IκB-kinase/nuclear factor-κB 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 IKB-kinase (IKK)/nuclear factor-KB signaling in intestinal mucosa maintains gut function through the regulation of the c-Jun NH2- terminal kinase (JNK) and p38 phosphorylation. Design: Prospective, experimental study. Setting: Research laboratory at a university hospital. Subjects: Thermal injury models in mice. Interventions: Conditional intestinal epithelial cell IKK beta knockout (Vil-Cre/Ikk beta(F/Delta)) mice and control (Ikk beta(F/Delta)) mice were sub-jected to 30% total body surface area third-degree burn. JNK inhibitor (SP600125) or p38 inhibitor (SB203580) was given to mice immediately after burn injury. Measurements and Main Results: Thermal injury induced a significant increase of intestinal permeability, nuclear factor-KB DNA-binding activity, phosphorylated JNK phosphorylated p38, and caspase 3 expression of intestinal mucosa in Vil-Cre/Ikk beta(F/Delta) mice compared with those of Ikk beta(F/Delta) mice. BCL-xL and cellular FLICE inhibitory protein, but not GADD45 beta (growth arrest and DNA damage-inducing protein beta), cellular inhibitor of apoptosis 1, BfI-1, or TRAIL, messenger RNA expression was significantly decreased in Vil-Cre/Ikk beta(F/Delta) mice compared with that of Ikk beta(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/Ikk beta(F/Delta) mice. SB203580 treatment enhanced thermal injury-induced gut damage in Vil-Cre/Ikk beta(F/Delta) mice. Conclusions: Thermal injury induces nuclear factor-KB 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.