Exogenous IL-6 Inhibits Acute Inflammatory Responses and Prevents Ischemia/Reperfusion Injury after Intestinal Transplantation

Kei Kimizuka, Atsunori Nakao, Michael A. Nalesnik, Anthony J. Demetris, Takashi Uchiyama, Kris Ruppert, Mitchell P. Fink, Donna B. Stolz, Noriko Murase

Research output: Contribution to journalArticle

46 Citations (Scopus)

Abstract

Interleukin-6 (IL-6) is a pleiotropic acute reactant cytokine involved in inflammatory responses. To explore the role of IL-6 in inflammation, this study examined the efficacy of exogenous IL-6 in preventing intestinal ischemia/reperfusion (I/R) injury associated with small bowel transplantation (SBTx). Syngenic orthotopic SBTx was performed in Lewis rats after 6-h graft preservation in University of Wisconsin (UW) at 4 °C. IL-6 mutein (IL-6m, 500 μg/kg), a recombinant molecular variant of human IL-6, was subcutaneously given to donors 2 h before harvesting (IL-6mD) or to excised grafts by luminal infusion (IL-6mG). Animal survival was 100% and 75% in IL-6mD (p < 0.05 vs. control) and IL-6mG groups, respectively, compared with 64.3% in untreated controls. The severity of I/R injury (e.g. epithelial denudation, villous congestion) was reduced with IL-6m, in addition to a striking increase in re-epithelization. With IL-6m, neutrophil extravasation was markedly reduced in intestinal grafts and in remote organs (e.g. lung). IL-6m mediated anti-inflammatory effects through the inhibition of I/R-induced up-regulation of intragraft and circulating IL-1-β, tumor necrosis factor-α (TNF-α) and IL-6. IL-6m also increased intestinal graft tissue blood flow. These results show that IL-6 is effective in protecting the intestine from cold I/R injury by maintaining graft blood flow and reducing pro-inflammatory cytokine up-regulation and neutrophil infiltration.

Original languageEnglish
Pages (from-to)482-494
Number of pages13
JournalAmerican Journal of Transplantation
Volume4
Issue number4
DOIs
Publication statusPublished - Apr 2004
Externally publishedYes

Keywords

  • IL-6
  • Intestinal transplantation
  • Ischemia/reperfusion injury
  • Polymorphonuclear neutrophiric granulocyte infiltration
  • Tight junction proteins

ASJC Scopus subject areas

  • Immunology and Allergy
  • Transplantation
  • Pharmacology (medical)

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