Clyde J. Wright

Acetaminophen ( N ‐acetyl‐ p ‐aminophenol [APAP]) toxicity is a common cause of acute liver failure. Innate immune signaling and specifically NFκB activation play a complex role in mediating the hepatic response to toxic APAP exposures. While inflammatory innate immune responses contribute to APAP‐induced injury, these same pathways play a role in regeneration and repair. Previous studies have shown that attenuating IκBβ/NFκB signaling downstream of TLR4 activation can limit injury, but whether this pathway contributes to APAP‐induced hepatic injury is unknown. We hypothesized that the absence of IκBβ/NFκB signaling in the setting of toxic APAP exposure would attenuate APAP‐induced hepatic injury. To test this, we exposed adult male WT and IκBβ −/− mice to APAP (280 mg/kg, IP) and evaluated liver histology at early (2–24 hr) and late (48–72 hr) time points. Furthermore, we interrogated the hepatic expression of NFκB inflammatory ( Cxcl1 , Tnf , Il1b , Il6 , Ptgs2 , and Ccl2 ), anti‐inflammatory ( Il10 , Tnfaip3 , and Nfkbia ), and Nrf2/antioxidant ( Gclc , Hmox , and Nqo1 ) target genes previously demonstrated to play a role in APAP‐induced injury. Conflicting with our hypothesis, we found that hepatic injury was similar in WT and IκBβ −/− mice. Acutely, the induced expression of some target genes was similar in WT and IκBβ −/− mice ( Tnfaip3 , Nfkbia , and Gclc ), while others were either not induced ( Cxcl1 , Tnf , Ptgs2 , and Il10 ) or significantly attenuated ( Ccl2 ) in IκBβ −/− mice. At later time points, APAP‐induced hepatic expression of Il1b , Il6 , and Gclc was significantly attenuated in IκBβ −/− mice. Based on these findings, the therapeutic potential of targeting IκBβ/NFκB signaling to treat toxic APAP‐induced hepatic injury is likely limited.