Regulation of Macrophage Cytokine Production by Prostaglandin E2

Abstract

Prostaglandin E 2 (PGE 2 ) modulates a variety of physiological processes including the production of inflammatory cytokines. There are two cyclooxygenase (Cox) enzymes, Cox-1 and Cox-2, that are responsible for initiating PGE 2 synthesis. These isozymes catalyze identical biosynthetic reactions but are regulated by different mechanisms in the cell. This report examines differences in the roles of Cox-1 and Cox-2 in regulating cytokine synthesis in macrophages. We employed agents that selectively modulate the activity of each isozyme and measured their effects on synthesis of interleukin (IL)-6, IL-1, and tumor necrosis factor-␣ by peritoneal macrophages. Among these three cytokines, only IL-6 synthesis was stimulated by production of endogenous PGE 2 . This effect was specifically linked to activation of Cox-2 and not Cox-1. The specificity derives, partly, from the timing of the production of PGE 2 following stimulation of each isozyme and from induction of ancillary signals that control the response to PGE 2 . The experimental findings demonstrate that the effects of Cox-1 and Cox-2 activity on macrophage IL-6 synthesis are segregated. This provides a mechanism for IL-6 to be induced selectively during inflammation.

Protective effect of the G-765C COX-2 polymorphism on subclinical atherosclerosis and inflammatory markers in asymptomatic subjects with cardiovascular risk factors

“…Whereas there are several evidences linking COX-2 expression and inflammation, the precise mechanism remains unclear [27 -29]. An association between COX-2 and IL-6 has been established in macrophages via PGE 2 [30]; furthermore, the magnitude of rise in CRP levels in cardiovascular patients was also found to be strongly dependent on the À 765G > C polymorphism [17]; since IL-6 is known to regulate CRP [31,32], it can be speculated that this polymorphism influences CRP levels via IL-6, which is also supported by our present findings. Subjects homozygous for the C allele also showed lower vWF levels, suggesting reduced endothelial damage [33] as compared with the remaining genotypes.…”

Prostaglandin Levels in Stimulated Macrophages Are Controlled by Phospholipase A2-activating Protein and by Activation of Phospholipase C and D

“…PGE 2 has been shown to increase cPLA 2 and COX-2 levels and thereby amplify its own production, as well as to increase synthesis of some inflammatory cytokines resulting in a perpetuation of the immune response (23,41,42).…”

Prostaglandins are required for CREB activation and cellular proliferation during liver regeneration

“…For example, the proinflammatory action of TNF␣ is in part mediated by its induction of the prostaglandin-synthesizing enzyme cyclooxygenase-2 (COX-2) (25). Furthermore, PGE 2 stimulates IL-6 production in macrophages (26).…”