Regulation of the RON Receptor Tyrosine Kinase Expression in Macrophages: Blocking the RON Gene Transcription by Endotoxin-Induced Nitric Oxide

Wang, Ming-Hai; Fung, Hai-Lin; Chen, Yiqing

doi:10.4049/jimmunol.164.7.3815

Cited by 19 publications

(11 citation statements)

References 38 publications

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“…Given that TNFα is predominately produced in macrophages, we postulated that Ron signaling may be modulating TNFα production by regulating the activity of pulmonary alveolar macrophages. Previous studies have shown Ron expression in murine peritoneal macrophages and Ron expression has been demonstrated in the lung epithelial cells by immunohistochemical staining [20, 21]. However, the expression and activity of Ron in primary pulmonary alveolar macrophages has not been characterized.…”

Section: Resultsmentioning

confidence: 99%

RON RECEPTOR TYROSINE KINASE NEGATIVELY REGULATES TNFα PRODUCTION IN ALVEOLAR MACROPHAGES BY INHIBITING NF-κB ACTIVITY AND ADAM17 PRODUCTION

Nikolaidis

Gray²,

Gurusamy³

et al. 2010

Shock

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The Ron receptor tyrosine kinase plays a regulatory role in the inflammatory response to acute lung injury induced by intranasal administration of bacterial lipopolysaccharide (LPS). Previously, we have showen that mice with a targeted deletion of the tyrosine kinase (TK) signaling domain of the Ron receptor exhibited more severe lung injury in response to intranasal LPS administration as evidenced by increased leakage of albumin in the lungs and a greater thickening of the alveolar septae compared to wild-type mice. In addition, lung injury in the Ron TK deficient (TK−/−) mice was associated with increased activation of the transcription factor, nuclear factor kappaB (NF-κB) and significantly increased intrapulmonary expression of tumor necrosis factor alpha (TNFα). TNFα, a multifunctional pro-inflammatory cytokine, is a central mediator in several disease states including rheumatoid arthritis and sepsis. Based on the observation that TNFα production is increased in the Ron TK−/− mice and that macrophages are a major source of this cytokine, we hypothesized that the alterations observed in Ron TK−/− mice may be due, in part, to Ron signaling specifically in alveolar macrophages. To test this hypothesis, wild-type and Ron TK−/− primary alveolar macrophages and the murine alveolar macrophage cell line, MH-S, were used to examine the effects of Ron activation on LPS-induced TNFα production and NK-κB activity. Here, we report that Ron is expressed on alveolar macrophages and MH-S cells. Activation of Ron by its ligand, hepatocyte growth factor-like protein (HGFL), decreases TNFα production in alveolar macrophages following LPS challenge. Decreased TNFα is associated with HGFL-induced decreases in NF-κB activation and increases in the NF-κB inhibitory protein, IκB. We also provide the first evidence for Ron as a negative regulator of Adam17, the metalloprotease involved in TNFα processing. . These results indicate that Ron plays a critical role in regulation of alveolar macrophage signaling, and validates this receptor as a target in TNFα-mediated pulmonary pathologies.

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Section: Resultsmentioning

confidence: 99%

RON RECEPTOR TYROSINE KINASE NEGATIVELY REGULATES TNFα PRODUCTION IN ALVEOLAR MACROPHAGES BY INHIBITING NF-κB ACTIVITY AND ADAM17 PRODUCTION

Nikolaidis

Gray²,

Gurusamy³

et al. 2010

Shock

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“…Tat also has been demonstrated to have several activities, including regulating transcription and cell growth and differentiation (80). Furthermore, cytokine production and inflammatory mediators initiated by HIV-1 infection in the brain (12, 13) could influence RON expression and function through an autocrine/paracrine mechanism (20,81). Finally, HIV-1-induced inflammation may lead to the death of cells that express RON, including neurons and astrocytes, as well as the infiltration and/or expansion of RON-negative lymphocytes and macrophages within the brain, resulting in an overall decrease in RON protein in the brain.…”

Section: Discussionmentioning

confidence: 99%

RON Receptor Tyrosine Kinase, a Negative Regulator of Inflammation, Inhibits HIV-1 Transcription in Monocytes/Macrophages and Is Decreased in Brain Tissue from Patients with AIDS

