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.