SULFASALAZINE INHIBITION OF HUMAN GRANULOCYTE ACTIVATION BY INHIBITION OF 2ND MESSENGER COMPOUNDS

The effects of sulphasalazine on the production of second messenger compounds in human granulocytes have been characterised by various stimuli. The increases in cytosolic calcium, inositol trisphosphate, diacylglycerol, and phosphatidic acid (all important mediators of intracellular signal transduction) triggered by stimulation were inhibited by sulphasalazine. The metabolites 5-aminosalicylic acid and sulphapyridine were less potent inhibitors than the mother compound. It is concluded that sulphasalazine inhibits the synthesis of phosphoinositide derived second messenger compounds at the level of phospholipase C or its regulatory guanosine 5'-triphosphate (GTP) binding protein. Inhibition of phosphatidic acid synthesis was either due to the same mechanism, or to interaction with a phospholipase D regulating GTP binding protein.