IKappaB-kinase/nuclear factor-kappaB signaling prevents thermal injury-induced gut damage by inhibiting c-Jun NH2-terminal kinase activation.
OBJECTIVE
The molecular mechanism of major burn-induced gut damage is not clear. This study is to determine whether IkappaB-kinase (IKK)/nuclear factor-kappaB signaling in intestinal mucosa maintains gut function through the regulation of the c-Jun NH2-terminal kinase (JNK) and p38 phosphorylation.


METHODS
Prospective, experimental study.


METHODS
Research laboratory at a university hospital.


METHODS
Thermal injury models in mice.


METHODS
Conditional intestinal epithelial cell IKKbeta knockout (Vil-Cre/Ikkbeta(F/Delta) mice and control (Ikkbeta(F/Delta) mice were subjected to 30% total body surface area third-degree burn. JNK inhibitor (SP600125) or p38 inhibitor (SB203580) was given to mice immediately after burn injury.


RESULTS
Thermal injury induced a significant increase of intestinal permeability, nuclear factor-kappaB DNA-binding activity, phosphorylated JNK, phosphorylated p38, and caspase 3 expression of intestinal mucosa in Vil-Cre/Ikkbeta(F/Delta) mice compared with those of Ikkbeta(F/Delta) mice. BCL-xL and cellular FLICE inhibitory protein, but not GADD45beta (growth arrest and DNA damage-inducing protein beta), cellular inhibitor of apoptosis 1, Bfl-1, or TRAIL, messenger RNA expression was significantly decreased in Vil-Cre/Ikkbeta(F/Delta) mice compared with that of Ikkbeta(F/Delta) mice. SP600125 decreased intestinal permeability and increased phosphorylated p38 and tumor necrosis factor receptor-associated factor 2 expression of intestinal mucosa in Vil-Cre/Ikkbeta(F/Delta) mice. SB203580 treatment enhanced thermal injury-induced gut damage in Vil-Cre/Ikkbeta(F/Delta) mice.


CONCLUSIONS
Thermal injury induces nuclear factor-kappaB activation of intestinal mucosa and IKK protects intestinal mucosa from thermal injury-induced gut damage. IKK blocks caspase 3 expression by up-regulating BCL-xL and cellular FLICE inhibitory protein expression. IKK inhibits JNK and p38 but not p44/42 phosphorylation of intestinal mucosa. JNK inhibition increases p38 and tumor necrosis factor receptor-associated factor 2 expression and decreases thermal injury-induced gut damage. Taken together with the enhanced thermal injury-induced gut damage by p38 inhibition, we conclude that IKK maintains gut function by inhibiting JNK phosphorylation, which suppresses p38 phosphorylation and induces gut damage.
Chen
Lee-Wei
LW
Department of Surgery, Kaohsiung Veterans General Hospital, National Yang-Ming Medical University, Taipei, Taiwan. chenlw2001@yahoo.com.tw
Chen
Pei-Hsuan
PH
Chang
Wei-Jung
WJ
Wang
Jyh-Seng
JS
Karin
Michael
M
Hsu
Ching-Mei
CM
D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D017209:Apoptosis; D002056:Burns / Q000378:metabolism*; D053148:Caspase 3 / Q000378:metabolism; D004195:Disease Models, Animal; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000378:metabolism; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism*; D007093:Imidazoles / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000293:injuries / Q000378:metabolism* / Q000473:pathology; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D010539:Permeability; D010766:Phosphorylation; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D051020:bcl-X Protein / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism*
D000873:Anthracenes; C494812:Bcl2l1 protein, mouse; D004791:Enzyme Inhibitors; D007093:Imidazoles; D016328:NF-kappa B; D011725:Pyridines; D012333:RNA, Messenger; D051020:bcl-X Protein; C432165:pyrazolanthrone; D051550:I-kappa B Kinase; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D053148:Caspase 3; C093642:SB 203580