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BACKGROUND & AIMS: The recruitment of lymphocytes to tissues via endothelium has been studied extensively but less is known about the signals that direct migration and positioning within tissues. Liver myofibroblasts associate with lymphocytes in hepatitis and are positioned below the sinusoidal endothelium, through which lymphocytes are recruited to the liver. We investigated whether activated human liver myofibroblasts (aLMF) affect the migration and accumulation of lymphocytes within the inflamed liver. METHODS: The ability of human aLMF and hepatic stellate cells to promote lymphocyte chemotaxis, adhesion, and migration was studied in vitro. RESULTS: When cultured in vitro, aLMF from diseased human liver and hepatic stellate cells from noninflamed liver secrete a distinct profile of cytokines comprising interleukin (IL)-6, IL-12, hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF), and the chemokines CCL2, CCL3, CCL5, CXCL8, CXCL9, and CXCL10. aLMF-conditioned media had chemotactic activity for lymphocytes, which partially was inhibited by pertussis toxin. IL-6, HGF, and VEGF all contributed to G-protein-coupled receptor-independent chemotaxis of lymphocytes. Lymphocytes adhered to aLMF via intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 and a proportion of adherent cells migrated through the fibroblast monolayer, mediated by IL-6, HGF, and VEGF. CONCLUSIONS: Human aLMF support G-protein coupled receptor-dependent and -independent lymphocyte adhesion and migration and thereby regulate the recruitment and positioning of lymphocytes in chronic hepatitis.

Original publication

DOI

10.1053/j.gastro.2008.10.020

Type

Journal article

Journal

Gastroenterology

Publication Date

02/2009

Volume

136

Pages

705 - 714

Keywords

Cell Adhesion, Cell Communication, Cell Movement, Cells, Cultured, Chemokines, Chemotaxis, Leukocyte, Cytokines, Fibroblasts, Hepatic Stellate Cells, Hepatitis, Hepatocyte Growth Factor, Humans, Intercellular Adhesion Molecule-1, Interleukin-6, Liver, Lymphocytes, Vascular Cell Adhesion Molecule-1, Vascular Endothelial Growth Factor A