Common and distinct signaling pathways mediate the induction of TNF-alpha and IL-5 in IgE plus antigen-stimulated mast cells.
A small number of signaling cascades represented by mitogen-activated protein kinases, phosphoinositol-3-kinase, protein kinase C, signal transducers and activators of transcription, Ca2+/calcineurin, and a few other molecules are linked to an incomparably large number of surface receptors. Parallel activation of several of these pathways and the existence of isozymes for a number of signal transmitting molecules generate the required complexity and specificity matching the receptor variety. Here we show that the proinflammatory mediator TNF-alpha and the growth factor IL-5 are activated along common and distinct signaling cascades in allergically stimulated murine mast cells. Both of them are dependent on Ca2+ influx, activation of calcineurin and nuclear factor of activated T cells as well as a member of the atypical PKC family, most likely PKCmu. Additionally, mitogen-activated protein kinases for TNF-alpha and members of the classical or nonclassical PKCs for IL-5, respectively, were identified as additional required pathways. Inhibition of the classical and nonclassical PKCs, however, does not abrogate IL-5 induction but instead leads to a switch to mitogen-activated protein kinases, which then become essential. The activated branches of this "salvage" signaling cascade are represented by extracellular signal-regulated kinase 1/2 and c-jun NH2 terminal kinase 1 in allergically stimulated mast cells.
Csonga
R
R
Department of Immunology, Novartis Research Institute, Vienna, Austria.
Prieschl
E E
EE
Jaksche
D
D
Novotny
V
V
Baumruker
T
T
D000818:Animals; D000941:Antigens; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology; D002227:Carbazoles / Q000494:pharmacology; D002478:Cells, Cultured; D020843:Chamomile; D004268:DNA-Binding Proteins / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D005786:Gene Expression Regulation; D007073:Immunoglobulin E / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology; D015848:Interleukin-5 / Q000096:biosynthesis*; D008407:Mast Cells / Q000276:immunology*; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D009822:Oils, Volatile / Q000494:pharmacology; D010946:Plants, Medicinal; D011401:Promoter Regions, Genetic; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000502:physiology; D015398:Signal Transduction; D014157:Transcription Factors / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
D000941:Antigens; D002227:Carbazoles; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D005419:Flavonoids; D007211:Indoles; D015848:Interleukin-5; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D009822:Oils, Volatile; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; C081021:Go 6976; D007073:Immunoglobulin E; D011493:Protein Kinase C; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one