COX was found to be a membrane-bound heme-containing glycoprotein that was highly abundant in the endoplasmic reticulum of cells that produce prostanoids. In the early 1990's, a second, inducible isoform of COX termed COX-2 was discovered. COX-2, unlike the constitutive isoform COX-1, is induced by several inflammatory and cell-activating stimuli including lipopolysaccharide (LPS), pro-inflammatory cytokines, phorbol esters, and growth factors. Antiinflammatory cytokines such as IL-10 as well as corticosteroids decrease COX-2 expression. COX-2 has multiple transcriptional regulatory sequences in its promoter region, including a TATA box, an NF-IL6 motif, 2 AP-2 sites, 3 Sp1 sites, 2 NF-κB sites, a CRE motif, and an E-box. Thus, COX-2 is the isoform responsible for ligand-induced prostanoid production.
While COX-1 is located both in the lumen of the endoplasmic reticulum and nuclear envelope, COX-2 is enriched in the nuclear envelope. Despite having the same substrate in arachidonic acid, COX-1 and COX-2 may utilize different pools of arachidonic acid to synthesize prostanoids. While COX-2 acts on arachidonic acid when it is present in concentrations less than 2.5 uM, which is characteristic of endogenous production of arachidonic acid, COX-1 preferentially oxygenates arachidonic acid when concentrations are greater than 10 uM, corresponding to arachidonic acid derived from an exogenous source. In this way the actions of COX-1 and COX-2 can be differentiated based on response to stimuli, intracellular distribution, and enzyme kinetics.
COX-2 is strongly implicated in a variety of pathophysiological processes including cancer, Alzheimer's disease, intestinal inflammation, and coronary heart disease (CHD). COX-2, which is over-expressed in many tumor tissues, plays a crucial role in carcinogenesis by potentiating angiogenic factors, circumventing apoptotic pathways, inducing tumor cell proliferation, and suppressing the immune response. Genetic depletion of COX-2 in mice dramatically reduces papillomas in a skin tumorigenesis model. Although COX-2 over-expression has been correlated to lung, breast, gastric, prostate, and pancreatic cancer, its role in colon cancer is the most well-characterized. COX-2 gene depletion reduces tumorigenesis in a model of intestinal neoplasia and coxibs demonstrate a stronger chemopreventive action than traditional NSAIDs in a model of rat colon carcinogenesis. Moreover, both celecoxib and rofecoxib reduce adenoma incidence and promote tumor regression in patients with familial polyposis .
COX-2 expression is increased in the brains of patients with Alzheimer's disease with the amount of expression correlating with the deposition of (β- amyloid in neuritic plaques. Genetic over-expression of COX-2 in transgenic mice increases susceptibility to (β-amyloid induced neurotoxicity. The positive correlation between COX-2 activity and disease progression may be linked to COX-2 mediated inflammation in microglia, the resident macrophages of the brain, when stressed with excess (β-amyloid. However, most of the data linking COX-2 and Alzheimer's disease are epidemiological, and precise mechanisms still have not been elucidated.
Unlike its proposed role in cancer and Alzheimer's disease, the role of COX-2 in acute and chronic lower gastrointestinal inflammation appears to be protective. COX-2 deficiency aggravates acute colitis in rodent models. The anti-inflammatory effects of COX-2 are thought to be mediated by PGE2 which maintains the integrity of the epithelial layer during intestinal inflammation. A newly appreciated role for COX-2 in inflammation resolution may contribute to its protective role in chronic inflammatory disorders of the intestine such as inflammatory bowel disease (IBD). The anti-inflammatory phase of COX-2 induction is associated with production of cyclopentenone prostaglandins which regulate an anti-inflammatory immune response. Accordingly, we have shown that COX-2-/- mice die of intestinal inflammation when stressed with a cholatecontaining atherogenic diet.
Reference:Ajay Janardhan Narasimha. The Role of COX-2 in Atherosclerosis