IL-6 Regulates Mcl-1L Expression through the JAK/PI3K/Akt/CREB Signaling Pathway in Hepatocytes: Implication of an Anti-Apoptotic Role during Liver Regeneration

Aims: To investigate the role and the regulation of the long variant of myeloid cell leukemia-1 protein (Mcl-1(L)) during liver regeneration. Background: Liver regeneration is an important phenomenon after liver injury. The rat partial hepatectomy (PH) model was used to characterize liver regeneration and Mcl-1(L) expression after PH. Methods: Male Wistar rats were subjected to 70% PH. The expression of mcl-1(L) mRNA was determined by quantitative RTPCR, and protein levels were analyzed by Western blot analysis and immunohistochemistry during liver regeneration. Functional evaluations of Mcl-1(L) were tested using chemical inhibition (flavopiridol), genetic inhibition (siRNA) of Mcl-1(L) production, and by assaying for annexin V levels and DNA ladder formation. Serum IL-6 levels were determined by enzyme immunoassays; signal transduction of IL-6-regulated Mcl-1(L) expression was verified by chemical inhibitors and decoy double-stranded oligodeoxynucleotides. Results: High levels of Mcl-1(L) were observed in remnant tissue at 4 h after PH. Administration of flavopiridol decreased Mcl-1(L) accumulation and also inhibited liver regeneration. IL-6 administration promoted the accumulation of Mcl-1(L) in rat hepatocytes, an effect that was impaired by siRNA treatments that reduced Mcl-1(L) production. Chemical inhibition and decoy oligonucleotide competition demonstrated that IL-6-induced Mcl-1(L) production required signaling mediated by JAK kinase, phosphoinositide 3-kinase (PI3K), and cAMP response-element-binding (CREB) proteins. Conclusion: Mcl-1(L) is an anti-apoptotic protein induced during liver regeneration after PH in rats. The expression of Mcl-1(L) is induced by IL-6 through the JAK/PI3K/Akt/CREB signaling pathway. Chemotherapy drugs that depend on Mcl-1(L)-or IL-6-related signaling should be considered carefully before use in patients undergoing hepatectomy for malignant tumor resection.