title: A novel role for Bruton's tyrosine kinase in hepatocyte growth factor-mediated immunoregulation of dendritic cells.
abstract: The limited success of dendritic cell (DC)-based immunotherapy in multiple myeloma is partly due to hepatocyte growth factor (HGF)-induced DC dysfunction. From a therapeutic standpoint, it is important to understand the molecular events involved in inhibition of DC activation/maturation by HGF. Because Bruton's tyrosine kinase (Btk) negatively regulates maturation and immunostimulatory function of DCs, a role for Btk in HGF-induced inhibition of both murine and human DCs was investigated. We demonstrate that Btk is a novel proximal component of HGF-induced c-MET (HGF receptor) signaling. Following HGF treatment, Btk binds to c-MET and becomes activated. Btk activation in turn blocks the NF-κB pathway and subsequent DC activation via the c-Src-PI3K-AKT-mammalian target of rapamycin (mTOR) pathway. Notably, Btk activation is necessary for HGF-induced association of c-Src and PI3K with c-MET. Furthermore, we provide the first evidence that HGF inhibits DC activation by inducing autocrine interleukin (IL)-10 secretion, which requires activation of Btk. Blocking activation of Btk and its downstream the c-Src-PI3K-AKT-mTOR pathway prevents HGF-induced IL-10 secretion by DCs. In addition, neutralization of IL-10 secretion from DCs impaired the inhibitory effect of HGF on DCs. Thus, our study identifies a novel role for Btk in HGF-induced DC inhibition.
authors.affiliation: Division of Cell Biology and Immunology, Institute of Microbial Technology, Council of Scientific and Industrial Research, Sector-39A, Chandigarh 160036, India.
authors.forename: Eshu
authors.initials: E
authors.lastname: Singhal
authors.forename: Prakash
authors.initials: P
authors.lastname: Kumar
authors.forename: Pradip
authors.initials: P
authors.lastname: Sen
mesh_terms: D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D000081247:CSK Tyrosine-Protein Kinase; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D004789:Enzyme Activation / Q000276:immunology; D017228:Hepatocyte Growth Factor / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D016753:Interleukin-10 / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000276:immunology / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000276:immunology* / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000276:immunology / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000276:immunology / Q000378:metabolism; D019061:src-Family Kinases
chemical_list: D000077329:Agammaglobulinaemia Tyrosine Kinase; D000081247:CSK Tyrosine-Protein Kinase; D017228:Hepatocyte Growth Factor; D016753:Interleukin-10; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D011505:Protein-Tyrosine Kinases; D019859:Proto-Oncogene Proteins c-met; D058570:TOR Serine-Threonine Kinases; D019061:src-Family Kinases; C066855:HGF protein, human; C553307:HGF protein, mouse; C508609:IL10 protein, human; C556062:IL10 protein, mouse; C546842:MTOR protein, human; C546843:mTOR protein, mouse; C000625949:BTK protein, human; C000625951:Btk protein, mouse; C000631346:CSK protein, human