Lymphotoxin-beta Receptor Signaling Regulates Hepatic Stellate Cell Function and Wound Healing in a Murine Model of Chronic Liver Injury

Lymphotoxin-beta (LT beta) is a proinflammatory cytokine and a member of the tumor necrosis factor (TNF) superfamily known for its role in mediating lymph node development and homeostasis. Our recent studies suggest a role for LT beta in mediating the pathogenesis of human chronic liver disease. We hypothesize that LT beta co-ordinates the wound healing response in liver injury via direct effects on hepatic stellate cells. This study used the choline-deficient, ethionine-supplemented (CDE) dietary model of chronic liver injury, which induces inflammation, liver progenitor cell proliferation, and portal fibrosis, to assess (1) the cellular expression of LT beta, and (2) the role of LT beta receptor (LT beta R) in mediating wound healing, in LT beta R-/- versus wild-type mice. In addition, primary isolates of hepatic stellate cells were treated with LT beta R-ligands LT beta and LT beta-related inducible ligand competing for glycoprotein D binding to herpesvirus entry mediator on T cells (LIGHT), and mediators of hepatic stellate cell function and fibrogenesis were assessed. LT beta was localized to progenitor cells immediately adjacent to activated hepatic stellate cells in the periportal region of the liver in wild-type mice fed the CDE diet. LT beta R-/- mice fed the CDE diet showed significantly reduced fibrosis and a dysregulated immune response. LT beta R was demonstrated on isolated hepatic stellate cells, which when stimulated by LT)3 and LIGHT, activated the nuclear factor kappa B (NF-kappa B) signaling pathway. Neither LT beta nor LIGHT had any effect on alpha-smooth muscle actin, tissue inhibitor of metalloproteinase 1, transforming growth factor beta, or procollagen eel (I) expression; however, leukocyte recruitment-associated factors intercellular adhesion molecule I and regulated upon activation T cells expressed and secreted (RANTES) were markedly up-regulated. RANTES caused the chemotaxis of a Ever progenitor cell line expressing CCR5. Conclusion: This study suggests that LT beta R on hepatic stellate cells may be involved in paracrine signaling with nearby LT beta-expressing liver progenitor cells mediating recruitment of progenitor cells, hepatic stellate cells, and leukocytes required for wound healing and regeneration during chronic liver injury. (HEPATOLOGY 2009;49:227-239.)