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

Wetzel, Cynthia C.; Leonis, Mike A.; Dent, Arlene E.; Olson, Meredith; Longmeier, Angela M.; Ney, Paul A.; Boivin, Greg P.; Kader, Sarah A.; Caldwell, Charles C.; Degen, Sandra J. Friezner; Waltz, Susan E.

doi:10.1152/ajpgi.00134.2006

Cited by 10 publications

(17 citation statements)

References 30 publications

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“…Therefore, the appearance of IL-10 increase is indicative of hepatocyte recovery. Recently, the treatment of LPS plus PEA, LPS alone, or Con-A resulted in a significant increase in INF-γ in mouse study [4,25]. In our study, a trace amount of INF-γ was detected, but not dose or time dependent, though.…”

Section: Discussioncontrasting

confidence: 47%

Pseudomonas aeruginosa Exotoxin A-Induced Hepatotoxicity: An Animal Model in Rats

Chiu

Chen²,

Chuang

et al. 2009

J. Vet. Med. Sci.

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ABSTRACT. Pseudomonas aeruginosa Exotoxin A (PEA) has been generally used to induce liver injury in mice for experimental study. No PEA-induced hepatotoxicity study has ever been conducted in rats, although rats are the most common rodents used in toxicologic bioassay and pharmacological evaluation. The present study was conducted in male Wistar rats that were injected (i.v.) with PEA at doses of 0, 10, 20, 30 or 40 µg/kg body weight and evaluated at 12, 24, 36, 48 and 60 hr post-exposure (HPE). Rats exposed to PEA at 40 µg/kg died before 36 HPE, and the mortality was dose and time dependent. Liver injury was noted as increases in serum enzymes, along with alterations of liver histology in the 40 µg/kg group at 12 HPE. TUNEL-positive staining indicative of hepatocyte apoptosis was observed in the 20 µg/kg group at 12 HPE. Significant levels of DNA fragmentation ladder were observed in the 30 µg/kg group starting at 24 HPE. Serum levels of TNF-α was increased in the 30 and 40 µg/kg groups at 48 and 24 HPE, respectively. Other cytokines, such as IL-2, IL-6, and IL-10 were also increased at various doses and times. Furthermore, the elevated serum heaptic index levels decreased significantly by dexamethasone pretreatment. In contrast, these markers were exacerbated by co-administration of a non-toxic dose LPS. In overall evaluation, the PEA-induced liver injury can be used as a model for study of hyperimmune-mediated hepatotoxicity.

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Section: Discussioncontrasting

confidence: 47%

Pseudomonas aeruginosa Exotoxin A-Induced Hepatotoxicity: An Animal Model in Rats

Chiu

Chen²,

Chuang

et al. 2009

J. Vet. Med. Sci.

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“…The gene encoding Ron contains an internal promoter that drives expression of an N-terminally truncated form of Ron that lacks the extracellular ligand binding domain but retains the transmembrane and kinase domains (Sf-Ron). The inflammatory defects observed in mice harboring an Sf-Ron–specific deletion support the concept that, like the full-length RON receptor, Sf-Ron also plays a critical role in the regulation of macrophage activation (30). To determine whether LPS regulates the expression of Ron and/or Sf-Ron in macrophages, we stimulated primary peritoneal macrophages with LPS and examined Ron and Sf-Ron expression by real-time PCR (Fig.…”

Section: Resultsmentioning

confidence: 65%

Inhibition of TLR4-Induced IκB Kinase Activity by the RON Receptor Tyrosine Kinase and Its Ligand, Macrophage-Stimulating Protein

