TUMOR NECROSIS FACTOR-ALPHA INHIBITS ALBUMIN GENE-EXPRESSION IN A MURINE MODEL OF CACHEXIA

The mechanisms responsible for decreased serum albumin levels in patients with cachexia-associated infection, inflammation, and cancer are unknown. Since tumor necrosis factor-α (TNFα) is elevated in cachexia-associated diseases, and chronic administration of TNFα induces cachexia in animal models, we assessed the regulation of albumin gene expression by TNFα in vivo. In this animal model of cachexia, Chinese hamster ovary cells transfected with the functional gene for human TNFα were inoculated into nude mice (TNFα mice). TNFα mice became cachectic and manifested decreased serum albumin levels, albumin synthesis, and albumin mRNA levels. However, even before the TNFα mice lost weight, their albumin mRNA steady-state levels were decreased ≈90%, and in situ hybridization revealed a low level of albumin gene expression throughout the hepatic lobule. The mRNA levels of several other genes were unchanged. Hepatic nuclei from TNFα mice before the onset of weight loss were markedly less active in transcribing the albumin gene than hepatic nuclei from control mice. Therefore, TNFα selectively inhibits the genetic expression of albumin in this model before weight loss.