CX3CL1/fractalkine shedding by human hepatic stellate cells: contribution to chronic inflammation in the liver.
Chemokines are the inflammatory mediators that modulate liver fibrosis, a common feature of chronic inflammatory liver diseases. CX3CL1/fractalkine is a membrane-associated chemokine that requires step processing for chemotactic activity and has been recently implicated in liver disease. Here, we investigated the potential shedding activities involved in the release of the soluble chemotactic peptides from CX3CL1 in the injured liver. We showed an increased expression of the sheddases ADAM10 and ADAM17 in patients with chronic liver diseases that was associated with the severity of liver fibrosis. We demonstrated that hepatic stellate cells (HSC) were an important source of ADAM10 and ADAM17 and that treatment with the inflammatory cytokine inter-feron-gamma induced the expression of CX3CL1 and release of soluble peptides. This release was inhibited by the metalloproteinase inhibitor batimastat; however, ADAM10/ADAM17 inhibitor GW280264X only partially affected shedding activity. By using selective tissue metalloprotease inhibitors and overexpression analyses, we showed that CX3CL1 was mainly processed by matrix metalloproteinase (MMP)-2, a metalloprotease highly expressed by HSC. We further demonstrated that the CX3CL1 soluble peptides released from stimulated HSC induced the activation of the CX3CR1-dependent signalling pathway and promoted chemoattraction of monocytes in vitro. We conclude that ADAM10, ADAM17 and MMP-2 synthesized by activated HSC mediate CX3CL1 shedding and release of chemotactic peptides, thereby facilitating recruitment of inflammatory cells and paracrine stimulation of HSC in chronic liver diseases.
INSERM U620/EA SeRAIC, University of Rennes, Rennes, France.
Katia
K
Bourd-Boittin
Laetitia
L
Basset
Dominique
D
Bonnier
Annie
A
L'helgoualc'h
Michel
M
Samson
Nathalie
N
Théret
D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism; D000072197:ADAM10 Protein; D000072198:ADAM17 Protein; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D054428:Chemokine CX3CL1 / Q000235:genetics / Q000378:metabolism*; D002908:Chronic Disease; D024042:Collagen Type I / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D055166:Hepatic Stellate Cells / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000378:metabolism* / Q000473:pathology*; D007371:Interferon-gamma / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D008103:Liver Cirrhosis / Q000201:enzymology / Q000473:pathology; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012995:Solubility / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
D054428:Chemokine CX3CL1; D024042:Collagen Type I; D008565:Membrane Proteins; D012333:RNA, Messenger; D007371:Interferon-gamma; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human