Interleukin-1 participates in the progression from liver injury to fibrosis
- 1 June 2009
- journal article
- research article
- Published by American Physiological Society in American Journal of Physiology-Gastrointestinal and Liver Physiology
- Vol. 296 (6), G1324-G1331
- https://doi.org/10.1152/ajpgi.90564.2008
Abstract
Interleukin-1 (IL-1) is rapidly expressed in response to tissue damage; however, its role in coordinating the progression from injury to fibrogenesis is not fully understood. Liver fibrosis is a consequence of the activation of hepatic stellate cells (HSCs), which reside within the extracellular matrix (ECM) of subsinusoids. We have hypothesized that, among the hepatic inflammatory cytokines, IL-1 may directly activate HSCs through autocrine signaling and stimulate the matrix metalloproteinases (MMPs) produced by HSCs within the space of Disse, resulting in liver fibrogenesis. In this study, we first established a temporal relationship between IL-1, MMPs, HSC activation, and early fibrosis. The roles of IL-1 and MMP-9 in HSC activation and fibrogenesis were determined by mice deficient of these genes. After liver injury, IL-1, MMP-9, and MMP-13 levels were found to be elevated before the onset of HSC activation and fibrogenesis. IL-1 receptor-deficient mice exhibited ameliorated liver damage and reduced fibrogenesis. Similarly, advanced fibrosis, as determined by type-I and -III collagen mRNA expression and fibrotic septa, was partially attenuated by the deficiency of IL-1. In the early phase of liver injury, the MMP-9, MMP-13, and TIMP-1 expression correlated well with IL-1 levels. In injured livers, MMP-9 was predominantly colocalized to desmin-positive cells, suggesting that HSCs are MMP-producing cells in vivo. MMP-9-deficient mice were partially protected from liver injury and HSC activation. Thus IL-1 is an important participant, along with other cytokines, and controls the progression from liver injury to fibrogenesis through activation of HSCs in vivo.Keywords
This publication has 46 references indexed in Scilit:
- A Matrix Metalloproteinase-9 Activation Cascade by Hepatic Stellate Cells in Trans-differentiation in the Three-dimensional Extracellular MatrixJournal of Biological Chemistry, 2007
- Matrix metalloproteinases and the regulation of tissue remodellingNature Reviews Molecular Cell Biology, 2007
- Matrix metalloproteinases, the pros and cons, in liver fibrosisJournal of Gastroenterology and Hepatology, 2006
- Reduced peribronchial fibrosis in allergen-challenged MMP-9-deficient miceAmerican Journal of Physiology-Lung Cellular and Molecular Physiology, 2006
- Liver fibrosis induced by hepatic overexpression of PDGF-B in transgenic miceJournal of Hepatology, 2006
- Interleukin-1β induces human proximal tubule cell injury, α-smooth muscle actin expression and fibronectin production1Kidney International, 2002
- Inflammatory Cytokines, Angiogenesis, and Fibrosis in the Rat PeritoneumThe American Journal of Pathology, 2002
- The role of TGFβ1 in initiating hepatic stellate cell activation in vivoJournal of Hepatology, 1999
- Temporal and spatial patterns of transin/stromelysin RNA expression following toxic injury in rat liverVirchows Archiv B Cell Pathology Including Molecular Pathology, 1991
- Collagen Type I and Iii Occur Together in Hybrid Fibrils in the Space of Disse of Normal Rat LiverHepatology, 1990