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Am J Physiol Gastrointest Liver Physiol (July 7, 2005). doi:10.1152/ajpgi.00223.2005
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Submitted on May 17, 2005
Accepted on July 1, 2005

Divergent functions of CD4+ T Lymphocytes in Acute Liver Inflammation and Injury after Ischemia/Reperfusion

Charles C. Caldwell1, Tomohisa Okaya1, Andre Martignoni1, Thomas Husted1, Rebecca Schuster1, and Alex B. Lentsch1*

1 The Laboratory of Trauma, Sepsis & Inflammation Research, Department of Surgery, University of Cincinnati, Cincinnati, OH, USA

* To whom correspondence should be addressed. E-mail: alex.lentsch{at}uc.edu.

Hepatic ischemia/reperfusion results in an acute inflammatory response culminating in the recruitment of activated neutrophils which directly injure hepatocytes. Recent evidence suggests that CD4+ lymphocytes may regulate this neutrophil-dependent injury, but the mechanisms by which this occurs remain to be elucidated. In the present study, we sought to determine the type of CD4+ lymphocytes recruited to the liver after ischemia/reperfusion and the manner in which these cells regulated neutrophil recruitment and tissue injury. Wild-type and CD4-knockout (CD4-/-) mice were subjected to hepatic ischemia/reperfusion. CD4+ lymphocytes were recruited into the liver within 1 hour of reperfusion and remained for at least 4 hours. These cells were comprised of conventional ({alpha}{beta}TCR-expressing), unconventional ({gamma}{delta}TCR-expressing), and natural killer T cells. CD4-/- mice were then used to determine the functional role of CD4+ lymphocytes in hepatic ischemia/reperfusion injury. Compared to wild-type mice, CD4-/- mice had significantly greater liver injury, yet far less neutrophil accumulation. Adoptive transfer of CD4+ lymphocytes into CD4-/- mice recapitulated the wild-type response. In wild-type mice, neutralization of IL-17, a cytokine released by activated CD4+ lymphocytes, significantly reduced neutrophil recruitment in association with suppression of MIP-2 expression. Finally, oxidative burst activity of liver-recruited neutrophils was higher in CD4-/- mice compared to those from wild-type mice. These data suggest that CD4+ lymphocytes are rapidly recruited to the liver after ischemia/reperfusion and facilitate subsequent neutrophil recruitment via an IL-17-dependent mechanism. However, these cells also appear to attenuate neutrophil activation. Thus, the data suggest that CD4+ lymphocytes have dual, opposing roles in the hepatic inflammatory response to ischemia/reperfusion.




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