Massive liver necrosis after provocation of imbalance between Th1 and Th2 immune reactions in osteopontin transgenic mice

Mimura, Sumie; Mochida, Satoshi; Inao, Mie; Matsui, Atsushi; Nagoshi, Sumiko; Yoshimoto, Takayuki; Fujiwara, Kenji

doi:10.1007/s00535-004-1403-0

Cited by 19 publications

(15 citation statements)

References 27 publications

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“…In this model, stimulation with ConA leads to infiltration of mononuclear cells, activation of T cells and natural killer T cells, and the release of proinflammatory cytokines, resulting in severe liver destruction (14,26). Of these proinflammatory cytokines, INF-␥ is especially critical in driving the pathological process, because liver injury is significantly reduced in INF-␥-deficient mice or in mice pretreated with INF-␥ neutralizing antibody (16,25).…”

Section: Discussionmentioning

confidence: 99%

Short-form Ron receptor is required for normal IFN-γ production in concanavalin A-induced acute liver injury

Wetzel

Leonis

Dent

et al. 2007

American Journal of Physiology-Gastrointestinal and Liver Physi

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Abrogation of Ron receptor tyrosine kinase function results in defects in macrophage activation and dysregulated acute inflammatory responses in vivo. Several naturally occurring constitutively active alternative forms of Ron have been identified, including from primary human tumors and tumor cell lines. One of these alternative forms, short-form (SF) Ron, is generated from an alternative start site in intron 10 of the Ron gene that eliminates most of the extracellular portion of the receptor and is overexpressed in several human cancers. To test the physiological significance of SF-Ron in vivo, mice were generated that solely express the full-length form of Ron (FL-Ron). Our results show that elimination of the capacity to express SF-Ron in vivo leads to augmented production of IFN-␥ from splenocytes following stimulation ex vivo with either concanavalin A or anti-CD3/T cell receptor monoclonal antibody. Moreover, in a concanavalin A-induced murine model of acute liver injury, FL-Ron mice have increased production of serum INF-␥ and serum alanine aminotransferase levels and worsened liver histology and overall survival compared with wild-type control mice. Taken together, these results suggest for the first time that SF-Ron impacts the progression of inflammatory immune responses in vivo and further support a role for the Ron receptor and its various forms in liver pathophysiology.receptor tyrosine kinases; regulation of cytokine production; animal models of liver injury RECEPTOR TYROSINE KINASES (RTK) play a critical role in multiple biological functions including immune system regulation. The Ron receptor is a member of a distinct family of multifunctional RTKs that also includes c-Met. Activation of Ron and Met results in pleiotropic biological responses, including a set of properties allowing cells to undergo "invasive growth" (4, 13, 33). In addition, Ron receptor activity is critical for proper modulation of inflammatory responses to toxic insults in vivo, including the necroinflammatory hepatic injury in an endotoxin-mediated murine model of acute liver failure (5,11,12,27).When mouse Ron (mRon) cDNA was cloned from hematopoietic stem cells, an alternative 1.9-kb short-form Ron (SF-Ron) transcript was identified in addition to the 4.8-kb full-length Ron (FL-Ron) mRNA transcript (9). SF-Ron is expressed in human lung, ovary, and tissues of the gastrointestinal tract and several human cancers and cancer cell lines; however, the tissue-specific expression of SF-Ron has not been fully characterized (1,7,9,22). The transcription start site for SF-Ron mRNA has been localized to intron 10 of the mRon gene (21, 30), and SF-Ron mRNA encodes a truncated Ron protein that possesses a truncated extracellular domain and the entire transmembrane and cytoplasmic tyrosine kinase domains. SF-Ron displays constitutive tyrosine kinase activity (1, 6), and overexpression of SF-Ron results in loss of an epithelial phenotype and aggressive cell behavior (1). Moreover, mouse strains that express SF-Ron transcript in adult bone ...

