title: Potential role for phosphatidic acid in mediating the inflammatory responses to TNF alpha and IL-1 beta.
abstract: Tumor necrosis factor alpha (TNF alpha), interleukin 1 beta (IL-1 beta), and endotoxin (LPS) are potent pro-inflammatory mediators which induce multiple and diverse biological responses in a wide variety of cell types. However, these pro-inflammatory mediators also have significant overlap and redundancy in their biological effects. This suggests that there is significant diversity in second messenger signal transduction systems induced by these stimuli to explain the diversity in biological responses, as well as significant redundancy. Here we show that one such second messenger common to several proinflammatory stimuli may be phosphatidic acid (PA). Intracellular PA species, which may have intracellular signaling functions, are rapidly induced in P388 monocytic leukemia cells by TNF alpha, IL-1 beta, or LPS. These PA species vary according to the bond type (i.e., sn-1 ester vs. ether vs. vinyl ether), acyl chain length, and the degree of saturation in the sn-1 and sn-2 positions. Although PA itself may have direct second messenger activities, many of the PA species induced are converted to diacylglycerol species (DG), which are structurally distinct from the DGs generated by phosphatidylcholine-specific phospholipase C (PC-PLC). Lisofylline [(R)-1-(5-hydroxyhexyl)-3,7-dimethylxanthine; LSF] selectively inhibits 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 TNF alpha-induced NF-kappa B activation and apoptosis are not inhibited by LSF. LSF has a marked protective effect in a variety of acute inflammatory animal models that may be due to inhibition of this shared second messenger pathway involving PA.
authors.affiliation: Cell Therapeutics Inc., Division of Lipid Biochemistry/Second Messenger Chemistry, Seattle, Washington 98119, USA.
authors.forename: S
authors.initials: S
authors.lastname: Bursten
authors.forename: R
authors.initials: R
authors.lastname: Weeks
authors.forename: J
authors.initials: J
authors.lastname: West
authors.forename: T
authors.initials: T
authors.lastname: Le
authors.forename: T
authors.initials: T
authors.lastname: Wilson
authors.forename: D
authors.initials: D
authors.lastname: Porubek
authors.forename: J A
authors.initials: JA
authors.lastname: Bianco
authors.forename: J W
authors.initials: JW
authors.lastname: Singer
authors.forename: G C
authors.initials: GC
authors.lastname: Rice
mesh_terms: D000818:Animals; D001483:Base Sequence; D002851:Chromatography, High Pressure Liquid; D004075:Diglycerides / Q000096:biosynthesis; D005260:Female; D007249:Inflammation / Q000209:etiology*; D007375:Interleukin-1 / Q000494:pharmacology*; D008070:Lipopolysaccharides; D013058:Mass Spectrometry; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism; D010431:Pentoxifylline / Q000031:analogs & derivatives / Q000494:pharmacology; D010712:Phosphatidic Acids / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*; D015290:Second Messenger Systems; D012772:Shock, Septic / Q000139:chemically induced / Q000503:physiopathology; D013109:Sphingomyelins / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D004075:Diglycerides; D007375:Interleukin-1; D008070:Lipopolysaccharides; D016328:NF-kappa B; D010712:Phosphatidic Acids; D013109:Sphingomyelins; D014409:Tumor Necrosis Factor-alpha; C025189:lisofylline; D010431:Pentoxifylline