DOWN-REGULATION OF HUMAN TUMOR NECROSIS FACTOR-BETA GENE-EXPRESSION BY CELLS WITH SUPPRESSIVE ACTIVITY

Human TNF-beta (lymphotoxin) gene expression is down-regulated by immu nosuppression. Induction of TNF-beta mRNA in lymphoid cells is greatly enhanced by gamma-irradiation, cyclophosphamide and cimetidine, agent s that each inhibit activation of suppressive cells. The level of TNF- beta mRNA expressed in response to stimulation, whether by mitogen or antigen, is reduced strongly by concomitant activation of suppressive cell subsets. Removal of CD8 or CD11b cells leads to a pronounced supe rinduction of TNF-beta mRNA in the depleted cell population. Induction of TNF-beta mRNA precedes appearance of suppressive cell activity, al lowing for temporary expression. The TNF-beta gene is as sensitive as IFN-gamma and IL-2 genes to suppression. Hence, three genes characteri stically expressed in Th1 cells, encoding IL-2, IFN-gamma, and TNF-bet a, are similarly regulated by cell-mediated suppression. Actual levels of TNF-beta during an immune response are determined by the balance b etween activities of expressing and suppressing cell subsets, both tra nsiently manifested. (C) 1996 Elsevier Science B.V.