Ray

Yu²,

Sharda

et al. 2010

The Journal of Immunology

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The RON receptor tyrosine kinase regulates the balance between classical (M1) and alternative (M2) macrophage activation. In primary macrophages, the ligand for Ron, macrophage-stimulating protein (MSP), inhibits the expression of inducible NO synthase, a marker of classically activated macrophages, whereas promoting the expression of arginase I, a marker of alternative activation. Ron−/− mice express increased levels of IL-12, a product of classically activated macrophages, after endotoxin administration, resulting in increased serum IFN-γ levels and enhanced susceptibility to septic shock. In this study, we demonstrate that MSP inhibits LPS-induced IL-12p40 expression, and this inhibition is dependent on the docking site tyrosines in Ron. To further define this inhibition, we examined the effect of Ron on signaling pathways downstream of Ron. We found that MSP does not inhibit the MyD88-independent activation of IFN regulatory factor 3 and production of IFN-β in response to LPS, nor does it inhibit MyD88-dependent TGF-β–activated kinase phosphorylation or MAPK activation in primary macrophages. However, the induction of IκB kinase activity, IκB degradation, and DNA binding of NF-κB after LPS stimulation is delayed in the presence of MSP. In addition, Ron inhibits serine phosphorylation of p65 and NF-κB transcriptional activity induced by LPS stimulation of TLR4. Finally, MSP inhibits the NF-κB–dependent upregulation of the nuclear IκB family member, IκBζ, a positive regulator of secondary response genes including IL-12p40. LPS also induces expression of Ron and an N-terminally truncated form of Ron, Sf-Ron, in primary macrophages, suggesting that the upregulation of Ron by LPS could provide classical feedback regulation of TLR signaling.

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“…Recent studies have also suggested that SF-Ron has nonredundant biological functions relative to full-length Ron in the progression of inflammatory immune responses in vivo. These observations suggest that the function of SF-Ron is biologically distinct from that of the fulllength receptor and may participate in tumorigenesis [25].…”

Section: Variant Forms Of the Ron Receptormentioning

confidence: 96%

“…Variants of Ron have been identified in both normal and malignant tissues. In mice, short-form (SF-)Ron is naturally expressed in select cells and tissues including expression in the spleen and in splenic T cells, bone marrow, testes, lung, ovary, peritoneal macrophages, and in several hematopoietic cells including stem cells [24,25]. SF-Ron is generated from an alternative start site located in intron 10 of the Ron gene and generates a Ron protein containing only a small extracellular portion along with the transmembrane and intracellular domains.…”

Section: Variant Forms Of the Ron Receptormentioning

confidence: 99%

“…A recent report has shown that the expression of full length Ron and SF-Ron may be the result of variations in the methylation patterns within two distinct CpG islands in the Ron proximal promoter, wherein widespread hypermethylation associates with lack of full length Ron expression whereas hypermethylation of the distal island associates with transcriptional activity of SF-Ron [26]. In vivo, SF-Ron confers susceptibility to Friend virus-induced erythroleukemia and SF-Ron kinase activity is required for erythropoietin-independent expansion of erythroid progenitors in response to Friend virus [25,27]. SF-Ron is also expressed in human ovarian and breast cancers as well as in several human cancer cell lines derived from the pancreas, breast, ovary, lung and leukemias [24].…”

Section: Variant Forms Of the Ron Receptormentioning

confidence: 99%

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Ron-Receptor Tyrosine Kinase In Tumorigenesis and Metastasis

2007

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SummaryThe Ron receptor tyrosine kinase has been increasingly recognized for its tumorigenic potential in the last decade. Ron receptor activation leads to the activation of common receptor tyrosine kinase downstream signaling pathways, and most prominently in tumor models, activation of MAPK, PI3K and β-catenin. Numerous experimental models of mammalian tumorigenesis have demonstrated that increased Ron receptor activity correlates with increased tumorigenesis in a variety of organs of epithelial origin. The evidence for Ron as an oncogene in human tumor biology is growing. The Ron receptor is overexpressed and over-activated in a large number of human tumors, and overexpression of Ron correlates with a worse clinical outcome for patients in at least two human cancer states, namely breast and bladder cancer. Several experimental approaches have been taken to successfully block Ron activity and function, and given this convincing data, approaches to block Ron receptor activity in targeted human cancers should prove to be fruitful in the setting of future clinical research trials.

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

Cited by 10 publications

References 30 publications

Pseudomonas aeruginosa Exotoxin A-Induced Hepatotoxicity: An Animal Model in Rats

Pseudomonas aeruginosa Exotoxin A-Induced Hepatotoxicity: An Animal Model in Rats

Inhibition of TLR4-Induced IκB Kinase Activity by the RON Receptor Tyrosine Kinase and Its Ligand, Macrophage-Stimulating Protein

Ron-Receptor Tyrosine Kinase In Tumorigenesis and Metastasis

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