Burn injury-triggered activation of lipopolysaccharide signaling via the CD14 pathway alters the expression of a variety of downstream genes contributing to pathogenic changes in distant organs. The regulation of CD14 and its role in the immediate-early response of c-Jun in the liver after burn injury were investigated in this study.An incidental identification of the differential induction of CD14 mRNA after an approximately 18% TBSA burn injury in mice was confirmed by RT-PCR and immunohistochemical analyses of CD14 expression. Subsequently, CD14's role in the immediate-early regulation of c-Jun expression in the liver after injury was examined by Western blot analysis using CD14 knockout (KO) mice.RT-PCR analysis demonstrated a rapid and transient induction of CD14 mRNA in the liver and lungs of mice after injury. Immunohistochemical analysis revealed a peak induction of CD14 reactivity in cells appearing to be Kupffer cells at day 1 after injury. Furthermore, an augmented and delayed induction of c-Jun mRNA was observed in the liver of CD14 KO mice after injury compared to wild-type controls. The induction of phosphorylated (serine 63 or serine 73) forms of c-Jun after injury was lower in the livers of CD14 KO mice than that in WT controls.This study provides evidence that injury elicits CD14 induction as well as hyperphosphorylation of the c-Jun N-terminus activation domain and that CD14 is involved in the modulation of c-Jun's transactivation potential via phosphorylation, which may be associated with hepatic pathogenesis after injury.