title: Aspirin (ASA) regulates 5-lipoxygenase activity and peroxisome proliferator-activated receptor alpha-mediated CINC-1 release in rat liver cells: novel actions of lipoxin A4 (LXA4) and ASA-triggered 15-epi-LXA4.
abstract: The mechanism of action of aspirin (ASA) is related to cyclooxygenase (COX) inhibition, but additional actions cannot be excluded for their antiinflammatory properties and antithrombotic activity. In the current investigation, we examined the effects of ASA on COX and 5-lipoxygenase (5-LO) pathways and its impact on peroxisome proliferator-activated receptor alpha (PPARalpha) and cytokine-induced neutrophil chemoattractant-1 (CINC-1) levels in rat liver cells. In Kupffer cells, the liver resident macrophages, ASA switched eicosanoid biosynthesis from prostaglandin E2 (PGE2) to leukotriene B4 (LTB4) and 15-epi-lipoxin A4 (15-epi-LXA4) formation. In hepatocytes, ASA significantly inhibited PPARalpha protein expression and CINC-1 secretion, effects that were also observed in hepatocytes exposed to the selective PPARalpha agonist Wy-14643. In contrast, treatment of hepatocytes with PGE2 in association with LTB4 had no significant effect on PPARalpha but stimulated CINC-1 release. Interestingly, the endogenous antiinflammatory eicosanoids LXA4 and ASA-triggered 15-epi-LXA4, in addition to inhibiting macrophage 5-LO activity to a similar extent as PGE2, significantly reduced PPARalpha and CINC-1 levels in hepatocytes. Taken together and because arachidonic acid-derived products, PPARalpha levels, and CINC-1 secretion are involved in the extent and duration of an inflammatory response, these findings provide additional molecular mechanisms for the pharmacological properties of ASA.
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism*; D016718:Arachidonic Acid / Q000378:metabolism; D001241:Aspirin / Q000494:pharmacology*; D054360:Chemokine CXCL1; D018925:Chemokines / Q000096:biosynthesis*; D019743:Chemokines, CXC; D002630:Chemotactic Factors / Q000096:biosynthesis*; D015232:Dinoprostone / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006893:Hydroxyeicosatetraenoic Acids / Q000096:biosynthesis / Q000494:pharmacology; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis*; D007728:Kupffer Cells / Q000187:drug effects / Q000378:metabolism; D007975:Leukotriene B4 / Q000378:metabolism; D044045:Lipoxins; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D008954:Models, Biological; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D054360:Chemokine CXCL1; D018925:Chemokines; D019743:Chemokines, CXC; D002630:Chemotactic Factors; C513297:Cxcl1 protein, rat; D006893:Hydroxyeicosatetraenoic Acids; D036341:Intercellular Signaling Peptides and Proteins; D044045:Lipoxins; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; C040527:lipoxin A4; D007975:Leukotriene B4; D016718:Arachidonic Acid; D001094:Arachidonate 5-Lipoxygenase; D015232:Dinoprostone; D001241:Aspirin