title: CCR1-mediated activation of Nuclear Factor-kappaB in THP-1 monocytic cells involves Pertussis Toxin-insensitive Galpha(14) and Galpha(16) signaling cascades.
abstract: Agonists of CC chemokine receptor CCR1 contribute to the pathogenesis of autoimmune and other inflammatory diseases, possibly via the regulation of the transcription factor NF-kappaB. CCR1 and CCR2b have been demonstrated to use PTX-insensitive Galpha(14) and Galpha(16) to stimulate PLCbeta in cotransfected cells, and Galpha(14) and Galpha(16) are capable of activating NF-kappaB. The coexpression of Galpha(14), Galpha(16), and CCR1 in human monocytic THP-1 cells suggests that CCR1 may use Galpha(14) or Galpha(16) to induce NF-kappaB activation. Here, we demonstrated that a CCR1 agonist, Lkn-1, stimulated NF-kappaB phosphorylation via PTX-insensitive G proteins in THP-1 cells. Lkn-1 also mediated IKK/NF-kappaB phosphorylations in HEK293 cells overexpressing CCR1 and Galpha(14/16). Using various kinase inhibitors, Raf-1, MEK1/2, PLCbeta, PKC, CaM, CaMKII, and c-Src were found to participate in Lkn-1-stimulated IKK/NF-kappaB phosphorylations in THP-1 and transfected HEK293 cells. Although c-Jun N-terminal kinase and p38 MAPK were activated by Lkn-1, they were not required in Lkn-1-induced IKK phosphorylation. The ability of CCR1 to signal through Galpha(14/16) thus provides a linkage for chemokines to regulate NF-kappaB-dependent responses.
authors.affiliation: Department of Biochemistry, Molecular Neuroscience Center, Biotechnology Research Institute, Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, China.
authors.forename: Maggie M K
authors.initials: MM
authors.lastname: Lee
authors.forename: Yung H
authors.initials: YH
authors.lastname: Wong
mesh_terms: D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000276:immunology*; D006801:Humans; D009000:Monocytes / Q000276:immunology*; D010766:Phosphorylation / Q000187:drug effects / Q000276:immunology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011494:Protein Kinases / Q000276:immunology; D054389:Receptors, CCR1 / Q000276:immunology*; D054390:Receptors, CCR2 / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology*; D020298:U937 Cells
chemical_list: C515300:CCR1 protein, human; D047428:Protein Kinase Inhibitors; D054389:Receptors, CCR1; D054390:Receptors, CCR2; D011494:Protein Kinases; C112631:G protein alpha 16; C119109:GNA14 protein, human; D043802:GTP-Binding Protein alpha Subunits, Gq-G11