Downregulation of tumor necrosis factor (TNF) sensitivity via modulation of TNF binding capacity by protein kinase C activators.

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Abstract
The regulatory action of activators for protein kinase C on the specific binding capacity for recombinant human tumor necrosis factor .alpha. (TNF-.alpha.) was studied on various human cell lines. Phorbol myristate acetate (PMA) and oleyl acetyl glycerol (OAG) both are able to rapidly downregulate TNF-binding capacity of normal and malignant cells derived from various tissues. As PMA treatment did not enhance internalization of TNF-.alpha.-receptor complexes at 37.degree. C, and since OAG was able to downregulate TNF-binding capacity under conditions where internalization and shedding of receptor protein are prevented, we conclude that protein kinase C controls ligand affinity of the TNF-receptor protein, possibly via direct phosphorylation. Protein kinase C triggered downregulation of TNF-.alpha.-binding capacity concomitantly resulted in reduction of TNF-.alpha.-sensitivity, as revealed from decreased cytotoxic action of TNF-.alpha. on L 929 cells and from inhibition of TNF-.alpha.-mediated enhancement of HLA class II antigen expression in Colo 205 cells. Restoration of TNF-binding capacity upon abrogation of protein kinase C stimulation leads to full recovery of TNF responsiveness, further supporting the close linkage of TNF-receptor expression and TNF sensitivity. These data suggest that regulation of TNF-binding capacity by protein kinase C is one of the cellular control mechanisms of TNF responsiveness.