Suppression of cytokine synthesis, integrin expression and chronic inflammation by inhibitors of cytosolic phospholipase A 2

Abstract

To define the isoform of phospholipases A 2 active in inflammation we evaluated the effects of low-molecular-weight inhibitors of secretory and cytosolic phospholipases A 2. We found that inhibitors of cytosolic phospholipase A 2 had therapeutic efficacy in an in vivo model of chronic inflammation (rat adjuvant arthritis), whereas inhibitors of secretory phospholipase A 2 had no beneficial effect. In vitro, inhibitors of cytosolic phospholipase A 2 diminished surface expression of Mac-1 (CD11b/CD18) β 2-integrin on calcium ionophore-stimulated human blood granulocytes and suppressed synthesis of interleukin-1β in lipopolysaccharide-stimulated human blood monocytes and U937 cells by reducing mRNA levels. Lipid mediators promote Mac-1 exocytosis and transcription of interleukin-1β, which further enhances cytosolic phospholipase A 2 activity and expression. Thus, superinduction of cytosolic phospholipase A 2 may establish a positive feedback loop, converting acute inflammation into chronic inflammation. Consequently, inhibitors of cytosolic phospholipase A 2 may prevent inflammation in vivo by interfering with cellular activation and infiltration. We conclude that cytosolic phospholipase A 2 but not secretory phospholipase A 2 is the predominant enzyme in inflammatory signalling.