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Ubiquitin-Editing Enzyme A20 Promotes Tolerance to Lipopolysaccharide in Enterocytes¹

Jin Wang^*, Yannan Ouyang, Yigit Guner^*,, Henri R. Ford^*, and Anatoly V. Grishin^2,*,

^* Division of Pediatric Surgery and Division of Pathology, Childrens Hospital Los Angeles, and Department of Surgery, University of Southern California, Los Angeles, CA 90027

Although enterocytes are capable of innate immune responses, the intestinal epithelium is normally tolerant to commensal bacteria. To elucidate the mechanisms of tolerance, we examined the effect of preexposure to LPS on activation of p38, c-Jun, and NF-B in enterocytes by several inflammatory and stress stimuli. Shortly after the initial LPS challenge, enterocytes become tolerant to restimulation with LPS or CpG DNA, but not with IL-17 or UV. The state of tolerance, which lasts 20–26 h, temporally coincides with LPS-induced expression of the anti-inflammatory ubiquitin-editing enzyme A20. Small interfering RNA silencing of A20 prevents tolerance, whereas ectopic expression of A20 blocks responses to LPS and CpG DNA, but not to IL-17 or UV. A20 levels in the epithelium of the small intestine are low at birth and following gut decontamination with antibiotics, but high under conditions of bacterial colonization. In the small intestine of adult rodents, A20 prominently localizes to the luminal interface of villus enterocytes. Lower parts of the crypts display relatively low levels of A20, but relatively high levels of phospho-p38. Gut decontamination with antibiotics reduces the levels of both A20 and phospho-p38. Along with the fact that A20-deficient mice develop severe intestinal inflammation, our results indicate that induction of A20 plays a key role in the tolerance of the intestinal epithelium to TLR ligands and bacteria.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants 5R01AI014032 and 5R01AI049473 (to H.R.F.).

² Address correspondence and reprint requests to Dr. Anatoly V. Grishin, Division of Pediatric Surgery, Childrens Hospital Los Angeles MS35, 4661 Sunset Boulevard, Los Angeles, CA 90027. E-mail address: agrishin{at}chla.usc.edu

³ Abbreviations used in this paper: Tollip, TLR-interacting protein; IF, immunofluorescence; IRAK-1, IL-1R-associated kinase 1; siRNA, small interfering RNA; TRAF6, TNF- receptor-associated factor 6.

⁴ The online version of this article contains supplemental material.

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