Nerve Growth Factor Protects Human Keratinocytes from Ultraviolet-B-Induced Apoptosis

Abstract

Ultraviolet radiation is a potent inducer of apoptosis, whereas autocrine nerve growth factor protects human keratinocytes from programmed cell death. To evaluate the role of nerve growth factor in the mechanisms of ultraviolet B-induced apoptosis, cultured human keratinocytes were ultraviolet B irradiated following pretreatment with K252, a specific inhibitor of the tyrosine kinase high-affinity nerve growth factor receptor. Here we report that the addition of K252 significantly enhanced keratinocyte apoptosis. We then transfected normal human keratinocytes with pNUT-hNGF. Nerve growth factor overexpressing keratinocytes secreted the highest amounts of nerve growth factor in culture supernatants, were more viable, and had a higher rate of proliferation than mock-transfected cells. Whereas ultraviolet B radiation downregulated nerve growth factor mRNA and protein as well as the tyrosine kinase high-affinity nerve growth factor receptor in normal keratinocytes, it failed to do so in nerve growth factor-transfected cells. Moreover, nerve growth factor overexpressing keratinocytes were partially resistant to apoptosis induced by increasing doses of ultraviolet B at 24 and 48 h. These results indicate that downregulation of nerve growth factor function plays an important part in the mechanisms of ultraviolet B-induced apoptosis in human keratinocytes. In addition, ultraviolet B caused a decrease in BCL-2 and BCL-xL expression in mock-transfected keratinocytes, but not in nerve growth factor overexpressing cells. Finally, nerve growth factor prevented the cleavage of the enzyme poly(ADP-ribose) polymerase induced in human keratinocytes by ultraviolet B. These results are consistent with a model whereby the autocrine nerve growth factor protects human keratinocytes from ultraviolet B-induced apoptosis by maintaining constant levels of BCL-2 and BCL-xL, which in turn might block caspase activation.

Modulation of ultraviolet‐induced hyperalgesia and cytokine upregulation by interleukins 10 and 13

“…UV exposure has been shown to increase NGF production by keratinocytes (Bull et al, 1998;Gillardon et al, 1995;Tron et al, 1990) and this modulation appears to rescue skin cells from UV-induced apoptosis Marconi et al, 1999;Zhai et al, 1996). The mentioned reports on its origins and upregulation by UV are in line with considerable evidence suggesting its key role in the hyperalgesia associated with in¯ammation of various origin (Kanaan et al, 1998;Sa®eh-Garabedian et al, 1997;Woolf et al, 1997 and for review, see Lewin & Mendell, 1993).…”

Nerve growth factor regulates the expression of vascular endothelial growth factor in human HaCaT keratinocytes via PI3K/mTOR pathway

“…to play an important role in normal maintenance, proliferation, and differentiation of not only cutaneous nerves, but also keratinocytes, melanocytes, and other cells in the skin (Marconi et al, 1999;Montano et al, 2010). Cellular responses to NGF are mediated by 2 classes of transmembrane receptors, a low-affinity receptor of ~75 kD (p75) (Johnson et al, 1986) and a highaffinity tyrosine kinase receptor of ~140 kD (TrkA) .…”

Fate of UVB-induced p53 mutations in SKH-hr1 mouse skin after discontinuation of irradiation: relationship to skin cancer development

“…Two mechanisms are believed to contribute to the selective expansion of p53-mutant cells: their resistance to UV-induced apoptosis and their proliferative advantage over normal keratinocytes in response to stimulation with UV radiation. While evidence supports the role of mutant p53 in enabling apoptosis resistance in keratinocytes (Ziegler et al, 1994;Tron et al, 1998;Zhang et al, 2001;Mudgil et al, 2003), the possibility that mutant p53 provides keratinocyte progenitors with proliferative advantages remains largely unexplored, even though two phenotypes may be related to the same underlying molecular changes (Kuhn et al, 1999;van Hogerlinden et al, 1999;Peus et al, 2000;Marconi et al, 2003). Nevertheless, discontinuation of UV irradiation has been shown to result in the fast spontaneous regression of some mutant p53 clones in mouse skin, although the mechanisms involved in this process are unclear (Berg et al, 1996;Rebel et al, 2001;Remenyik et al, 2003).…”