CCR1-mediated activation of Nuclear Factor-kappaB in THP-1 monocytic cells involves Pertussis Toxin-insensitive Galpha(14) and Galpha(16) signaling cascades.
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.
Lee
Maggie M K
MM
Department of Biochemistry, Molecular Neuroscience Center, Biotechnology Research Institute, Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, China.
Wong
Yung H
YH
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
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