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. 2009 Jun;296(6):G1324-31.
doi: 10.1152/ajpgi.90564.2008. Epub 2009 Apr 2.

Interleukin-1 participates in the progression from liver injury to fibrosis

Roben G Gieling  1 , Karen Wallace, Yuan-Ping Han
Affiliations

Interleukin-1 participates in the progression from liver injury to fibrosis

Roben G Gieling et al. Am J Physiol Gastrointest Liver Physiol. 2009 Jun.

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.

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Figures

Fig. 1.
Fig. 1.
Early events in liver injury and fibrogenesis. A: hematoxylin and eosin (H and E) staining. FVB, C57BL/6, and BALB/c mice (n = 6 per experimental condition) were injected intraperitoneally with saline or thioacetamide (TAA) (0.2 mg/g body wt ip), and livers were harvested at the indicated time points. B: alanine transaminase (ALT) level in the serum. C: zymography of liver tissues. D: double immunofluorescent staining of liver tissue at day 3. Matrix metalloproteinase (MMP)-9 is expressed by desmin-positive cells with cytoplasmic extensions, the typical phenotypes of hepatic stellate cells (HSCs) in liver. E: real-time RT-PCR analysis of liver tissues. The gene expression levels are normalized by the mRNA of GAPDH. *P < 0.05 between groups indicated in graph. F: Western blot analysis of liver tissues. The positive control is the cell lysate from rat primary HSCs cultured on plastic for 5 days, by which the quiescent cells are converted to myofibroblasts. G: proposed schematic model of the chronological events in the liver injury, HSC activation, and fibrogenesis. TIMP, tissue inhibitor of MMP; SMA, smooth muscle actin; ECM, extracellular matrix.
Fig. 2.
Fig. 2.
IL-1 in liver injury and onset of fibrogenesis. A: H and E staining. C57BL/6 and IL-1R knockout (KO) (n = 6 per group) were subjected to TAA injection (intraperitoneally), and the livers were harvested at 24 h. B: time course of ALT levels in serum. C: zymography of liver tissue. D: real-time RT-PCR analysis of liver tissues. E: Western blot of liver tissue. *P < 0.05 between groups indicated in graph. WT, wild-type.
Fig. 3.
Fig. 3.
IL-1 in advanced liver fibrosis. A: Sirius red staining. The C57BL/6 and IL-1R KO mice (n = 6 per group) were subjected to TAA (0.2 mg/g body wt) twice a week for 8 wk. B: densitometry scanning of fibrotic region. C: Western blot analysis of α-SMA. D: real-time RT-PCR analysis. E: zymography. To reveal weak gelatinases in the fibrotic liver, this gel was developed for 48 h rather than the standard 24 h, as used in other experiments. F: mRNA levels of MMP-9 in liver of acute vs. chronic TAA treatment. *P < 0.05 between groups indicated in graph.
Fig. 4.
Fig. 4.
MMP-9 in liver injury and early fibrogenesis. A: H and E staining. FVB and MMP-9 KO mice (n = 6 per group) were injected with TAA (0.2 mg/g body wt ip) and euthanized at the indicated time points. B: zymography analysis of liver tissues. C: ALT levels of serum. D: real-time RT-PCR analysis. E: Western blot analysis of liver tissues. F: quantification of α-SMA by densitometry scanning. *P < 0.05 as statistically significant.
Fig. 5.
Fig. 5.
MMP-9 in advanced liver fibrosis. A: FVB and MMP-9 KO mice (n = 6 for each group) were injected with TAA (0.2 mg/g body wt ip) twice a week for 8 wk. Sirius red staining of the liver tissue. B: real-time RT-PCR analysis of the liver tissue of the mice subjected to TAA for 8 wk. C: zymography of liver tissue. FVB and MMP-9 KO mice were subjected to bile duct ligation for 4 wk (n = 8 per group). D: H and E staining of the liver tissues. *P < 0.05 as statistically significant.
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