A Representative GIIA Phospholipase A₂ Activates Preadipocytes to Produce Inflammatory Mediators Implicated in...

Adipose tissue secretes proinflammatory mediators which promote systemic and adipose tissue inflammation seen in obesity. Group IIA (GIIA)-secreted phospholipase A₂ (sPLA₂) enzymes are found to be elevated in plasma and adipose tissue from obese patients and are active during inflammation, generating proinflammatory mediators, including prostaglandin E₂ (PGE₂). PGE₂ exerts anti-lipolytic actions and increases triacylglycerol levels in adipose tissue. However, the inflammatory actions of GIIA sPLA₂s in adipose tissue cells and mechanisms leading to increased PGE₂ levels in these cells are unclear. This study investigates the ability of a representative GIIA sPLA₂, MT-III, to activate proinflammatory responses in preadipocytes, focusing on the biosynthesis of prostaglandins, adipocytokines and mechanisms involved in these effects. Our results showed that MT-III induced biosynthesis of PGE₂, PGI₂, MCP-1, IL-6 and gene expression of leptin and adiponectin in preadipocytes. The MT-III-induced PGE₂ biosynthesis was dependent on cytosolic PLA₂ (cPLA₂)-α, cyclooxygenases (COX)-1 and COX-2 pathways and regulated by a positive loop via the EP₄ receptor. Moreover, MT-III upregulated COX-2 and microsomal prostaglandin synthase (mPGES)-1 protein expression. MCP-1 biosynthesis induced by MT-III was dependent on the EP4 receptor, while IL-6 biosynthesis was dependent on EP3 receptor engagement by PGE₂. These data highlight preadipocytes as targets for GIIA sPLA₂s and provide insight into the roles played by this group of sPLA₂s in obesity.