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-alpha and TNF-alpha, were regulated differently in the mast cell, T cell, and macrophage cell lines REL-2H3, MLA-144, and U-9 37, respectively. TGF-alpha was produced and released constitutively i n all three cell lines. When, however, the cell lines were stimulated with Ag, LPS, or calcium ionophore plus PMA, acceleration of release a nd some additional production of TGF-beta were apparent. In contrast, TNF-alpha was produced and released only when these lines were stimula ted. Although neither the glucocorticoid, dexamethasone, nor the prote in kinase C inhibitor, Ro31-7549, suppressed constitutive production o r release of TGF-beta, these agents inhibited TNF-alpha production and the inducible component of TGF-beta production noted above. The relea se of these cytokines, whether constitutive or inducible, was dependen t on Golgi-processing as indicated by inhibition with brefeldin A. The refore, although both types of cytokines were processed by Golgi, only TNF-alpha and the inducible component of TGF-beta production were pro tein kinase C or steroid-regulated processes. These findings suggested that constitutive and inducible pathways exist for production and rel ease of cytokines and that the inducible pathways can be selectively s uppressed by pharmacologic agents.