Regulation of Cyclooxygenase-2 by Hypoxia and Peroxisome Proliferators in the Corneal Epithelium

Abstract

Hypoxic injury provokes inflammation of many tissues including the ocular surface. In rabbit corneal epithelial cells, both peroxisome proliferator-activated receptor (PPAR)-inducible cytochrome P450 4B1 and cyclooxygenase-2 (COX-2) mRNAs were increased by hypoxia. PPAR ␣ and ␤ but not ␥ mRNAs were detected in these cells. The PPAR activator, WY-14,643 increased COX-2 expression. Similarly, non-steroidal anti-inflammatory drugs with the ability to activate PPARs induced COX-2 independently of prostaglandin synthesis inhibition. COX-2 protein overexpression by hypoxia and PPAR activation was not associated with a parallel increase in prostaglandin E 2 accumulation. However, the enzyme regained full catalytic activity when: 1) hypoxic cells were re-exposed to normoxic conditions in the presence of heme and arachidonic acid, and 2) WY-14,643-treated cells were depleted of intracellular GSH. Consistent with previous observations showing that the corneal production of cytochrome P450-derived inflammatory eicosanoids is elevated by hypoxia and inflammation, the current data suggest that hypoxic injury is a model of inflammation in which molecules other than COX-derived arachidonic acid metabolites play a major proinflammatory role. This study also suggests that increased cellular GSH may be the mechanism responsible for the characteristic dissociation of PPAR-induced COX-2 expression and activity. Moreover, we provide new insights into the commonly observed lack of efficacy of classical non-steroidal anti-inflammatory drugs in the treatment of hypoxia-related ocular surface inflammation.

Hypoxia-Inducible Factor 1-Mediated Inhibition of Peroxisome Proliferator-Activated Receptor α Expression During Hypoxia

“…Alternatively, it is possible that PPAR-␣ interacts with other inflammatory pathways (e.g., NF-B, mitogen-activated protein kinases) and that PPAR-␣ activity on ICAM-1 is indirect, particularly since the activity of the PPAR-␣ ligand required additional inflammatory stimuli (i.e., IFN-␥). Nonetheless, our data that PPAR-␣ ligand-mediated induction of proinflammatory signals (e.g., ICAM-1) are consistent with previous observations that PPAR-␣ ligands enhance cyclooxygenase 2 in colonic and corneal epithelial cells (4,5), and such observations may indicate that PPAR-␣ provides a proinflammatory signal to epithelial cells. Of note, the ␥ isoform of PPAR, which was not regulated by hypoxia (see Fig.…”

“…Previous studies have suggested that the PPAR-␣ ligands such as pirixinic acid (WY14643) may enhance proinflammatory gene expression in epithelial cells (4,5). Thus, as a functional assay for PPAR-␣ activation, we examined the induction of epithelial ICAM-1 by IFN-␥ (22,26) in the presence and absence of PPAR activators.…”

Cyclooxygenase-2 Expression by Nonsteroidal Anti-inflammatory Drugs in Human Airway Smooth Muscle Cells: Role of Peroxisome Proliferator-Activated Receptors

“…1B and 2B). Alternatively, Flur may have a different effect on COX-2 expression in different cells since the same authors also report that Flur, like Indo, significantly increases COX-2 expression in corneal epithelial cells (33), and different culture conditions may have an effect on HASM cell PPAR expression and consequently their response to NSAIDs.…”

Cytochrome P450 gene expression levels in peripheral blood mononuclear cells in comparison with the liver

“…Furthermore, induced CYP4B1 gene expression levels in PBL were closely correlated to those in the non-tumor part of the liver. CYP4B1 is induced by hypoxia, 23) and hypoxia also stimulates the synthesis of CYP-derived inflammatory eicosanoids in a rabbit corneal epithelial model. 24) These results suggest that induced CYP4B1 gene expression levels are a good index of the systemic status of metabolism and inflammation.…”