Abstract
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.
Highlights
Obesity is a chronic low-grade inflammatory condition in which adipose tissue serves as the source of inflammatory mediators
We show for the first time that preadipocytes are target cells for the action of MT-III, a representative group IIA (GIIA) secreted phospholipase A2 (sPLA2), which triggers inflammatory pathways implicated in the development of obesity
In view of previous evidence that the engagement of distinct EP receptors by prostaglandin E2 (PGE2) triggers signalling pathways linked to the biosynthesis of proinflammatory cytokines [77,78], our findings indicate that PGE2 biosynthesis, induced by MT-III, is an essential step for the activation of proinflammatory pathways linked to cytokine production in preadipocytes stimulated by the phospholipase A2
Summary
Obesity is a chronic low-grade inflammatory condition in which adipose tissue serves as the source of inflammatory mediators. Besides their role in cell membrane physiology, mammalian group IIA sPLA2 are known as important autocrine and paracrine players in inflammatory processes by releasing fatty acids from cell membranes leading to production of pro-inflammatory mediators such as leukotrienes and prostaglandins [3,4,5] Their role in metabolic diseases, such as obesity, has been shown [1,4,6]. This enzyme is able to upregulate the differentiation of macrophages into foam cells [20], which are closely associated with diseases linked to lipid imbalance, including obesity [21,22] On these bases, in this study, the ability of MT-III to activate proinflammatory responses in preadipocytes focusing on the biosynthesis of lipid mediators, cytokines and adipokines and the mechanisms involved in this process were investigated. EP3 and EP4 receptors play key roles in the release of PGE2 and cytokines
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