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LIVER AND BILIARY TRACT

Hepatic leukocyte recruitment in response to time-limited expression of TNF- and IL-1

¹Department of Medicine, McMaster University, and ²The Henderson Research Center, Hamilton, Ontario, Canada

Submitted 8 February 2007 ; accepted in final form 18 July 2007

The development of chronic liver diseases is mediated by sustained hepatic inflammation. Our objective was to characterize the molecular mechanisms responsible for the hepatic inflammatory response to time-limited TNF- and IL-1 expression. C57Bl/6 mice were injected with 2 x 10⁷ plaque forming units intraperitoneally of an adenoviral vector containing TNF- or IL-1 (AdTNF- or AdIL-1). A nonreplicating adenoviral vector served as control. Four days later, under ketamine and xylazine anesthesia, the liver microvasculature was examined by intravital microscopy. In the postsinusoidal venules, leukocyte rolling increased significantly in response to both AdTNF- and AdIL-1, compared with controls. This response was significantly reduced following injection of an anti-₄-integrin monoclonal antibody (MAb). Postsinusoidal rolling was further reduced to baseline following injection of an anti-P-selectin or anti-L-selectin MAb. Sinusoidal adhesion was greater in mice treated with AdIL-1 than with AdTNF-. Blocking ₄-integrin, P-selectin, or L-selectin had no significant effect on sinusoidal or postsinusoidal adhesion. In separate experiments, we administered AdTNF- or AdIL-1 to mice deficient in ICAM-1. In ICAM-1–/– mice, postsinusoidal leukocyte rolling significantly increased following expression of IL-1 but not TNF-. AdIL-1- but not AdTNF--mediated sinusoidal adhesion was ICAM-1 dependent. AdTNF--induced sinusoidal adhesion was significantly reduced following 4 days of anti-MIP-2 MAb and anti-KC MAb. Prolonged expression of the cytokines TNF- and IL-1 increases hepatic leukocyte-endothelial cell interactions. Interestingly, the mechanisms through which these cytokines bring about adhesion within the sinusoids differ; AdIL-1 sinusoidal adhesion uses an ICAM-1-dependent mechanism whereas AdTNF--mediated adhesion is ICAM-1 independent but CXC chemokine dependent.

chemokine; hepatic sinusoid; intravital microscopy; adhesion molecules