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

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) beta(2)-integrin on calcium ionophore stimulated human blood granulocytes and suppressed synthesis of interleukin-1 beta in lipopolysaccharide-stimulated human blood monocytes and U937 cells by reducing mRNA levels. Lipid mediators promote Mac-1 exocytosis and transcription of interleukin-1 beta, 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.