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Section: Discussionmentioning

confidence: 99%

Short-form Ron receptor is required for normal IFN-γ production in concanavalin A-induced acute liver injury

Wetzel

Leonis

Dent

et al. 2007

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…This cytokine is involved in cell adhesion, chemo-attraction, and immunomodulation (13)(14)(15). In particular, OPN is highly secreted by macrophages at inflammation sites where it mediates monocyte adhesion, migration, and differentiation as well as phagocytosis (16 -18).…”

Section: Conclusion-mentioning

confidence: 99%

Elevated Expression of Osteopontin May Be Related to Adipose Tissue Macrophage Accumulation and Liver Steatosis in Morbid Obesity

et al. 2009

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OBJECTIVE-Osteopontin (OPN) plays an important role in the development of insulin resistance and liver complications in dietary murine models. We aimed to determine the expression pattern of OPN and its receptor CD44 in obese patients and mice according to insulin resistance and liver steatosis.RESEARCH DESIGN AND METHODS-OPN and CD44 expressions were studied in 52 morbidly obese patients and in mice. Cellular studies were performed in HepG2 cells. RESULTS-HepaticOPN and CD44 expressions were strongly correlated with liver steatosis and insulin resistance in obese patients and mice. This increased OPN expression could be due to the accumulation of triglycerides, since fat loading in HepG2 promotes OPN expression. In contrast, OPN expression in adipose tissue (AT) was enhanced independently of insulin resistance and hepatic steatosis in obese patients. The elevated OPN expression in AT was paralleled with the AT macrophage infiltration, and both phenomena were reversed after weight loss. The circulating OPN level was slightly elevated in obese patients and was not related to liver steatosis. Further, AT did not appear to secrete OPN. In contrast, bariatric surgery-induced weight loss induced a strong increase in circulating OPN. CONCLUSIONS-The modestly elevated circulating OPN levels in morbidly obese patients were not related to liver steatosis and did not appear to result from adipose tissue secretion. In subcutaneous AT, expression of OPN was directly related to macrophage accumulation independently from liver complications. In contrast, hepatic OPN and CD44 expressions were related to insulin resistance and steatosis, suggesting their local implication in the progression of liver injury. Diabetes 58: 125-133, 2009

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“…We have demonstrated in this model that osteopontin (OPN) plays an important role in the progression from steatosis to steatohepatitis and liver fibrosis (30). OPN is synthesized and secreted by immune cells as well as epithelial, endothelial, and smooth muscle cells (19) and has been shown to function as a Th1 cytokine in the pathogenesis of fibroinflammatory diseases in various organ systems including the liver (1,8,9,12,13,16,21,24,37). We have shown that hepatocytes in culture synthesize and secrete OPN and that its expression is upregulated by TNF-␣, transforming growth factor (TGF)-␤, and leptin (30).…”

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confidence: 99%

Roles of phosphatidylinositol 3-kinase and osteopontin in steatosis and aminotransferase release by hepatocytes treated with methionine-choline-deficient medium

Sahai

Pan²,

Paul³

et al. 2006

American Journal of Physiology-Gastrointestinal and Liver Physi

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Massive liver necrosis after provocation of imbalance between Th1 and Th2 immune reactions in osteopontin transgenic mice

Abstract: Th1 and Th2 immune reactions were deranged after concanavalin-A treatment, with Th1 immunity predominating in transgenic mice expressing osteopontin in hepatocytes; this immunological imbalance may contribute to massive liver necrosis.

Cited by 19 publications

References 27 publications

Short-form Ron receptor is required for normal IFN-γ production in concanavalin A-induced acute liver injury

Short-form Ron receptor is required for normal IFN-γ production in concanavalin A-induced acute liver injury

Elevated Expression of Osteopontin May Be Related to Adipose Tissue Macrophage Accumulation and Liver Steatosis in Morbid Obesity

Roles of phosphatidylinositol 3-kinase and osteopontin in steatosis and aminotransferase release by hepatocytes treated with methionine-choline-deficient medium

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