Enhancement of TNF-alpha synthesis by overexpression of G alpha z in a mast cell line.
Ag stimulation of mast cells via the IgE receptor (Fc epsilon RI) elicits production and release of numerous cytokines. This activation of Fc epsilon RI initiates various tyrosine kinase-dependent signaling cascades, which ultimately result in the de novo synthesis of cytokines. To date, no heterotrimeric G proteins have been implicated in this process. Here we report that the alpha subunit of the heterotrimeric G protein, Gz, can regulate production of the cytokine, TNF-alpha. The alpha subunit was overexpressed in a cultured mast cell line (RBL-2H3) known to contain G alpha z. In stimulated cells, overexpression of G alpha z significantly enhanced the production of TNF-alpha. This effect of G alpha z appeared to be restricted in that constitutive synthesis of the cytokine, TGF-beta, and Ag-stimulation of the phosphoinositide-dependent secretory pathway were not significantly affected. Thus, G alpha z, a heterotrimeric G protein, appeared to modulate the stimulatory pathways for induction of TNF-alpha synthesis in RBL-2H3 cells.
Baumgartner
R A
RA
Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Hirasawa
N
N
Ozawa
K
K
Gusovsky
F
F
Beaven
M A
MA
D000818:Animals; D001483:Base Sequence; D018076:DNA, Complementary / Q000235:genetics; D003907:Dexamethasone / Q000494:pharmacology; D044385:GTP-Binding Protein alpha Subunits; D019204:GTP-Binding Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D005786:Gene Expression Regulation; D015973:Gene Expression Regulation, Leukemic; D020962:Heterotrimeric GTP-Binding Proteins; D006801:Humans; D007073:Immunoglobulin E / Q000502:physiology; D015471:Leukemia, Basophilic, Acute / Q000473:pathology; D008407:Mast Cells / Q000378:metabolism*; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D010716:Phosphatidylinositols / Q000502:physiology; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D017455:Receptors, IgE / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000235:genetics
D018076:DNA, Complementary; C099387:GNAZ protein, human; D044385:GTP-Binding Protein alpha Subunits; C490963:Gnaz protein, rat; D009363:Neoplasm Proteins; D016376:Oligonucleotides, Antisense; D010716:Phosphatidylinositols; D017455:Receptors, IgE; D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha; D007073:Immunoglobulin E; D003907:Dexamethasone; D011493:Protein Kinase C; D019204:GTP-Binding Proteins; D020962:Heterotrimeric GTP-Binding Proteins