Nuclear export of phosphorylated C/EBP beta mediates the inhibition of albumin expression by TNF-alpha

Decreased albumin expression is a frequent feature of cachexia patients aff licted with chronic diseases, including cancer, and a major contributor to their morbidity. Here we show that tumor necrosis-alpha (TNF-alpha) treatme nt of primary mouse hepatocytes or TNF-alpha overexpression in a mouse mode l of cachexia induces oxidative stress, nitric oxide synthase (NOS) express ion and phosphorylation of C/EBP beta on Ser239, within the nuclear localiz ation signal, thus inducing its nuclear export, which inhibits transcriptio n from the albumin gene. SIN-1, a NO donor, duplicated the TNF-alpha effect s on hepatocytes. We found similar molecular abnormalities in the liver of patients with cancer-cachexia. The cytoplasmic localization and association of C/EBP beta- Ser239 with CRM1 (exportin-1) in TNF-alpha -treated hepatoc ytes was inhibited by leptomycin B, a blocker of CRM1 activity. Hepatic cel ls expressing the non-phosphorylatable C/EBP beta alanine mutant were refra ctory to the inhibitory effects of TNF-alpha on albumin transcription since the mutant remained localized to the nucleus. Treatment of TNF-alpha mice with antioxidants or NOS inhibitors prevented phosphorylation of C/EBP beta on Ser239 and its nuclear export, and rescued the abnormal albumin gene ex pression.