Signaling events involved in cytokine and chemokine production induced by secretory phospholipase A2 in human lung macrophages.

Secretory phospholipases A(2) (sPLA(2)) are enzymes released during inflammatory reactions. These molecules activate immune cells by mechanisms either related or unrelated to their enzymatic activity. We examined the signaling events activated by group IA (GIA) and group IB (GIB) sPLA(2) in human lung macrophages leading to cytokine/chemokine production. sPLA(2) induced the production of cytokines (TNF-alpha, IL-6 and IL-10) and chemokines (CCL2, CCL3, CCL4 and CXCL8), whereas no effect was observed on IL-12, CCL1, CCL5 and CCL22. sPLA(2) induced the phosphorylation of the MAPK p38 and ERK1/2, and inhibition of these kinases by SB203580 and PD98059, respectively, reduced TNF-alpha and CXCL8 release. Suppression of sPLA(2) enzymatic activity by a site-directed inhibitor influenced neither cytokine/chemokine production nor activation of MAPK, whereas alteration of sPLA(2) secondary structure suppressed both responses. GIA activated the phosphatidylinositol 3-kinase (PI3 K)/Akt system and a specific inhibitor of PI3 K (LY294002) reduced sPLA(2)-induced release of TNF-alpha and CXCL8. GIA promoted phosphorylation and degradation of IkappaB and inhibition of NF-kappaB by MG-132 and 6-amino-4-phenoxyphenylethylamino-quinazoline suppressed the production of TNF-alpha and CXCL8. These results indicate that sPLA(2) induce the production of cytokines and chemokines in human macrophages by a non-enzymatic mechanism involving the PI3 K/Akt system, the MAPK p38 and ERK1/2 and NF-kappaB.