Mechanism of age-associated up-regulation in macrophage PGE2 synthesis

Abstract

Many physiological functions of the body change during the aging process. Dysregulated immune and inflammatory responses have been well documented in both humans and animals. The investigation into the cellular and molecular mechanism underlying these disorders has provided compelling evidence that up-regulated cyclooxygenase (COX)-2 and its product, particularly prostaglandin (PG)E2, play a critical role in the age-associated dysregulation of the immune and inflammatory responses. In particular, several studies have shown that increased PGE2 production in old macrophages (Mphi) contributes to the suppression of T cell function with aging. Furthermore, interventions targeted at decreasing PGE2 production have been shown to enhance T cell-mediated function. COX-2 and its catalytic products are also suggested to play a key role in age-related neurodegenerative diseases such as Alzheimer's and Parkinson's disease. Administration of anti-inflammatory drugs which inhibit COX activity has been shown, by some investigators, to be beneficial in preventing and treating these diseases. It is, thus, important to understand the underlying mechanisms of age-related COX-2 up-regulation and to delineate the factors, which contribute to this age-related change. This review focuses on the regulation of PGE2 production in murine Mphi; the age-associated changes in COX-2 expression; and its implication for certain disorders observed in the aged immune system and brain. Increased PGE2 production has been shown to be mainly due to an increase in COX activity, which is, in turn, due to an increase in COX-2 protein and mRNA expression. Elevated COX-2 mRNA represents a higher transcription rate rather than an altered stability of COX-2 mRNA. Upon stimulation, Mphi from old mice generate more ceramide, a sphingolipid, than those from young mice. Ceramide has been shown to induce, by itself, and also augment, LPS-stimulated COX-2 expression and PGE2 production. Several lines of evidence indicate that the higher ceramide levels in old Mphi are an important contributor to the age-associated up-regulation of COX-2 in Mphi. Ceramide up-regulates COX-2 transcription by increasing activation of transcription factor NF-kappaB. Further understanding of molecular mechanisms involved in COX-2 up-regulation will help in delineating fundamental age-related changes, which lead to the development of immune and neurological disorders in the aged.