Hepatocyte Growth Factor Attenuates Airway Hyperresponsiveness, Inflammation, and Remodeling

Ito, Wataru; Kanehiro, Arihiko; Matsumoto, Kunio; Hirano, Atsushi; Ono, Katsuichiro; Maruyama, Hiromi; Kataoka, Masao; Nakamura, Toshikazu; Gelfand, Erwin W.; Tanimoto, Mitsune

doi:10.1165/rcmb.2004-0058oc

Cited by 64 publications

(72 citation statements)

References 57 publications

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“…HGF has been shown previously to be protective in various animal models of immune-mediated diseases such as myocarditis (32,33), glomerulonephritis (30,34), inflammatory bowel disease (35), collagen-induced arthritis (36), pulmonary fibrosis (37), allogeneic heart transplantation (45), graft-vs.-host disease (46), and asthma (47). According to these studies, HGF may ameliorate both Th1-type-dominated (33,36) and Th2-type-dominated (40,47) autoimmune responses.…”

Section: Discussionmentioning

confidence: 94%

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Hepatocyte growth factor inhibits CNS autoimmunity by inducing tolerogenic dendritic cells and CD25 ⁺ Foxp3 ⁺ regulatory T cells

Benkhoucha

Santiago-Raber

Schneiter

et al. 2010

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

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187

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Immune-mediated diseases of the CNS, such as multiple sclerosis and its animal model, experimental autoimmune encephalitis (EAE), are characterized by the activation of antigen-presenting cells and the infiltration of autoreactive lymphocytes within the CNS, leading to demyelination, axonal damage, and neurological deficits. Hepatocyte growth factor (HGF) is a pleiotropic factor known for both neuronal and oligodendrocytic protective properties. Here, we assess the effect of a selective overexpression of HGF by neurons in the CNS of C57BL/6 mice carrying an HGF transgene (HGF-Tg mice). EAE induced either by immunization with myelin oligodendrocyte glycoprotein peptide or by adoptive transfer of T cells was inhibited in HGF-Tg mice. Notably, the level of inflammatory cells infiltrating the CNS decreased, except for CD25 + Foxp3 + regulatory T (T reg ) cells, which increased. A strong T-helper cell type 2 cytokine bias was observed: IFN-γ and IL-12p70 decreased in the spinal cord of HGF-Tg mice, whereas IL-4 and IL-10 increased. Antigen-specific response assays showed that HGF is a potent immunomodulatory factor that inhibits dendritic cell (DC) function along with differentiation of IL-10-producing T reg cells, a decrease in IL-17-producing T cells, and down-regulation of surface markers of T-cell activation. These effects were reversed fully when DC were pretreated with anti-cMet (HGF receptor) antibodies. Our results suggest that, by combining both potentially neuroprotective and immunomodulatory effects, HGF is a promising candidate for the development of new treatments for immune-mediated demyelinating diseases associated with neurodegeneration such as multiple sclerosis.cMet (HGF receptor) | experimental autoimmune encephalitis | immune tolerance | multiple sclerosis | neuroprotection

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Section: Discussionmentioning

confidence: 94%

“…According to these studies, HGF may ameliorate both Th1-type-dominated (33,36) and Th2-type-dominated (40,47) autoimmune responses. Interestingly, a recent report demonstrated that, in an experimental model of airway allergy, HGF might repress DC function without up-regulation of IL-10 (40).…”

Section: Discussionmentioning

confidence: 96%

Hepatocyte growth factor inhibits CNS autoimmunity by inducing tolerogenic dendritic cells and CD25 ⁺ Foxp3 ⁺ regulatory T cells

Benkhoucha

Santiago-Raber

Schneiter

et al. 2010

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

Self Cite

171

187

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“…HGF, a pleiotropic ligand of the tyrosine kinase receptor c-Met, suppresses both acute and chronic inflammation and injury in a variety of organ systems (12)(13)(14)(15)(16)(17). This protective action was recently ascribed, at least in part, to potent antiinflammatory actions.…”

Section: Discussionmentioning

confidence: 99%

Hepatocyte Growth Factor Suppresses Proinflammatory NFκB Activation through GSK3β Inactivation in Renal Tubular Epithelial Cells

Gong

Rifai

et al. 2008

Journal of Biological Chemistry

108

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Activation of NF B is a fundamental cellular event central to all inflammatory diseases. Hepatocyte growth factor (HGF) ameliorates both acute and chronic inflammation in a multitude of organ systems through modulating NF B activity; nevertheless, the exact molecular mechanism remains uncertain. Here we report that HGF through inactivation of GSK3␤ suppresses NF B p65 phosphorylation specifically at position Ser-468. The Ser-468 of RelA/p65 situates in a GSK3␤ consensus motif and could be directly phosphorylated by GSK3␤ both in vivo and in vitro, signifying Ser-468 of RelA/p65 as a putative substrate for GSK3␤. In addition, the C terminus of RelA/p65 harbors a highly conserved domain homologue of the consensus docking sequence for GSK3␤. Moreover, this domain was required for efficient phosphorylation of Ser-468 and was indispensable for the physical interaction between RelA/p65 and GSK3␤. HGF substantially intercepted this interaction by inactivating GSK3␤. Functionally, phosphorylation of Ser-468 of RelA/p65 was required for the induced expression of a particular subset of proinflammatory NF B-dependent genes. Diminished phosphorylation at Ser-468 by HGF resulted in a gene-specific inhibition of these genes' expression. The action of HGF on proinflammatory NF B activation was consistently mimicked by a selective GSK3␤ inhibitor or GSK3␤ knockdown by RNA interference but largely abrogated in cells expressing the mutant uninhibitable GSK3␤. Collectively, our findings suggest that HGF has a potent suppressive effect on NF B activation, which is mediated by GSK3␤, an important signaling transducer controlling RelA/p65 phosphorylation specificity and directing the transcription of selective proinflammatory cytokines implicated in inflammatory kidney disease.

