EFFECT OF PROPRANOLOL AND IFN-BETA ON THE INDUCTION OF MHC CLASS-II EXPRESSION AND CYTOKINE PRODUCTION BY IFN-GAMMA IN THP-1 HUMAN MONOCYTIC CELLS

This study was undertaken to investigate the effects of propranolol, I FN-beta, and the protein kinase modulators on IFN-gamma induction of M HC class II antigen expression and cytokine production in THP-1 human monocytic cells. IFN-gamma induced expression of HLA-DR and DQ molecul es and secretion of the monokines IL-1 beta and TNF-alpha in THP-1 cel ls in a time and dose-dependent manner. The effect of IFN-gamma on cla ss II HLA antigens was dose-dependently inhibited by IFN-beta. H-7, ph loretin, staurosporine as well as GF 109203X are selective enzyme inhi bitors of protein kinase C (PKC), down-regulating IFN-gamma induced MH C class II expression and cytokine production. Stimulators of PKC, lik e PMA, replaced IFN-gamma in the induction of monokines in THP-1 cells , whereas the addition of HA 1004 or arachidonic acid to the culture h ad no effect on IFN-gamma mediated changes. Blocking of phospholipase D (PLD)-derived diacylglycerol (DAG) formation by propranolol abrogate d IFN-gamma increased HLA class II expression and IL-1 beta secretion, but had little effect on IFN-gamma induced TNF-alpha production. Thes e findings appear to suggest that PLD-derived phosphatidate is not the primary source of DAG production in IFN-gamma-induced TNF-alpha secre tion, but may be necessary for IFN-gamma-mediated MHC class II inducti on and IL-1 beta production in human monocytes, whereas phospholipase A(2) may not be required for IFN-gamma activation of PKC in the proces s.