Inflammatory cytokine tumor necrosis factor-alpha enhances nerve growth factor production in human keratinocytes, HaCaT cells.

The skin lesions of inflammatory skin diseases (e.g., atopic dermatitis or psoriasis) accompany infiltration of inflammatory cells like macrophages, where abnormal sensory innervations and elevation of nerve growth factor (NGF) level are observed. It is thought that increased NGF mediates the abnormal innervations and this may cause the hypersensitivity of the skin. However, the mechanism of this increased NGF production in the skin is still unknown. Here, we show that tumor necrosis factor (TNF)-alpha, but not interferon-gamma or interleukin-6, enhanced the NGF production in human keratinocytes. The enhanced NGF production was abolished by both Raf-1 kinase and MEK inhibitors, whereas specific inhibitors of p38 mitogen-activated protein kinase and c-Jun N-terminal kinase did not. The extracellular signal-regulated kinase (ERK) phosphorylation and expression of NGF mRNA were accelerated by TNF-alpha treatment. Furthermore, serum was necessary for the NGF production and epidermal growth factor could substitute for serum in the effect on NGF secretion. These results indicate that TNF-alpha enhances NGF production via the Raf-1 / MEK / ERK pathway in human keratinocytes, suggesting that regulating TNF-alpha is a therapeutic target to control NGF production and subsequent sensory innervations.