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Titolo:
Different mitogen-activated protein kinase signaling pathways cooperate toregulate tumor necrosis factor a gene expression in T lymphocytes
Autore:
Hoffmeyer, A; Grosse-Wilde, A; Flory, E; Neufeld, B; Kunz, M; Rapp, UR; Ludwig, S;
Indirizzi:
Inst Med Strahlenkunde & Zellforsch MSZ, D-97078 Wurzburg, Germany Inst Med Strahlenkunde & Zellforsch MSZ Wurzburg Germany D-97078 Germany Univurg,zburg, Klin & Poliklin Haut & Geschlechtskrankheiten, D-97078 Wurzb Univ Wurzburg Wurzburg Germany D-97078 hlechtskrankheiten, D-97078 Wurzb
Titolo Testata:
JOURNAL OF BIOLOGICAL CHEMISTRY
fascicolo: 7, volume: 274, anno: 1999,
pagine: 4319 - 4327
SICI:
0021-9258(19990212)274:7<4319:DMPKSP>2.0.ZU;2-V
Fonte:
ISI
Lingua:
ENG
Soggetto:
FACTOR-ALPHA GENE; CENTRAL-NERVOUS-SYSTEM; TRANSCRIPTIONAL ACTIVATION; TRANSDUCTION PATHWAY; TNF-ALPHA; CELLS; P38; MAP; PROMOTER; PHOSPHORYLATION;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
56
Recensione:
Indirizzi per estratti:
Indirizzo: Ludwig, S Inst Med Strahlenkunde & Zellforsch MSZ, Versbacherstr 5, D-97078 Wurzburg, Inst Med Strahlenkunde & Zellforsch MSZ Versbacherstr 5 Wurzburg Germany D-97078
Citazione:
A. Hoffmeyer et al., "Different mitogen-activated protein kinase signaling pathways cooperate toregulate tumor necrosis factor a gene expression in T lymphocytes", J BIOL CHEM, 274(7), 1999, pp. 4319-4327

Abstract

Tumor necrosis factor a (TNF-alpha) is a potent proinflammatory cytokine and plays a crucial role in early events of inflammation. TNF-alpha is primarily produced by monocytes and T lymphocytes, In particular, T-cell-derivedTNF-alpha plays a critical role in autoimmune inflammation and superantigen-induced septic shock. However, little is known about the intracellular signaling pathways that regulate TNF expression in T cells. Here we show thatextracellular signal-regulated kinase (ERK), c-dun N-terminal kinase (JNK), and p38-mitogen-activated protein kinase (MaPK) pathways control the transcription and synthesis of TNF-alpha in A3.01 T cells that produce the cytokine upon T cell activation by costimulation with 12-O-tetradecanoylphorbol-13-acetate (TPA) and ionomycin, Selective activation of each if the distinct MaPK pathways by expression of constitutively active kinases is sufficient for TNF-alpha promoter induction. Furthermore, blockage of all three pathways almost abolishes TPA/ionomycin-induced transcriptional activation of the TNF-alpha promoter. Selective inhibition of one or more MATH pathways impairs TNF-alpha induction by TPA/ionomycin, indicating a cooperation between these signal transduction pathways. Our approach revealed that the MAPK kinase 6 (MKK6)/p38 pathway is involved in both transcriptional and posttranscriptional regulation of TNF expression. Moreover, analysis of the progressive 5' deletion mutants of the TNF-cr promoter indicates that distinct promoter regions are targeted by either ERK-, JNK-, or p38-activating pathways. Thus, unlike what has been reported for other TNF-alpha-producing cells,all three MAPK pathways are critical and cooperate to regulate transcription of the TNF-alpha gene in T lymphocytes, suggesting a T-cell-specific regulation of the cytokine.

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Documento generato il 01/10/20 alle ore 06:45:54