REGULATION OF EXPRESSION OFF TRANSMEMBRANE AND SOLUBLE 75 KDA TUMOR-NECROSIS-FACTOR RECEPTORS BY INTERFERON-GAMMA AND GRANULOCYTE-MACROPHAGE COLONY-STIMULATING FACTOR INVOLVES TRANSCRIPTIONAL ACTIVATION

The receptors for tumor necrosis factor (TNF) play an important role i n the response to this cytokine, both as signal transducing molecules and, in their shed forms, as regulators of TNF availability, Expressio n of the receptors was studied in the human monocytic leukemia line TH P-1. Within two days of incubation, the proinflammatory cytokines, int erferon (IFN)-gamma and granulocyte-macrophage colony-stimulating fact or (GM-CSF), each induced a slight increase in cell surface expression of the 75 kDa TNF receptors (TNF-R75), and a more pronounced increase in the generation of soluble TNF-R75. Similarly receptor mRNA levels were increased in response to both cytokines, GM-CSF and IFN-gamma in combination induced a much stronger increase in cell surface and solub le receptors as weal as in receptor mRNA. Expression of the 55 kDa TNF receptor and its mRNA was largely unaffected by the two cytokines. Ex periments using TNF-neutralizing antibodies indicate that the changes in TNF-R75 expression occurred independently olf endogenously-produced TNF, The half life of TNF-R75 mRNA in cells exposed to GM-CSF + IFN-g amma did not differ significantly from that in untreated cells. Accord ing to nuclear run-on assays the synthesis of TNF-R75 mRNA in cells tr eated with GM-CSF + IFN-gamma, as well as with the phorbol ester TPA, was markedly increased compared to untreated cells, indicating that th e observed changes in receptor expression primarily involve altered tr anscription of the gene, The results suggest that in inflammatory proc esses, GM-CSF and IFN-gamma contribute to increased synthesis of TNF-R 75 by monocytic cells, a prerequisite for the formation of large amoun ts of soluble receptors.