title: The role of tumor progression locus 2 protein kinase in glial inflammatory response.
abstract: Tumor progression locus 2 (Tpl2)/cancer Osaka thyroid kinase is a newer member of MAP3K family that is now known for its essential role in tumor necrosis factor-aplha (TNFα) expression in macrophages, but its pro-inflammatory signaling, if any, in glia is unknown. When cultures of murine microglia and astrocytes were exposed to lipopolysaccharide, there was a rapid activation (i.e., phosphorylation) of Tpl2 in parallel to the activation of down-stream effector MAPKs, that is, extracellular signal regulated kinase (ERK), p38 MAPK and C-Jun N-terminal kinase (JNK). Pre-incubation of the cultures with a Tpl2 inhibitor selectively suppressed the activation of the primary down-stream target, that is, ERK relative to p38 MAPK and JNK. That Tpl2 activation was functionally involved in glial inflammatory response was indicated by a reduced release of the cytokines, i.e. TNFα and the expression of inducible nitric oxide synthase in the presence of the kinase inhibitor. Furthermore, over-expression of a wild-type Tpl2 construct in C-6 glia resulted in an enhanced transcriptional activation of inducible nitric oxide synthase, while transfection with a dominant negative form of Tpl-2 had the opposite effect. The findings assign an important pro-inflammatory signaling function for Tpl2 pathway in glial cells.
authors.affiliation: Department of Neurosciences, Medical University of South Carolina, Charleston, South Carolina, USA.
authors.forename: Joshua
authors.initials: J
authors.lastname: Hirschhorn
authors.forename: Sangeeta
authors.initials: S
authors.lastname: Mohanty
authors.forename: Narayan R
authors.initials: NR
authors.lastname: Bhat
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000201:enzymology* / Q000276:immunology; D002478:Cells, Cultured; D005260:Female; D015870:Gene Expression / Q000276:immunology; D008070:Lipopolysaccharides / Q000494:pharmacology; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000166:cytology / Q000201:enzymology* / Q000276:immunology; D009443:Neuritis / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D011247:Pregnancy; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D008070:Lipopolysaccharides; D011518:Proto-Oncogene Proteins; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D020930:MAP Kinase Kinase Kinases; C489843:Map3k8 protein, mouse
keywords: MAP kinase; astrocytes; cytokines; microglia; neuroinflammation; nitric oxide