Liver myofibroblasts regulate infiltration and positioning of lymphocytes in human liver.
OBJECTIVE
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.
Holt
Andrew P
AP
Liver Research Group, Institute of Biomedical Research, Division of Medicine, University of Birmingham, Birmingham, United Kingdom.
Haughton
Emma L
EL
Lalor
Patricia F
PF
Filer
Andrew
A
Buckley
Christopher D
CD
Adams
David H
DH
D002448:Cell Adhesion / Q000502:physiology; D002450:Cell Communication / Q000502:physiology*; D002465:Cell Movement / Q000502:physiology*; D002478:Cells, Cultured; D018925:Chemokines / Q000378:metabolism; D002634:Chemotaxis, Leukocyte / Q000502:physiology*; D016207:Cytokines / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000473:pathology / Q000502:physiology*; D055166:Hepatic Stellate Cells / Q000166:cytology / Q000378:metabolism / Q000473:pathology*; D006505:Hepatitis / Q000378:metabolism / Q000473:pathology; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000378:metabolism / Q000473:pathology*; D008214:Lymphocytes / Q000166:cytology / Q000473:pathology / Q000502:physiology*; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D018925:Chemokines; D016207:Cytokines; D015850:Interleukin-6; D019010:Vascular Cell Adhesion Molecule-1; D042461:Vascular Endothelial Growth Factor A; D018799:Intercellular Adhesion Molecule-1; D017228:Hepatocyte Growth Factor