CD23-Mediated Nitric Oxide Synthase Pathway Induction in Human Keratinocytes Is Inhibited by Retinoic Acid Derivatives

Abstract

Retinoids exert various functions including anti-proliferative and anti-inflammatory effects on many cell types including keratinocytes and are widely used in skin diseases, such as psoriasis and acne. We have previously shown that human keratinocytes express low affinity immunoglobulin E receptor (FcepsilonRII/CD23) when stimulated with interleukin-4. Immunoglobulin E ligates CD23 and induces the production of nitrites (reflecting the mobilization of the nitric oxide [NO]-pathway) and tumor necrosis factor-alpha by human keratinocytes. Here, 13-cis and all-trans retinoic acid (RA) were shown to reduce the production of nitrites by immunoglobulin E-activated keratinocytes by 80% in a time- and concentration-dependent fashion. As a consequence, RA derivatives also reduced the production of tumor necrosis factor alpha by these cells by 70%. The level of inducible NO synthase activity in activated human keratinocytes was significantly decreased upon treatment of the cells with RA derivatives (inhibition by 60% of the mean inducible NO synthase activity with 13-cis RA, 2 microM). Treatment for 24 h with RA derivatives almost completely abolished transcription of inducible NO synthase-specific mRNA in activated keratinocytes. Therefore, RA derivatives downregulate tumor necrosis factor-alpha release and the NO-transduction pathway through the inhibition of inducible NO synthase transcription. Together, our data provide evidence for inhibition of the NO-pathway by 13-cis and all-trans retinoic acid on CD23-activated human keratinocytes. These data may clarify the mechanism of the anti-inflammatory activity of RA derivatives in skin diseases.

Exogenous nitric oxide enhances the synthesis of type I collagen and heat shock protein 47 by normal human dermal fibroblasts

“…In the epidermis, NO causes several biological effects including allergic reaction [5], immunomodulation [6], the formation of sunburn erythema and edema [7], and melanogenesis [8]. Some reports have been published on the contribution of NO to wound healing [9][10][11].…”

Unilateral Darier's disease associated with migraine headache responsive to isotretinoin

“…Improvement in DD with isotretinoin may involve dynamic changes in intracellular epidermal calcium and/or nitric oxide because of the effects of retinoids on these molecules within keratinocytes. 6,7 Because calcium regulation and nitric oxide are also involved in the pathogenesis of migraines, isotretinoin may be acting through these mechanisms in the relief of our patient's migraines. 8 The findings of DD and migraine in our patient may represent a true pathogenic relationship or reflect an alteration in calcium homeostasis lowering migraine headache threshold.…”

Mining connections between chemicals, proteins, and diseases extracted from Medline annotations

“…During the treatment with isotretinoin the headaches ceased, but once the treatment concluded and she stopped taking isotretinoin, the migraines returned. Retinoic acid also has a link to nitric oxide: in keratinocytes retinoic acid has been shown to reduce inflammation through inhibiting the synthesis of nitric oxide[39]. …”