, Animal
  • NF-kappa B / metabolism
  • Nitric Oxide / biosynthesis
  • Nitric Oxide Synthase / biosynthesis
  • Nitric Oxide Synthase Type II
  • Oxidative Stress / drug effects*
  • Oxidative Stress / physiology
  • Proto-Oncogene Proteins c-rel / metabolism
  • Rats
  • Rats, Inbred Lew
  • Reperfusion Injury / metabolism
  • Reperfusion Injury / physiopathology*

Substances

  • Interleukin-2
  • NF-kappa B
  • Proto-Oncogene Proteins c-rel
  • Interleukin-10
  • Nitric Oxide
  • Nitric Oxide Synthase
  • Nitric Oxide Synthase Type II
  • Nos2 protein, rat
  • Heme Oxygenase (Decyclizing)
  • Heme Oxygenase-1
  • Glutathione