Release by ultraviolet B (u.v.B) radiation of nitric oxide (NO) from human keratinocytes: a potential role for nitric oxide in erythema production

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Abstract
1 The mechanism of human sunburn is poorly understood but its characteristic features include the development of erythema. In this study we attempted to determine whether human keratinocytes possess a nitric oxide (NO) synthase (NOS), if this enzyme could be activated to release NO following exposure to ultraviolet B (u.v.B) and to define whether this photo-induced response could be involved in the pathogenesis of sunburn erythema. 2 Treatment of human keratinocytes with various doses of u.v.B (290–320 nm) radiation (up to 100 mJ cm−2) resulted in a dose-dependent release of NO and cyclic GMP production that was reduced by NG-monomethyl-l-arginine (l-NMMA). 3 u.v.B irradiation of keratinocyte cytosol at varying doses (up to 50 mJ cm−2), resulted in a gradual rise in NO production, with a concomitant increase in soluble guanylate cyclase activity (sGC). 4 NOS isolated from the keratinocyte cytosol was constitutively expressed and was dependent on NADPH, Ca2+/calmodulin, tetrahydrobiopterin and flavins. 5 In reconstitution experiments, when purified NOS was added to purified sGC, both isolated from keratinocyte cytosol, a four fold increase in cyclic GMP was observed. The GMP was increased by NO synthesized following u.v.B radiation (up to 20 mJ cm−2) of NOS. 6 In in vivo experiments, guinea-pigs were subjected to u.v.B light. A Protection Factor (PF) of 8.71 ± 2.85 was calculated when an emulsified cream formulation containing l-NMMA (2%) was applied to their skin. 7 The present results indicate that u.v.B radiation acts as a potent stimulator of NOS in keratinocytes. NO is lipophilic and may diffuse out of the keratinocytes, activating sGC in endothelial cells and neighbouring smooth muscle cells. This may be a major part of the integrated response of the skin leading to vasodilatation and erythema.

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