Cyclooxygenase-2 Generates the Endogenous Mutagen trans-4-Hydroxy-2-nonenal in Enterococcus faecalis-infected Macrophages.

Cyclooxygenase-2 Generates the Endogenous Mutagen trans-4-Hydroxy-2-nonenal in Enterococcus faecalis-infected Macrophages.

Cancer Prev Res (Phila). 2013 Jan 15;

Authors: Wang X, Allen T, Yang Y, Moore DR, Huycke MM

Abstract
Infection of macrophages by the human intestinal commensal Enterococcus faecalis generates DNA damage and chromosomal instability in mammalian cells through bystander effects. These effects are characterized by clastogenesis and damage to mitotic spindles in target cells and are mediated, in part, by trans-4-hydroxy-2-nonenal (4-HNE). In this study we investigated the role of cyclooxygenase (COX) and lipoxygenase (LOX) in producing this reactive aldehyde using E. faecalis-infected macrophages and interleukin-10 knockout mice colonized with this commensal. 4-HNE production by E. faecalis-infected macrophages was significantly reduced by COX and LOX inhibitors. The infection of macrophages led to decreased Cox1 and Alox5 expression while COX-2 and 4-HNE increased. Silencing Alox5 and Cox1 with gene-specific siRNAs had no effect on 4-HNE production. In contrast, silencing Cox2 significantly decreased 4-HNE production by E. faecalis-infected macrophages. Depleting intracellular glutathione increased 4-HNE production by these cells. Next, to confirm COX-2 as a source for 4-HNE, we assayed the products generated by recombinant human COX-2 and found 4-HNE in a concentration-dependent manner using arachidonic acid as a substrate. Finally, tissue macrophages in colon biopsies from interleukin-10 knockout mice colonized with E. faecalis were positive for COX-2 by immunohistochemical staining. This was associated with increased staining for 4-HNE-protein adducts in surrounding stroma. These data show that E. faecalis, a human intestinal commensal, can trigger macrophages to produce 4-HNE through COX-2. Importantly, it reinforces the concept of COX-2 as a procarcinogenic enzyme capable of damaging DNA in target cells through bystander effects that contribute to colorectal carcinogenesis.

PMID: 23321929 [PubMed - as supplied by publisher]

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