Tumor necrosis factor-alpha inhibits collagen alpha1(I) gene expression and wound healing in a murine model of cachexia

Abstract

The mechanisms responsible for impaired wound healing in patients with cachexia-associated infection, inflammation, and cancer are unknown. As tumor necrosis factor (TNF)-alpha is elevated in these diseases, and TNF-alpha inhibits collagen alpha1(I) gene expression in cultured fibroblasts, we analyzed whether chronically elevated serum TNF-alpha affects collagen metabolism in vivo by inoculating nude mice with Chinese hamster ovary cells secreting TNF-alpha (TNF-alpha mice) or control Chinese hamster ovary cells (control mice). Before the onset of weight loss, TNF-alpha mice had a selective decrease in collagen synthesis and collagen alpha1(I) mRNA in the skin. In addition, TNF-alpha mice displayed impaired healing of incisional and excisional skin wounds, compared with control animals, before the onset of cachexia. The expression of transforming growth factor-beta1, a potent fibrogenic factor, was inhibited by TNF-alpha in the skin. In studies with transgenic mice expressing the human growth hormone under the direction of 5' regulatory regions of the human collagen alpha1(I) gene, TNF-alpha treatment inhibited the expression of the collagen alpha1(I) human growth hormone transgene containing -2.3 kb of the 5' region, whereas transgene expression directed by -0.44 kb of the 5' region was not affected. These experiments suggest that TNF-alpha may play an important role in the impaired wound healing of chronic diseases that are characterized by a high production of this cytokine and provide insights for potential therapeutic approaches.