Immunohistochemical study of macrophage migration inhibitory factor in rat liver fibrosis induced by thioacetamide

Hori, Yuuka; Sato, Shin; Yamate, Jyoji; Kurasaki, Masaaki; Nishihira, Jun; Hosokawa, Tsunemichi; Fujita, Hiroshi; Saito, Takeshi

doi:10.4081/842

Cited by 22 publications

(20 citation statements)

References 25 publications

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“…After this initial early increase in plasma MIF, hepatic MIF mRNA increased, followed by a second peak of plasma MIF content at 48 h post-CCl 4 administration. These data suggest that MIF is acting in the liver and systemically, consistent with a previous report of increased MIF expression, followed by the appearance of macrophages near fibrotic scars in rat liver during thioacetamide-induced fibrosis [41].…”

Section: Discussionsupporting

confidence: 92%

Macrophage migration inhibitory factor is required for recruitment of scar-associated macrophages during liver fibrosis

Barnes

McMullen

Roychowdhury

et al. 2014

Journal of Leukocyte Biology

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Recruitment of peripheral monocytes to the liver is a key contributor to the response to injury. MIF can act as a chemokine and cytokine, regulating innate immune responses in many tissues and cell types. We hypothesized that MIF contributes to the progression of CCl4-induced hepatic fibrosis by regulating recruitment of SAM. SAMs dynamically regulate HSC activation and ECM degradation. To gain insight into the role of MIF in progression of liver fibrosis, we investigated markers of fibrosis and immune responses after chronic CCl4 administration to female C57BL/6 and MIF(-/-) mice. Chronic CCl4 exposure increased activation of HSC in WT mice, indicated by increased expression of αSMA mRNA and protein, as well as mRNA for collagen 1α1; these responses were blunted in female MIF(-/-) mice. Despite lower activation of HSC in MIF(-/-) mice, accumulation of ECM was similar in WT and MIF(-/-)mice, suggesting a decreased rate of ECM degradation. Recruitment of SAMs was lower in MIF(-/-) mice compared with WT mice, both in their initial inflammatory phenotype, as well as in the later phase as proresolution macrophages. The decreased presence of resolution macrophages was associated with lower expression of MMP13 in MIF(-/-) mice. Taken together, these data indicate that MIF-dependent recruitment of SAMs contributes to degradation of ECM via MMP13, highlighting the importance of appropriate recruitment and phenotypic profile of macrophages in the resolution of fibrosis.

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Section: Discussionsupporting

confidence: 92%

Macrophage migration inhibitory factor is required for recruitment of scar-associated macrophages during liver fibrosis

Barnes

McMullen

Roychowdhury

et al. 2014

Journal of Leukocyte Biology

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“…MIF is expressed in the liver, with hepatocytes and Kupffer cells identified as origins of hepatic MIF production (18). Also, MIF is up‐regulated in toxin‐induced, inflammatory, autoimmune, and fibrotic liver disease in animal models and human disease (19–21), but functional studies to examine the role of MIF in liver disease have been limited. In ethanol‐induced liver injury, Mif ‐deficient mice exhibit reduced steatosis, inflammation, and steatohepatitis (22).…”

mentioning

confidence: 99%

Protective role of macrophage migration inhibitory factor in nonalcoholic steatohepatitis

