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

Hepatic leukocyte recruitment in response to time-limited expression of TNF-alpha and IL- 1 beta. Am J Physiol Gastrointest Liver Physiol 293: G663-G672, 2007. First published July 26, 2007; doi:10.1152/ajpgi.00070.2007. -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-alpha and IL- 1 beta expression. C57Bl/6 mice were injected with 2 x 107 plaque forming units intraperitoneally of an adenoviral vector containing TNF-alpha or IL-1 beta (AdTNF-alpha or AdIL-1 beta). 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-alpha and AdIL-1 beta, compared with controls. This response was significantly reduced following injection of an anti-alpha(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 beta than with AdTNF-alpha. Blocking alpha(4)-integrin, P-selectin, or L-selectin had no significant effect on sinusoidal or postsinusoidal adhesion. In separate experiments, we administered AdTNF-alpha or AdIL-1 beta to mice deficient in ICAM-1. In ICAM- 1 -/- mice, postsinusoidal leukocyte rolling significantly increased following expression of IL-1 beta but not TNF-alpha. AdIL-1 beta- but not AdTNF-alpha-mediated sinusoidal adhesion was ICAM-1 dependent. AdTNF-alpha-induced sinusoidal adhesion was significantly reduced following 4 days of anti-MIP-2 MAb and anti-KC MAb. Prolonged expression of the cytokines TNF-alpha and IL-1 beta increases hepatic leukocyte-endothelial cell interactions. Interestingly, the mechanisms through which these cytokines bring about adhesion within the sinusoids differ; AdIL-1 beta sinusoidal adhesion uses an ICAM-1-dependent mechanism whereas AdTNF-alpha-mediated adhesion is ICAM-1 independent but CXC chemokine dependent.