The PTGS2/COX2-PGE2 signaling cascade in inflammation: Pro or anti? A case study with type 1 diabetes mellitus

Abstract

Prostaglandins are lipid mediators involved in physiological processes, such as constriction or dilation of blood vessels, but also pathophysiological processes, which include inflammation, pain and fever. They are produced by almost all cell types in the organism by activation of Prostaglandin endoperoxide synthases/Cyclooxygenases. The inducible Prostaglandin Endoperoxide Synthase 2/Cyclooxygenase 2 (PTGS2/COX2) plays an important role in pathologies associated with inflammatory signaling. The main product derived from PTGS2/COX2 expression and activation is Prostaglandin E₂ (PGE₂), which promotes a wide variety of tissue-specific effects, pending environmental inputs. One of the major sources of PGE₂ are infiltrating inflammatory cells - the production of this molecule increases drastically in damaged tissues. Immune infiltration is a hallmark of type 1 diabetes mellitus, a multifactorial disease that leads to autoimmune-mediated pancreatic beta cell destruction. Controversial effects for the PTGS2/COX2-PGE₂ signaling cascade in pancreatic islet cells subjected to diabetogenic conditions have been reported, allocating PGE₂ as both, cause and consequence of inflammation. Herein, we review the main effects of this molecular pathway in a tissue-specific manner, with a special emphasis on beta cell mass protection/destruction and its potential role in the prevention or development of T1DM. We also discuss strategies to target this pathway for future therapies.

Keywords: Beta cells; Cyclooxygenases; Inflammation; Pancreatic Islets; Prostaglandin; Type 1 Diabetes Mellitus.

Figure 1

PGE₂ synthesis via the Arachidonic Acid pathway. Biosynthesis of prostaglandins. AA is liberated from membrane phospholipids by the action of Phospholipase A₂, that is then converted into PGH₂ by the action of the Cyclooxygenases, a rate-limiting step for prostaglandin biosynthesis. Prostaglandin H₂ (PGH₂) is the unstable precursor of Prostaglandin F₂ (PGF₂), Prostaglandin D₂ (PGD₂), Prostaglandin I₂ (PGI₂), Thromboxane A₂ (TxA₂) and Prostaglandin E₂ (PGE₂). PGE₂ receptors and their related downstream signaling are also shown.

Figure 2

Roles of PTGS2/COX2-PGE₂ in different inflammatory situations. Schematic view of the role and effects of PTGS2/COX2-PGE₂ upon different inflammation-related environments.

Figure 3

Summary of the main signaling pathways activated upon the 4 subtypes of PTGERs/EPs and the physiological outcomes in terms of beta cell survival. Proposed model of shift in receptor selectivity upon elevated production of PGE₂.