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Hepatocyte Growth Factor: a Regulator of Inflammation and Autoimmunity

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Hepatocyte Growth Factor: a Regulator of Inflammation and Autoimmunity Autoimmunity Reviews 14 (2015) 293–303 Contents lists available at ScienceDirect Autoimmunity Reviews journal homepage: www.elsevier.com/locate/autrev Review Hepatocyte growth factor: A regulator of inflammation and autoimmunity Nicolas Molnarfi a,b,1, Mahdia Benkhoucha a,b,1, Hiroshi Funakoshi d, Toshikazu Nakamura e, Patrice H. Lalive a,b,c,⁎ a Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland b Department of Clinical Neurosciences, Division of Neurology, Unit of Neuroimmunology and Multiple Sclerosis, University Hospital of Geneva, Geneva, Switzerland c Department of Genetics and Laboratory Medicine, Laboratory Medicine Service, University Hospital of Geneva, Geneva, Switzerland d Center for Advanced Research and Education, Asahikawa Medical University, Asahikawa, Japan e Neurogen Inc., Nakahozumi, Ibaraki, Osaka, Japan article info abstract Article history: Hepatocyte growth factor (HGF) is a pleiotropic cytokine that has been extensively studied over several decades, Received 20 November 2014 but was only recently recognized as a key player in mediating protection of many types of inflammatory and au- Accepted 25 November 2014 toimmune diseases. HGF was reported to prevent and attenuate disease progression by influencing multiple Available online 1 December 2014 pathophysiological processes involved in inflammatory and immune response, including cell migration, matura- tion, cytokine production, antigen presentation, and T cell effector function. In this review, we discuss the actions Keywords: fl HGF and mechanisms of HGF in in ammation and immunity and the therapeutic potential of this factor for the treat- fl c-Met ment of in ammatory and autoimmune diseases. Inflammation © 2014 Elsevier B.V. All rights reserved. Autoimmunity Autoimmune regulator Therapy Contents 1. Introduction............................................................. 294 2. Hepatocytegrowthfactor(HGF).................................................... 294 2.1. StructuralandfunctionalcharacteristicsofHGF.......................................... 294 2.2. HGFreceptor(c-Met)...................................................... 294 3. RegulationandroleoftheHGF/c-Metaxisduringimmunereactions.................................... 294 3.1. Monocytesandmacrophages.................................................. 295 3.2. Dendriticcells(DCs)...................................................... 295 3.3. Tlymphocytes......................................................... 296 3.4. Blymphocytes......................................................... 296 3.5. Neutrophils.......................................................... 297 3.6. Naturalkillercells....................................................... 297 4. Role of HGF in inflammatory-mediateddiseaseanimalmodels....................................... 297 4.1. Rheumatoidarthritis...................................................... 297 4.2. Autoimmune neuroinflammation ................................................ 297 4.3. Graft-versus-hostdisease(GVHD)................................................ 297 4.4. Kidneydiseases ........................................................ 298 4.5. Cardiacdiseases........................................................ 298 4.6. Inflammatoryboweldisease(IBD)................................................ 298 4.7. Lungdisease.......................................................... 298 ⁎ Corresponding author at: Department of Clinical Neurosciences, Division of Neurology, Unit of Neuroimmunology and Multiple Sclerosis, Geneva University Hospital, Faculty of Medicine, Gabrielle-Perret-Gentil 4, 1211 Geneva 14, Switzerland. Tel.: +41 22 372 83 18; fax: +41 22 372 83 82. E-mail address: [email protected] (P.H. Lalive). 1 These authors contributed equally to this work. http://dx.doi.org/10.1016/j.autrev.2014.11.013 1568-9972/© 2014 Elsevier B.V. All rights reserved. 294 N. Molnarfi et al. / Autoimmunity Reviews 14 (2015) 293–303 4.8. Liverdisease.......................................................... 298 5. HGFastherapeuticagent........................................................ 298 6. Concludingremarks.......................................................... 299 7. Futuredirections ........................................................... 299 Take-homemessages............................................................ 300 Acknowledgments............................................................. 300 References................................................................. 