Constitutive and inducible mechanisms for synthesis and release of cytokines in immune cell lines.
We found that production and release of two functionally antagonistic cytokines, TGF-beta and TNF-alpha, were regulated differently in the mast cell, T cell, and macrophage cell lines RBL-2H3, MLA-144, and U-937, respectively. TGF-beta was produced and released constitutively in all three cell lines. When, however, the cell lines were stimulated with Ag, LPS, or calcium ionophore plus PMA, acceleration of release and some additional production of TGF-beta were apparent. In contrast, TNF-alpha was produced and released only when these lines were stimulated. Although neither the glucocorticoid, dexamethasone, nor the protein kinase C inhibitor, Ro31-7549, suppressed constitutive production or release of TGF-beta, these agents inhibited TNF-alpha production and the inducible component of TGF-beta production noted above. The release of these cytokines, whether constitutive or inducible, was dependent on Golgi-processing as indicated by inhibition with brefeldin A. Therefore, although both types of cytokines were processed by Golgi, only TNF-alpha and the inducible component of TGF-beta production were protein kinase C or steroid-regulated processes. These findings suggested that constitutive and inducible pathways exist for production and release of cytokines and that the inducible pathways can be selectively suppressed by pharmacologic agents.
Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
R A
RA
Baumgartner
V A
VA
Deramo
M A
MA
Beaven
D000818:Animals; D020126:Brefeldin A; D003517:Cyclopentanes / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation; D006056:Golgi Apparatus / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D015471:Leukemia, Basophilic, Acute / Q000473:pathology; D008213:Lymphocyte Activation / Q000187:drug effects; D016403:Lymphoma, Large B-Cell, Diffuse / Q000378:metabolism / Q000473:pathology; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000378:metabolism; D008301:Maleimides / Q000494:pharmacology; D008407:Mast Cells / Q000378:metabolism; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D051381:Rats; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000096:biosynthesis* / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000378:metabolism
D003517:Cyclopentanes; D004791:Enzyme Inhibitors; D007211:Indoles; D008301:Maleimides; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D020126:Brefeldin A; D003907:Dexamethasone; D011493:Protein Kinase C; C064755:Ro 31-7549