IL-10 increases tissue injury after selective intestinal ischemia/reperfusion.
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.
Nüssler
Natascha C
NC
Department of Surgery, Charité, Campus Virchow-Klinikum, Humboldt University of Berlin, Augustenburger Platz 1, 13353 Berlin, Germany. natascha.nuessler@charite.de
Müller
Andrea R
AR
Weidenbach
Hans
H
Vergopoulos
Athanasios
A
Platz
Klaus P
KP
Volk
Hans-Dieter
HD
Neuhaus
Peter
P
Nussler
Andreas K
AK
D000818:Animals; D015870:Gene Expression / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism; D006419:Heme Oxygenase (Decyclizing) / Q000096:biosynthesis; D051547:Heme Oxygenase-1; D016753:Interleukin-10 / Q000494:pharmacology*; D007376:Interleukin-2 / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008297:Male; D023421:Models, Animal; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis; D019001:Nitric Oxide Synthase / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D020569:Proto-Oncogene Proteins c-rel / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D015427:Reperfusion Injury / Q000378:metabolism / Q000503:physiopathology*
D007376:Interleukin-2; D016328:NF-kappa B; D020569:Proto-Oncogene Proteins c-rel; D016753:Interleukin-10; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; D005978:Glutathione