300 1. Introduction HGF has a high affinity for its receptor c-Met, but the activation of the HGF/c-Met signaling is dependent on the subsequent binding of the β- Hepatocyte growth factor (HGF), also called scatter factor, is a poly- chain [25]. In addition to the major transcript encoding HGF, alternative peptide growth factor that belongs to the plasminogen family. Based on splicing of the HGF primary transcript generates natural variants that biological and gene expression assays, HGF has been described as a retained the c-Met-binding ability and have partial agonistic and antag- pleiotropic factor that is primarily secreted by mesenchymal cells [1] onistic activities on the full-length HGF protein [26]. and that elicits motility, proliferation, morphogenesis and proliferation of epithelia expressing the HGF receptor c-Met [2–5]. The importance 2.2. HGF receptor (c-Met) of HGF in mesenchyme-directed epithelial growth during embryogene- sis and organ development was evidenced by the demonstration that All biological activities of the mature HGF are mediated via the high mice with conventional c-Met- or HGF-null mutations died in utero affinity cell-surface receptor c-Met, a product encoded by the c-Met due to defects in placenta, liver and muscle development [6–8].Thesub- proto-oncogene [27]. Like its ligand, this receptor is a disulfide-linked sequent development of tissue-specific knockout mice further evi- α–β heterodimer that originates from the proteolytic cleavage of a sin- denced a major role for the HGF/c-Met signaling pathway as an gle chain precursor. The c-Met receptor is expressed in the normal epi- essential factor for mature tissue survival, protection and regeneration, thelium of the majority of tissues where it is primarily located at the and of particular interest, in providing less susceptibility to fibrosis and intercellular junctions together with cell adhesion molecules such as chronic inflammation [9]. In recent years, our work and that of others E-cadherin [28]. The c-Met protein is composed of a single-pass trans- have further shown that HGF regulates acute and chronic inflammation membrane β-chain (145 kDa) and a completely extracellular α-chain in a variety of disease models, including collagen-induced arthritis, au- (50 kDa). The α-subunit and the amino-terminal region of the β- toimmune neuroinflammation, inflammatory bowel disease and airway subunit form the extracellular domain. The remainder of the β-chain inflammation. This suggests that HGF modulates central inflammatory spans the plasma membrane and harbors a cytoplasmic region with and immune events that are common to many diseases and organ sys- tyrosine kinase-containing activity. tems. We discuss here the mechanisms by which HGF suppresses in- The binding of HGF to c-Met induces the kinase catalytic activity of flammatory immune responses. the receptor, which triggers the transphosphorylation of the tyrosines (Tyr) 1234 and Tyr 1235 and the engagement of various signal transduc- ers. Because of the multitude of transducers, c-Met initiates a whole 2. Hepatocyte growth factor (HGF) spectrum of biological activities. The transducers either directly interact with c-Met, such as the growth factor receptor-bound protein 2 2.1. Structural and functional characteristics of HGF (GRB2) [29], the c-Src tyrosine kinase [29], the adaptor Src Homology (SHC) 2 domain [30], the p85 subunit of phosphatidylinositol 3-kinase In the early 1980s, HGF was identified as a hormone-like substance in (PI3K) [31], and the signal transducer and activator of transcription 3 the serum of partially hepatectomized rats, based on its ability to stimu- (STAT3) [32], or indirectly through the GRB2-associated binding protein late DNA synthesis in cultured hepatocytes [10,11]. Within a few years, it 1(Gab1)[33], such as the phospholipase C-γ (PLC-γ) [34]. In a compara- became however evident that HGF elicits multiple biological activities in ble manner to HGF, the related plasminogen family member HGF-like/ multiple cell types [12]. In addition to serve as a mitogen for hepatocytes, macrophage stimulating protein (MSP) has been shown to mediate its independent studies identified HGF as a potent epithelial mitogen [2,13], biological activities through a unique cell-surface receptor characterized growth factor [14], morphogen [4], as well as a chemoattractant for mo- as Ron (recepteur d'origine nantais), a tyrosine kinase receptor that toneurons [15] and a cytotoxic factor toward tumor cell lines [16].Dueto structurally resembles to c-Met and that exhibits analogous biological ac- the homology in amino acid sequence of HGF to factors of the clotting tivities on target cells [35]. While c-Met alone is able to mediate signal- and fibrinolysis cascades, such as prothrombin and plasminogen, HGF ing, it has also been shown that c-Met could form heterodimers with belongs to the family of plasminogen-related growth factors, which other cellular surface receptors to mediate distinct signaling
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