Abstract
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-κB 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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1384-1392 |
| Number of pages | 9 |
| Journal | Journal of Immunology |
| Volume | 183 |
| Issue number | 2 |
| DOIs | |
| State | Published - Jul 15 2009 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Immunology and Allergy
- Immunology
Cite this
Ubiquitin-editing enzyme A20 promotes tolerance to lipopolysaccharide in enterocytes. / Wang, Jin; Ouyang, Yannan; Guner, Yigit; Ford, Henri; Grishin, Anatoly V.
In: Journal of Immunology, Vol. 183, No. 2, 15.07.2009, p. 1384-1392.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Ubiquitin-editing enzyme A20 promotes tolerance to lipopolysaccharide in enterocytes
AU - Wang, Jin
AU - Ouyang, Yannan
AU - Guner, Yigit
AU - Ford, Henri
AU - Grishin, Anatoly V.
PY - 2009/7/15
Y1 - 2009/7/15
N2 - 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-κB 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.
AB - 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-κB 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.
UR - http://www.scopus.com/inward/record.url?scp=70249108531&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=70249108531&partnerID=8YFLogxK
U2 - 10.4049/jimmunol.0803987
DO - 10.4049/jimmunol.0803987
M3 - Article
C2 - 19570823
AN - SCOPUS:70249108531
VL - 183
SP - 1384
EP - 1392
JO - Journal of Immunology
JF - Journal of Immunology
SN - 0022-1767
IS - 2
ER -