Exogenous IL-6 inhibits acute inflammatory responses and prevents ischemia/reperfusion injury after intestinal transplantation.
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 degrees C. IL-6 mutein (IL-6m, 500 microg/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-beta, tumor necrosis factor-alpha (TNF-alpha) 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.
Kimizuka
Kei
K
Thomas E Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA 15261, USA.
Nakao
Atsunori
A
Nalesnik
Michael A
MA
Demetris
Anthony J
AJ
Uchiyama
Takashi
T
Ruppert
Kris
K
Fink
Mitchell P
MP
Stolz
Donna B
DB
Murase
Noriko
N
D000208:Acute Disease; D000818:Animals; D052160:Benzothiazoles; D015153:Blotting, Western; D016207:Cytokines / Q000096:biosynthesis / Q000378:metabolism; D003959:Diamines; D007150:Immunohistochemistry; D007249:Inflammation / Q000188:drug therapy*; D007375:Interleukin-1 / Q000096:biosynthesis; D015850:Interleukin-6 / Q000378:metabolism / Q000502:physiology*; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000098:blood supply / Q000473:pathology*; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008297:Male; D009154:Mutation; D009504:Neutrophils / Q000378:metabolism; D016377:Organ Transplantation / Q000379:methods*; D009930:Organic Chemicals / Q000494:pharmacology; D009195:Peroxidase / Q000378:metabolism; D011804:Quinolines; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D015427:Reperfusion Injury / Q000517:prevention & control*; D012097:Repressor Proteins / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D013997:Time Factors; D014157:Transcription Factors / Q000096:biosynthesis; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D015854:Up-Regulation
D052160:Benzothiazoles; D016207:Cytokines; D003959:Diamines; D007375:Interleukin-1; D015850:Interleukin-6; D009930:Organic Chemicals; D011804:Quinolines; D012333:RNA, Messenger; D012097:Repressor Proteins; C106644:SOCS3 protein, human; C491410:Socs3 protein, rat; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; C098022:SYBR Green I; D009195:Peroxidase