TLR4-mediated Cox-2 expression increases intestinal ischemia/reperfusion-induced damage.
Mesenteric IR induces significant inflammation and immune-mediated mucosal damage. TLR4 is a critical receptor in the induction of the inflammatory response and plays a role in intestinal homeostasis. To determine the role of TLR4 in IR-induced epithelial damage, we performed IR studies using TLR4(lps-def) and TLR4(lps-n) mice and analyzed mucosal damage and inflammation. We found that the absence of TLR4 or TLR4-induced signaling attenuated local mucosal damage with significantly decreased cytokine and eicosanoid secretion including PGE2 production. Similar results were seen in MyD88-/- mice. Wild-type mice treated with NS-398 (a Cox-2 inhibitor) not only decreased PGE2 production but also attenuated tissue damage. In contrast, PGE2 was not sufficient to induce damage in the TLR4(lps-def) mice. Together, these data indicate that TLR4 stimulation of Cox-2 activation of PGE2 production is necessary but not sufficient for intestinal IR-induced damage and inflammation.
Moses
Tiffany
T
Division of Biology, Kansas State University, Manhattan, KS 66506, USA.
Wagner
Lynn
L
Fleming
Sherry D
SD
D000818:Animals; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000276:immunology*; D016207:Cytokines / Q000276:immunology; D015232:Dinoprostone / Q000235:genetics / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000276:immunology*; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000473:pathology; D007410:Intestinal Diseases / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D007413:Intestinal Mucosa / Q000276:immunology* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000276:immunology; D015427:Reperfusion Injury / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D015398:Signal Transduction / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology*
D016207:Cytokines; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D015232:Dinoprostone