title: Toll-like receptor 2 and mitogen- and stress-activated kinase 1 are effectors of Mycobacterium avium-induced cyclooxygenase-2 expression in macrophages.
abstract: Understanding how pathogenic mycobacteria subvert the protective immune response is crucial to the development of strategies aimed at controlling mycobacterial infections. Prostaglandin E(2) exerts an immunosuppressive function in the context of mycobacterial infection. Because cyclooxygenase-2 (COX-2) is a rate-limiting enzyme in prostaglandin biosynthesis, there is a need to delineate the mechanisms through which pathogenic mycobacteria regulate COX-2 expression in macrophages. Our studies demonstrate that the NF-kappaB and CRE elements of the COX-2 promoter are critical to Mycobacterium avium-induced COX-2 gene expression. M. avium-triggered signaling originates at the Toll-like receptor 2 (TLR2). Ras associates with TLR2 and activates the mitogen-activated protein kinase (MAPK) extracellular signal-regulated kinase (ERK), whereas tumor necrosis factor receptor-associated factor 6 (TRAF6)/transforming growth factor beta-activated kinase 1 (TAK1)-dependent signaling activates p38 MAPK. Both ERK and p38 MAPK activation converge to regulate the activation of mitogen- and stress-activated kinase 1 (MSK1). MSK1 mediates the phosphorylation of the transcription factor CREB accounting for its stimulatory effect on CRE-dependent gene expression. M. avium-triggered cytoplasmic NF-kappaB activation following IkappaB phosphorylation is necessary but not sufficient for COX-2 promoter-driven gene expression. MSK1 activation is also essential for M. avium-triggered NF-kappaB-dependent gene expression, presumably mediating nucleosomal modifications. These studies demonstrate that the nuclear kinase MSK1 is necessary in regulating the pathogen-driven expression of a gene by controlling two transcription factors. The attenuation of MSK1 may therefore have potential benefit in restricting survival of pathogenic mycobacteria in macrophages.
authors.affiliation: Department of Chemistry, Bose Institute, 93/1 Acharya Prafulla Chandra Road, Calcutta 700009, India.
authors.forename: Sushil Kumar
authors.initials: SK
authors.lastname: Pathak
authors.forename: Asima
authors.initials: A
authors.lastname: Bhattacharyya
authors.forename: Shresh
authors.initials: S
authors.lastname: Pathak
authors.forename: Chaitali
authors.initials: C
authors.lastname: Basak
authors.forename: Debabrata
authors.initials: D
authors.lastname: Mandal
authors.forename: Manikuntala
authors.initials: M
authors.lastname: Kundu
authors.forename: Joyoti
authors.initials: J
authors.lastname: Basu
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001665:Binding Sites; D015153:Blotting, Western; D002460:Cell Line; D051546:Cyclooxygenase 2; D017931:DNA Primers / Q000737:chemistry; D015232:Dinoprostone / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005786:Gene Expression Regulation; D020672:I-kappa B Proteins / Q000378:metabolism; D007124:Immunoenzyme Techniques; D008024:Ligands; D008156:Luciferases / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D008264:Macrophages / Q000201:enzymology* / Q000378:metabolism / Q000382:microbiology*; D008562:Membrane Glycoproteins / Q000502:physiology*; D051379:Mice; D008954:Models, Biological; D009162:Mycobacterium avium / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D009707:Nucleosomes / Q000378:metabolism; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D011090:Polyenes / Q000494:pharmacology; D053284:Polyunsaturated Alkamides; D011401:Promoter Regions, Genetic; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis*; D011956:Receptors, Cell Surface / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism; D013997:Time Factors; D051195:Toll-Like Receptor 2; D051193:Toll-Like Receptors; D014157:Transcription Factors; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D000900:Anti-Bacterial Agents; D051546:Cyclooxygenase 2; D017931:DNA Primers; D015232:Dinoprostone; D048049:Extracellular Signal-Regulated MAP Kinases; D020672:I-kappa B Proteins; D008024:Ligands; D008156:Luciferases; D020930:MAP Kinase Kinase Kinases; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D009707:Nucleosomes; D011090:Polyenes; D053284:Polyunsaturated Alkamides; D011451:Prostaglandin-Endoperoxide Synthases; D011956:Receptors, Cell Surface; D038744:Ribosomal Protein S6 Kinases, 90-kDa; D048029:TNF Receptor-Associated Factor 6; D051195:Toll-Like Receptor 2; D051193:Toll-Like Receptors; D014157:Transcription Factors; D048051:p38 Mitogen-Activated Protein Kinases; D018631:ras Proteins; D000099151:MAP Kinase Kinase Kinase 7; C116919:mitogen and stress-activated protein kinase 1; C054474:manumycin