Differential role of p38 in IL-1alpha induction of MMP-9 and MMP-13 in an established liver myofibroblast cell line.
Interleukin-1 (IL-1) has been implicated in the regulation of the expression of various matrix metalloproteinases (MMPs) in many mesenchymal cell types, but its role in liver myofibroblasts (MFs) has not been elucidated. A myofibroblast-like cell line, MG2, was derived from an isolate of rat hepatic stellate cells (HSCs). These cells expressed desmin, vimentin, smooth muscle alpha-actin, and fibulin-2. Using a recombinant IL-1alpha at 5 ng/ml, it was shown that IL-1alpha would upregulate, while IL-1Ra, an IL-1 receptor antagonist, would down-regulate the expression of IL-1alpha mRNA in MG2 cells, indicating the presence of an autostimulatory loop of IL-1alpha in these cells. Besides, a paracrine source of IL-1 may be produced from Kupffer cells, as we showed primarily cultured Kupffer cells responded much more remarkably than MG2 cells to lipopolysaccharide stimuli to produce both IL-1alpha and IL-1beta. Recombinant IL-1alpha upregulated the expression of both MMP-9 and -13, and the induction of MMP-13 but not MMP-9 could be inhibited by SB203580, an inhibitor of p38. Similarly, in primarily cultured human liver MFs, upregulation of MMP-1 by IL-1alpha was also shown to be inhibited by SB203580. All of these data suggested that, during liver inflammation, IL-1 produced by an autocrine model from MFs or by a paracrine model from Kupffer cells might play a crucial role in the remodeling of liver fibrosis through an either p38-dependent or p38-independent pathway to regulate the expression of various MMPs by liver MFs.
Lee
Hsuan-Shu
HS
Department of Internal Medicine, National Taiwan University Hospital, No. 7 Chang-Shan South Road, Taipei 100, Taiwan.
Miau
Luo-Hwa
LH
Chen
Chien-Hung
CH
Chiou
Ling-Ling
LL
Huang
Guan-Tarn
GT
Yang
Pei-Ming
PM
Sheu
Jin-Chuan
JC
D000818:Animals; D015152:Blotting, Northern; D002452:Cell Count; D045744:Cell Line, Tumor; D017364:Collagenases / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects*; D004797:Enzyme-Linked Immunosorbent Assay; D006652:Histological Techniques; D006801:Humans; D007093:Imidazoles / Q000378:metabolism; D007375:Interleukin-1 / Q000494:pharmacology*; D007728:Kupffer Cells / Q000187:drug effects; D008070:Lipopolysaccharides / Q000378:metabolism; D008103:Liver Cirrhosis / Q000503:physiopathology; D053509:Matrix Metalloproteinase 13; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011725:Pyridines / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation / Q000187:drug effects*; D048051:p38 Mitogen-Activated Protein Kinases
D007093:Imidazoles; D007375:Interleukin-1; D008070:Lipopolysaccharides; D011725:Pyridines; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D017364:Collagenases; C507079:MMP13 protein, human; D053509:Matrix Metalloproteinase 13; C507083:Mmp13 protein, rat; D020780:Matrix Metalloproteinase 9; C093642:SB 203580