The chemokine CCL21 modulates lymphocyte recruitment and fibrosis in chronic hepatitis C.
OBJECTIVE
The chemokines CCL19 and CCL21 bind CCR7, which is involved in the organization of secondary lymphoid tissue and is expressed during chronic tissue inflammation. We investigated the expression of CCL21 and CCR7 in chronic hepatitis C. The effects of CCL21 on hepatic stellate cells (HSCs) were also studied.


METHODS
Expression of CCL21 was assessed by in situ hybridization and immunohistochemistry. CCR7 on T cells was analyzed by flow cytometry. Cultured human HSCs were studied in their activated phenotype.


RESULTS
In patients with chronic hepatitis C, expression of CCL21 and CCR7 was up-regulated. CCL21 was detected in the portal tracts and around inflammatory lymphoid follicles, in proximity to T lymphocytes and dendritic cells, which contributed to expression of this chemokine. Expression of CCR7 was also increased in patients with primary biliary cirrhosis. Intrahepatic CD8(+) T lymphocytes isolated from patients with chronic hepatitis C had a significantly higher percentage of positivity for CCR7 than those from healthy controls, and the expression of CCR7 was associated with that of CXCR3. Cultured HSCs expressed functional CCR7, the activation of which stimulated cell migration and accelerated wound healing in an in vitro model. Exposure of HSCs to CCL21 triggered several signaling pathways, including extracellular signal-regulated kinase, Akt, and nuclear factor kappaB, resulting in induction of proinflammatory genes.


CONCLUSIONS
Expression of CCL21 during chronic hepatitis C is implicated in the recruitment of T lymphocytes and the organization of inflammatory lymphoid tissue and may promote fibrogenesis in the inflamed areas via activation of CCR7 on HSCs.
D002465:Cell Movement / Q000187:drug effects / Q000276:immunology*; D002467:Cell Nucleus / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D054421:Chemokine CCL21; D019742:Chemokines, CC / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D015870:Gene Expression / Q000276:immunology; D019698:Hepatitis C, Chronic / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D008099:Liver / Q000166:cytology; D008103:Liver Cirrhosis / Q000276:immunology* / Q000473:pathology / Q000821:virology; D008221:Lymphoid Tissue / Q000276:immunology / Q000473:pathology; D048370:MAP Kinase Kinase 2; D048728:MAP Kinase Kinase Kinase 1; D020935:MAP Kinase Signaling System / Q000276:immunology; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D054400:Receptors, CCR7; D019707:Receptors, Chemokine / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D013601:T-Lymphocytes / Q000473:pathology* / Q000502:physiology
C515478:CCL21 protein, human; C515370:CCR7 protein, human; D054421:Chemokine CCL21; D019742:Chemokines, CC; D016328:NF-kappa B; D054400:Receptors, CCR7; D019707:Receptors, Chemokine; D011994:Recombinant Proteins; C482128:MAP2K2 protein, human; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D020928:Mitogen-Activated Protein Kinases; D048728:MAP Kinase Kinase Kinase 1; C482576:MAP3K1 protein, human; D048370:MAP Kinase Kinase 2; D020929:Mitogen-Activated Protein Kinase Kinases