Suppression of cytokine synthesis, integrin expression and chronic inflammation by inhibitors of cytosolic phospholipase A2.
To define the isoform of phospholipases A2 active in inflammation we evaluated the effects of low-molecular-weight inhibitors of secretory and cytosolic phospholipases A2. We found that inhibitors of cytosolic phospholipase A2 had therapeutic efficacy in an in vivo model of chronic inflammation (rat adjuvant arthritis), whereas inhibitors of secretory phospholipase A2 had no beneficial effect. In vitro, inhibitors of cytosolic phospholipase A2 diminished surface expression of Mac-1 (CD11b/CD18) beta2-integrin on calcium ionophore-stimulated human blood granulocytes and suppressed synthesis of interleukin-1beta in lipopolysaccharide-stimulated human blood monocytes and U937 cells by reducing mRNA levels. Lipid mediators promote Mac-1 exocytosis and transcription of interleukin-1beta, which further enhances cytosolic phospholipase A2 activity and expression. Thus, superinduction of cytosolic phospholipase A2 may establish a positive feedback loop, converting acute inflammation into chronic inflammation. Consequently, inhibitors of cytosolic phospholipase A2 may prevent inflammation in vivo by interfering with cellular activation and infiltration. We conclude that cytosolic phospholipase A2 but not secretory phospholipase A2 is the predominant enzyme in inflammatory signalling.
Amandi-Burgermeister
E
E
Department of Molecular Pharmacology, Boehringer Mannheim GmbH, Nonnewald 2, Penzberg, Germany.
Tibes
U
U
Kaiser
B M
BM
Friebe
W G
WG
Scheuer
W V
WV
D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy; D000001:Calcimycin / Q000037:antagonists & inhibitors; D002460:Cell Line; D002908:Chronic Disease; D016207:Cytokines / Q000096:biosynthesis*; D003600:Cytosol / Q000187:drug effects* / Q000201:enzymology; D003864:Depression, Chemical; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D007249:Inflammation / Q000188:drug therapy*; D016023:Integrins / Q000096:biosynthesis*; D008297:Male; D008970:Molecular Weight; D010741:Phospholipases A / Q000037:antagonists & inhibitors*; D054467:Phospholipases A2; D051381:Rats; D011917:Rats, Inbred Lew
D016207:Cytokines; D004791:Enzyme Inhibitors; D016023:Integrins; D000001:Calcimycin; D010741:Phospholipases A; D054467:Phospholipases A2