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

Abstract

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-α and IL-1β expression. C57Bl/6 mice were injected with 2 × 107plaque forming units intraperitoneally of an adenoviral vector containing TNF-α or IL-1β (AdTNF-α or AdIL-1β). 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-α and AdIL-1β, compared with controls. This response was significantly reduced following injection of an anti-α4-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-1β than with AdTNF-α. Blocking α4-integrin, P-selectin, or L-selectin had no significant effect on sinusoidal or postsinusoidal adhesion. In separate experiments, we administered AdTNF-α or AdIL-1β to mice deficient in ICAM-1. In ICAM-1−/− mice, postsinusoidal leukocyte rolling significantly increased following expression of IL-1β but not TNF-α. AdIL-1β- but not AdTNF-α-mediated sinusoidal adhesion was ICAM-1 dependent. AdTNF-α-induced sinusoidal adhesion was significantly reduced following 4 days of anti-MIP-2 MAb and anti-KC MAb. Prolonged expression of the cytokines TNF-α and IL-1β increases hepatic leukocyte-endothelial cell interactions. Interestingly, the mechanisms through which these cytokines bring about adhesion within the sinusoids differ; AdIL-1β sinusoidal adhesion uses an ICAM-1-dependent mechanism whereas AdTNF-α-mediated adhesion is ICAM-1 independent but CXC chemokine dependent.

CD40 Mediates Retinal Inflammation and Neurovascular Degeneration

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Activation of hepatic stellate cells is associated with cytokine expression in thioacetamide-induced hepatic fibrosis in mice

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Intravital 2-photon imaging of leukocyte trafficking in beating heart

“…(A, Supplemental Video 9) Sequential video-rate frames of 2 neutrophils (yellow arrowhead with yellow track and white arrowhead with white track) moving through a coronary artery. The measured speed of the neutrophil marked in yellow is 1875. independently of ICAM-1 (19,20). ICAM-1 is upregulated on endothelial cells of coronary vessels following ischemia, which is in large part due to the release of proinflammatory cytokines such as TNF-α (21,22).…”