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“…Given what is known of the roles of HGF in pathobiology, inactivation by inflammatory peptidases could limit proliferation, migration, or differentiation of c-met-bearing cells in acute response to infection, injury, or allergen exposure. More specifically, selective hydrolysis may oppose HGF effects on epithelial repair in pneumonia, allergic airway inflammation (12), and ischemia-reperfusion injury (13). By interrupting control of epithelial to mesenchymal transformation by HGF, proteolytic inactivation may promote lung and airway fibrosis (11).…”

Section: Discussionmentioning

confidence: 99%

Mast Cell and Neutrophil Peptidases Attack an Inactivation Segment in Hepatocyte Growth Factor to Generate NK4-like Antagonists

Raymond

Cruz

Caughey

2006

Journal of Biological Chemistry

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Hepatocyte growth factor (HGF) is a plasminogen-like protein with an α chain linked to a trypsinlike β chain without peptidase activity. The interaction of HGF with c-met, a receptor tyrosine kinase expressed by many cells, is important in cell growth, migration, and formation of endothelial and epithelial tubes. Stimulation of c-met requires two-chain, disulfide-linked HGF. Portions of an α chain containing an N-terminal segment and four kringle domains (NK4) antagonize HGF activity. Until now, no physiological pathway for generating NK4 was known. Here we show that chymases, which are chymotryptic peptidases secreted by mast cells, hydrolyze HGF, thereby abolishing scatter factor activity while generating an NK4-like antagonist of HGF scatter factor activity. Thus, chymase interferes with HGF directly by destroying active protein and indirectly by generating an antagonist. The site of hydrolysis, Leu 480 , lies in the α chain on the N-terminal side of the cysteine linking the α and β chains. This site appears to be specific for HGF because chymase does not hydrolyze other plasminogen-like proteins, such as macrophage-stimulating protein and plasminogen itself. Mast cell/neutrophil cathepsin G and neutrophil elastase generate similar fragments of HGF by cleaving near the chymase site. Mast cell and neutrophil peptidases are secreted during tissue injury, infection, ischemia, and allergic inflammation, where they may oppose HGF effects on epithelial repair. Thus, HGF possesses an "inactivation segment" that serves as an Achilles' heel attacked by inflammatory proteases. This work reveals a potential physiological pathway for inactivation of HGF and generation of NK4-like antagonists.HGF 2 is a mitogen, motogen, and morphogen for epithelial and mesenchymal cells (1). It is also known as scatter factor because it disperses epithelial cells in culture (2). Genetic deletion in mice suggests that HGF is critical for embryonic development (3). Adult mesenchymal cells also produce HGF, which is thought to regulate tissue regeneration and repair after injury (4, 5), epithelial to mesenchymal transitions, and formation of vessels and other tube-like structures (6). HGF production is inducible. Circulating levels rise markedly in several types of tissue injury, as in liver damage (7), arterial thrombosis (8), or acute rejection of a transplanted lung (9). When used as a drug, HGF stimulates lung regrowth after pneumonectomy (10), diminishes lung fibrosis (11) and allergic airway remodeling (12), and The present work focuses on major inflammatory cell peptidases, including the human mast cell chymotryptic peptidase, chymase, a mouse enzyme, mast cell protease (MCP)4, with similar tissue distribution and enzymatic properties (20)(21)(22), and human neutrophil elastase and cathepsin G. Cathepsin G possesses tryptic, chymotryptic, and metase activity (23) and is expressed by mast cells as well as by neutrophils. Human chymase and cathepsin G are expressed in a subset of mast cells inhabiting the dermis and certain oth...

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Hepatocyte Growth Factor Attenuates Airway Hyperresponsiveness, Inflammation, and Remodeling

Cited by 64 publications

References 57 publications

Hepatocyte growth factor inhibits CNS autoimmunity by inducing tolerogenic dendritic cells and CD25 ⁺ Foxp3 ⁺ regulatory T cells

Hepatocyte growth factor inhibits CNS autoimmunity by inducing tolerogenic dendritic cells and CD25 ⁺ Foxp3 ⁺ regulatory T cells

Hepatocyte Growth Factor Suppresses Proinflammatory NFκB Activation through GSK3β Inactivation in Renal Tubular Epithelial Cells

Mast Cell and Neutrophil Peptidases Attack an Inactivation Segment in Hepatocyte Growth Factor to Generate NK4-like Antagonists

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Hepatocyte Growth Factor Attenuates Airway Hyperresponsiveness, Inflammation, and Remodeling

Cited by 64 publications

References 57 publications

Hepatocyte growth factor inhibits CNS autoimmunity by inducing tolerogenic dendritic cells and CD25 + Foxp3 + regulatory T cells

Hepatocyte growth factor inhibits CNS autoimmunity by inducing tolerogenic dendritic cells and CD25 + Foxp3 + regulatory T cells

Hepatocyte Growth Factor Suppresses Proinflammatory NFκB Activation through GSK3β Inactivation in Renal Tubular Epithelial Cells

Mast Cell and Neutrophil Peptidases Attack an Inactivation Segment in Hepatocyte Growth Factor to Generate NK4-like Antagonists

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Product

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Hepatocyte growth factor inhibits CNS autoimmunity by inducing tolerogenic dendritic cells and CD25 ⁺ Foxp3 ⁺ regulatory T cells

Hepatocyte growth factor inhibits CNS autoimmunity by inducing tolerogenic dendritic cells and CD25 ⁺ Foxp3 ⁺ regulatory T cells