POTENTIAL ROLE FOR PHOSPHATIDIC-ACID IN MEDIATING THE INFLAMMATORY RESPONSES TO TNF-ALPHA AND IL-1-BETA

Tumor necrosis factor alpha (TNF alpha), interleukin 1 beta (IL-1 beta ), and endotoxin (LPS) are potent pro-inflammatory mediators which ind uce multiple and diverse biological responses in a wide variety of cel l types. However, these pro-inflammatory mediators also have significa nt overlap and redundancy in their biological effects. This suggests t hat there is significant diversity in second messenger signal transduc tion systems induced by these stimuli to explain the diversity in biol ogical responses, as well as significant redundancy. Here we show that one such second messenger common to several proinflammatory stimuli m ay be phosphatidic acid (PA). Intracellular PA species, which may have intracellular signaling functions, are rapidly induced in P388 monocy tic leukemia cells by TNF alpha, IL-1 beta, or LPS. These PA species v ary according to the bond type (i.e., sn-1 ester vs. ether vs. vinyl e ther), acyl chain length, and the degree of saturation in the sn-1 and sn-2 positions. Although PA itself may have direct second messenger a ctivities, many of the PA species induced are converted to diacylglyce rol species (DG), which are structurally distinct from the DGs generat ed by phosphatidylcholine-specific phospholipase C (PC-PLC). Lisofylli ne [(R)-1-(5-hydroxyhexyl)-3,7-dimethylxanthine; LSF] selectively inhi bits generation of selected species of PA in P388 cells induced by TNF alpha, IL-1 beta, or LPS. TNF alpha-induced sphingomyelin hydrolysis, PLC-mediated PC hydrolysis, and DG kinase-mediated PA formation or TN F alpha-induced NF-kappa B activation and apoptosis are not inhibited by LSF. LSF has a marked protective effect in a variety of acute infla mmatory animal models that may be due to inhibition of this shared sec ond messenger pathway involving PA. (C) 1994 Wiley-Liss, Inc.