title: p38 mitogen-activated protein kinase controls NF-kappaB transcriptional activation and tumor necrosis factor alpha production through RelA phosphorylation mediated by mitogen- and stress-activated protein kinase 1 in response to Borrelia burgdorferi antigens.
abstract: The interaction of Borrelia burgdorferi, the causative agent of Lyme borreliosis, with phagocytic cells induces the activation of NF-kappaB and the expression of proinflammatory cytokines including tumor necrosis factor alpha (TNF-alpha). B. burgdorferi-induced TNF-alpha production is also dependent on the activation of p38 mitogen-activated protein (MAP) kinase. The specific contribution of these signaling pathways to the response of phagocytic cells to the spirochete and the molecular mechanisms underlying this response remain unresolved. We now show that p38 MAP kinase activity regulates the transcriptional activation of NF-kappaB in response to spirochetal lysate stimulation of phagocytic cells. The regulation occurs at the nuclear level and is independent of the translocation of the transcription factor to the nucleus or its capacity to bind to specific DNA target sequences. In RAW264.7 cells, p38alpha MAP kinase regulates the phosphorylation of NF-kappaB RelA. p38 MAP kinase phosphorylates the nuclear kinase mitogen- and stress-activated protein kinase 1 (MSK1). MSK1 in turn phosphorylates the transcriptionally active subunit of NF-kappaB, RelA. The repression of MSK1 expression with small interfering RNA results in reduced RelA phosphorylation and a significant decrease in the production of TNF-alpha in response to B. burgdorferi lysates. Overall, these results clarify the contribution of the signaling pathways that are activated in response to the interaction of spirochetes with phagocytic cells to TNF-alpha production. Our results situate p38 MAP kinase activity as a central regulator of the phagocytic proinflammatory response through MSK1-mediated transcriptional activation of the transcription factor NF-kappaB.
authors.affiliation: Department of Veterinary and Animal Sciences, University of Massachusetts Amherst, 103 Paige Lab., 161 Holdsworth Way, Amherst, MA 01003, USA.
authors.forename: Chris M
authors.initials: CM
authors.lastname: Olson
authors.forename: Michael N
authors.initials: MN
authors.lastname: Hedrick
authors.forename: Hooman
authors.initials: H
authors.lastname: Izadi
authors.forename: Tonya C
authors.initials: TC
authors.lastname: Bates
authors.forename: Elias R
authors.initials: ER
authors.lastname: Olivera
authors.forename: Juan
authors.initials: J
authors.lastname: Anguita
mesh_terms: D000818:Animals; D000942:Antigens, Bacterial / Q000276:immunology*; D015153:Blotting, Western; D025065:Borrelia burgdorferi / Q000276:immunology; D024202:Electrophoretic Mobility Shift Assay; D006790:Host-Parasite Interactions / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D048055:Mitogen-Activated Protein Kinase 8 / Q000276:immunology / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000276:immunology / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics*; D010586:Phagocytes / Q000276:immunology / Q000382:microbiology; D010766:Phosphorylation; D011494:Protein Kinases / Q000276:immunology / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology; D051996:Transcription Factor RelA / Q000276:immunology / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000276:immunology; D048051:p38 Mitogen-Activated Protein Kinases / Q000276:immunology* / Q000378:metabolism
chemical_list: D000942:Antigens, Bacterial; D016328:NF-kappa B; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D011494:Protein Kinases; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases