Leukocyte lipid body formation and eicosanoid generation: cyclooxygenase-independent inhibition by aspirin.
Lipid bodies, cytoplasmic inclusions that develop in cells associated with inflammation, are inducible structures that might participate in generating inflammatory eicosanoids. Cis-unsaturated fatty acids (arachidonic and oleic acids) rapidly induced lipid body formation in leukocytes, and this lipid body induction was inhibited by aspirin and nonsteroidal antiinflammatory drugs (NSAIDs). Several findings indicates that the inhibitory effect of aspirin and NSAIDs on lipid body formation was independent of cyclooxygenase (COX) inhibition. First, the non-COX inhibitor, sodium salicylate, was as potent as aspirin in inhibiting lipid body formation elicited by cis-fatty acids. Second, cis-fatty acid-induced lipid body formation was not impaired in macrophages from COX-1 or COX-2 genetically deficient mice. Finally, NSAIDs inhibited arachidonic acid-induced lipid body formation likewise in macrophages from wild-type and COX-1- and COX-2-deficient mice. An enhanced capacity to generate eicosanoids developed after 1 hr concordantly with cis-fatty acid-induced lipid body formation. Arachidonic and oleic acid-induced lipid body numbers correlated with the enhanced levels of leukotrienes B4 and C4 and prostaglandin E2 produced after submaximal calcium ionophore stimulation. Aspirin and NSAIDs inhibited both induced lipid body formation and the enhanced capacity for forming leukotrienes as well as prostaglandins. Our studies indicate that lipid body formation is an inducible early response in leukocytes that correlates with enhanced eicosanoid synthesis. Aspirin and NSAIDs, independent of COX inhibition, inhibit cis-fatty acid-induced lipid body formation in leukocytes and in concert inhibit the enhanced synthesis of leukotrienes and prostaglandins.
Bozza
P T
PT
Harvard Thorndike Laboratory, Beth Israel Hospital, Harvard Medical School, Boston, MA 02215-5491, USA.
Payne
J L
JL
Morham
S G
SG
Langenbach
R
R
Smithies
O
O
Weller
P F
PF
D000328:Adult; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001168:Arthritis / Q000473:pathology; D001241:Aspirin / Q000494:pharmacology*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D015777:Eicosanoids / Q000378:metabolism; D006801:Humans; D050356:Lipid Metabolism; D051379:Mice; D009504:Neutrophils / Q000378:metabolism / Q000648:ultrastructure*; D015388:Organelles / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D015777:Eicosanoids; D011451:Prostaglandin-Endoperoxide Synthases; D001241:Aspirin