Lee

Kalantari

Tsutsui³

et al. 2004

The Journal of Immunology

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Activation of macrophages and microglia cells after HIV-1 infection and their production of inflammatory mediators contribute to HIV-associated CNS diseases. The mechanisms that initiate and maintain inflammation after HIV-1 infection in the brain have not been well studied. Furthermore, it is not understood why in HIV-associated CNS disease, macrophages and microglia are biased toward inflammation rather than production of mediators that control inflammation. We have focused on the receptor tyrosine kinase RON, a critical negative regulator of macrophage function and inflammation, to determine whether this receptor regulates HIV-1 expression. Overexpressing RON in monocytes/macrophages demonstrates that RON inhibits HIV-1 proviral transcription in part by decreasing the binding activity of NF-κB to the HIV-1 long terminal repeat. Because macrophages and microglia cells are a critical reservoir for HIV-1 in the CNS, we examined brain tissues for RON expression and detected RON in astrocytes, cortical neurons, and monocytoid cells. RON was detected in all control patients who were HIV seronegative (n = 7), whereas six of nine brain samples obtained from AIDS patients exhibited reduced RON protein. These data suggest that RON initiates signaling pathways that negatively regulate HIV-1 transcription in monocytes/macrophages and that HIV-1 suppresses RON function by decreasing protein levels in the brain to assure efficient replication. Furthermore, HIV-1 infection would compromise the ability of RON to protect against inflammation and consequent CNS damage.

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“…RON ligand, macrophage-stimulating protein (MSP), was originally found to modulate the function of certain macrophage by a variety of means. For example, addition of MSP not only induced shape changes, chemotaxis, macropinocytosis, and phagocytosis (4) but also inhibited lipopolysaccharide (LPS)-induced production of inflammatory mediators such as inducible nitric oxide (5), nitric oxide (6), prostaglandins, and cyclooxygenase-2 (7). Consistent with this notion that RON negatively regulates inflammation is the observation that activated macrophages from adult RON knockout mice produced increased levels of nitric oxide both in vitro and in vivo, thus rendering them more susceptible to LPS-induced endotoxic shock (8)(9)(10).…”

Section: Introductionmentioning

confidence: 99%

Therapeutic Implications of a Human Neutralizing Antibody to the Macrophage-Stimulating Protein Receptor Tyrosine Kinase (RON), a c-MET Family Member

O'Toole¹,

Rabenau²,

Burns³

et al. 2006

Cancer Research

107

137

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RON is a member of the c-MET receptor tyrosine kinase family. Like c-MET, RON is expressed by a variety of epithelial-derived tumors and cancer cell lines and it is thought to play a functional role in tumorigenesis. To date, antagonists of RON activity have not been tested in vivo to validate RON as a potential cancer target. In this report, we used an antibody phage display library to generate IMC-41A10, a human immunoglobulin G1 (IgG1) antibody that binds with high affinity (ED 50 = 0.15 nmol/L) to RON and effectively blocks interaction with its ligand, macrophage-stimulating protein (MSP; IC 50 = 2 nmol/L). We found IMC-41A10 to be a potent inhibitor of receptor and downstream signaling, cell migration, and tumorigenesis. It antagonized MSP-induced phosphorylation of RON, mitogen-activated protein kinase (MAPK), and AKT in several cancer cell lines. In HT-29 colon, NCI-H292 lung, and BXPC-3 pancreatic cancer xenograft tumor models, IMC-41A10 inhibited tumor growth by 50% to 60% as a single agent, and in BXPC-3 xenografts, it led to tumor regressions when combined with Erbitux. Western blot analyses of HT-29 and NCI-H292 xenograft tumors treated with IMC-41A10 revealed a decrease in MAPK phosphorylation compared with control IgG-treated tumors, suggesting that inhibition of MAPK activity may be required for the antitumor activity of IMC-41A10. To our knowledge, this is the first demonstration that a RON antagonist and specifically an inhibitory antibody of RON negatively affects tumorigenesis. Another major contribution of this report is an extensive analysis of RON expression in f100 cancer cell lines and f300 patient tumor samples representing 10 major cancer types. Taken together, our results highlight the potential therapeutic usefulness of RON activity inhibition in human cancers. (Cancer Res 2006; 66(18): 9162-70)

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Regulation of the RON Receptor Tyrosine Kinase Expression in Macrophages: Blocking the RON Gene Transcription by Endotoxin-Induced Nitric Oxide

Cited by 19 publications

References 38 publications

RON RECEPTOR TYROSINE KINASE NEGATIVELY REGULATES TNFα PRODUCTION IN ALVEOLAR MACROPHAGES BY INHIBITING NF-κB ACTIVITY AND ADAM17 PRODUCTION

RON RECEPTOR TYROSINE KINASE NEGATIVELY REGULATES TNFα PRODUCTION IN ALVEOLAR MACROPHAGES BY INHIBITING NF-κB ACTIVITY AND ADAM17 PRODUCTION

RON Receptor Tyrosine Kinase, a Negative Regulator of Inflammation, Inhibits HIV-1 Transcription in Monocytes/Macrophages and Is Decreased in Brain Tissue from Patients with AIDS

Therapeutic Implications of a Human Neutralizing Antibody to the Macrophage-Stimulating Protein Receptor Tyrosine Kinase (RON), a c-MET Family Member

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