et al. 2014

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MIF is an inflammatory cytokine but is hepatoprotective in models of hepatotoxin-induced liver fibrosis. Hepatic fibrosis can also develop from metabolic liver disease, such as nonalcoholic fatty liver disease (NASH). We investigated the role of MIF in high-fat or methionine- and choline-deficient diet mouse models of NASH. Mif(-/-) mice showed elevated liver triglyceride levels (WT, 53±14 mg/g liver; Mif(-/-), 103±7 mg/g liver; P<0.05) and a 2-3-fold increased expression of lipogenic genes. Increased fatty degeneration in the livers of Mif(-/-) mice was associated with increased hepatic inflammatory cells (1.6-fold increase in F4/80(+) macrophages) and proinflammatory cytokines (e.g., 2.3-fold increase in Tnf-α and 2-fold increase in Il-6 expression). However, inflammatory cells and cytokines were decreased by 50-90% in white adipose tissue (WAT) of Mif(-/-) mice. Subset analysis showed that macrophage phenotypes in livers of Mif(-/-) mice were skewed toward M2 (e.g., 1.7-fold and 2.5-fold increase in Arg1 and Il-13, respectively, and 2.5-fold decrease in iNos), whereas macrophages were generally reduced in WAT of these mice (70% reduction in mRNA expression of F4/80(+) macrophages). The protective MIF effect was scrutinized in isolated hepatocytes. MIF reversed inflammation-induced triglyceride accumulation in Hepa1-6 cells and primary hepatocytes and also attenuated oleic acid-elicited triglyceride increase in 3T3-L1 adipocytes. Protection from fatty hepatocyte degeneration was paralleled by a 2- to 3-fold reduction by MIF of hepatocyte proinflammatory cytokine production. Blockade of MIF receptor cluster of differentiation 74 (CD74) but not of CXCR2 or CXCR4 fully reverted the protective effect of MIF, comparable to AMPK inhibition. In summary, we demonstrate that MIF mediates hepatoprotection through the CD74/AMPK pathway in hepatocytes in metabolic models of liver injury.

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“…MIF is also expressed within the liver and is up-regulated during thioacetamide (TAA)-induced liver fibrosis in rats (19). In Con A-induced hepatic damage, a model of T-cell mediated hepatitis (20), Mif-deficient mice were protected from severe acute liver injury (21), suggesting that MIF can display detrimental effects in the liver.…”

mentioning

confidence: 99%

Macrophage migration inhibitory factor (MIF) exerts antifibrotic effects in experimental liver fibrosis via CD74

Heinrichs¹,

Knauel

Offermanns³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

135

122

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Macrophage migration inhibitory factor (MIF) is a pleiotropic inflammatory cytokine that has been implicated in various inflammatory diseases. Chronic inflammation is a mainstay of liver fibrosis, a leading cause of morbidity worldwide, but the role of MIF in liver scarring has not yet been elucidated. Here we have uncovered an unexpected antifibrotic role for MIF. Mice genetically deleted in Mif ( Mif −/− ) showed strongly increased fibrosis in two models of chronic liver injury. Pronounced liver fibrosis in Mif −/− mice was associated with alterations in fibrosis-relevant genes, but not by a changed intrahepatic immune cell infiltration. Next, a direct impact of MIF on hepatic stellate cells (HSC) was assessed in vitro. Although MIF alone had only marginal effects on HSCs, it markedly inhibited PDGF-induced migration and proliferation of these cells. The inhibitory effects of MIF were mediated by CD74, which we detected as the most abundant known MIF receptor on HSCs. MIF promoted the phosphorylation of AMP-activated protein kinase (AMPK) in a CD74-dependent manner and, in turn, inhibition of AMPK reversed the inhibition of PDGF-induced HSC activation by MIF. The pivotal role of CD74 in MIF-mediated antifibrotic properties was further supported by augmented liver scarring of Cd74 −/− mice. Moreover, mice treated with recombinant MIF displayed a reduced fibrogenic response in vivo. In conclusion, we describe a previously unexplored antifibrotic function of MIF that is mediated by the CD74/AMPK signaling pathway in HSCs. The results imply MIF and CD74 as targets for treatment of liver diseases.

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Immunohistochemical study of macrophage migration inhibitory factor in rat liver fibrosis induced by thioacetamide

Cited by 22 publications

References 25 publications

Macrophage migration inhibitory factor is required for recruitment of scar-associated macrophages during liver fibrosis

Macrophage migration inhibitory factor is required for recruitment of scar-associated macrophages during liver fibrosis

Protective role of macrophage migration inhibitory factor in nonalcoholic steatohepatitis

Macrophage migration inhibitory factor (MIF) exerts antifibrotic effects in experimental liver fibrosis via CD74

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