TNF-induced activation of NF-kappa B.
Tumor Necrosis Factor (TNF) is one of the most potent physiological inducers of the nuclear transcription factor NF-kappa B. In light of the pivotal role of NF-kappa B in the development of immune responses and activation of HIV replication, the identification of TNF signal transduction pathways involved in NF-kappa B activation is of particular interest. Data from our laboratory demonstrate that the TNF signal transduction pathway-mediating NF-kappa B activation involves two phospholipases, a phosphatidylcholine-specific phospholipase C (PC-PLC) and an endosomal acidic sphingomyelinase (aSMase). The aSMase activation by TNF is secondary to the generation of 1,2-diacylglycerol (DAG) produced by a TNF-responsive PC-PLC. SMase and its product ceramide induce degradation of the NF-kappa B inhibitor I kappa B as well as NF-kappa B activation. Besides endosomal acidic SMase, TNF also rapidly activates a plasmamembrane-associated neural SMase (nSMase), that, however is not involved in TNF-induced NF-kappa B activation. NSMase and aSMase are activated by different cytoplasmic domains of the 55 kDa TNF-receptor and are coupled to select pathways of TNF signaling. Ceramide generated by nSMase directs the activation of proline-directed serin/threonine protein kinases and phospholipase A2 and ceramide produced by aSMase triggers the activation of NF-kappa B. No apparent crosstalk was detected between nSMase and aSMase pathways, indicating that ceramide action depends on the topology of its production.
Institut für Medizinische Mikrobiologie und Hygiene, Technische Universität München, Germany.
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S
Schütze
K
K
Wiegmann
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T
Machleidt
M
M
Krönke
D000595:Amino Acid Sequence; D000818:Animals; D006801:Humans; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000096:biosynthesis* / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha