Enhanced interstitial collagenase (matrix metalloproteinase-13) production of Kupffer cell by gadolinium chloride prevents pig serum-induced rat liver fibrosis.
Hepatic fibrosis results from an imbalance between fibrogenesis and fibrolysis in the liver. It remains uninvestigated whether Kupffer cells produce matrix metalloproteinase-13 (MMP-13), which mainly hydrolyzes extracellular matrix (ECM). We sought to determine the role of Kupffer cells in fibrogenesis/fibrolysis. In vivo, we used the rat model of pig serum-induced liver fibrosis. A subset was treated with gadolinium chloride (GdCl(3)), which specifically acts on Kupffer cells. Administration of GdCl(3) remarkably decreased the hydroxyproline content of the liver and increased the expression of MMP-13 mRNA in the liver without a difference in procollagen type I and tissue inhibitors of metalloproteinase-1 (TIMP-1) mRNA expression on Northern blot analysis with the elimination of ED2-positive cells. In vitro, addition of GdCl(3) to isolated Kupffer cells showed increased type I collagen-degrading activity in a dose-dependent manner as well as MMP-13 mRNA expression on Northern blot analysis. It is concluded that Kupffer cells are a major source of MMP-13 and modulation of Kupffer cells by GdCl(3) prevents liver fibrosis with increased expression of MMP-13 mRNA and protein, whereas procollagen type I and TIMP-1 mRNA, which encode two major effectors of fibrogenesis, were unchanged. This is the first report showing that Kupffer cells produce interstitial collagenase (MMP-13) resulting in the reduction of ECM. This discovery may provide new insights into therapy for hepatic fibrosis.
Hironaka
K
K
School of Medicine, Yamaguchi University, Ube, Yamaguchi Prefecture, 755-8505, Japan.
Sakaida
I
I
Matsumura
Y
Y
Kaino
S
S
Miyamoto
K
K
Okita
K
K
D000818:Animals; D016913:Blood Component Transfusion; D017364:Collagenases / Q000235:genetics*; D005682:Gadolinium / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D007728:Kupffer Cells / Q000201:enzymology*; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*; D008106:Liver Cirrhosis, Experimental / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000235:genetics*; D053509:Matrix Metalloproteinase 13; D020782:Matrix Metalloproteinases / Q000235:genetics*; D011347:Procollagen / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D013552:Swine; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects
D011347:Procollagen; D012333:RNA, Messenger; D019715:Tissue Inhibitor of Metalloproteinase-1; D005682:Gadolinium; D017364:Collagenases; D053509:Matrix Metalloproteinase 13; D020782:Matrix Metalloproteinases; C507083:Mmp13 protein, rat; D020781:Matrix Metalloproteinase 1; C038958:gadolinium chloride