Absence of IκBβ/NFκB signaling does not attenuate acetaminophen-induced hepatic injury.

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.