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Patented natural avocado sugars modulate the HBD-2 expression in human keratinocytes through the involvement of protein kinase C and protein tyrosine kinases
Archives of Dermatological Research, 09/24/09

Tufano MA et al. – The authors data provide information on signalling pathways in which the activation of protein tyrosine kinases (PTKs) and protein kinase C (PKC) takes place and leads to AP–1 and HBD–2 gene activation.

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Maria Antonietta Tufano, 10/22/09

Skin keratinocytes constitute a protective mechanical barrier against invading microorganisms. Stimulated keratinocytes produce endogenous peptides such as the beta-defensins that have direct antimicrobial activity against a broad spectrum of pathogens, including most bacteria, certain fungi, and enveloped viruses. In particular, human beta-defensin 2 (HBD-2) is virtually absent in normal skin and its expression in human keratinocytes requires stimulation by cytokines or bacteria. AV119, a patented avocado sugar, triggers the up-regulation of HBD-2, but the signalling mechanisms involved in this up-regulation in stimulated keratinocytes are not fully understood. In this study, the authors examined the intracellular signalling pathways and nuclear responses in skin keratinocytes that contribute to HBD-2 gene expression upon stimulation with AV119. The results indicates that in AV119-treated keratinocytes the activation of PTKs is associated to HBD-2 up-regulation, whereas the inhibition of PTKs activity decreases HBD-2 induction. AV119 not only up-regulated HBD-2 through PTKs activity but it also activates other signalling components belonging to the S/T kinase family. AV119 induces phosphorylation of PKC, but not of PKA. The inhibition of PKC activity significantly suppresses the induction of HBD-2, suggesting that phosphorylation of PKC is important for the induction of HBD-2. Furthermore, the results indicate that PLCgamma activation occurs in PKC activation induced by AV119. Consequently, we can suppose that AV119 activates PTKs and these kinases phosphorylate phospholipase Cgammawhich through the induction of a second messenger, might activate PKC, as described elsewhere for other models. HBD-2 promoter contains NF- kB or AP-1-binding sequences, and these transcription factors may transactivate this gene. AV119 led to the nuclear translocation of AP-1 and that both the fos and jun family proteins were involved, but did not alter NF- kB activity. In addition, when keratinocytes were pre-treated with PTKs or PKC inhibitors and then treated with AV119, the activation of c-fos and c-jun decreased, demonstrating that the AP-1 activation is mediated by PTKs or PKC activation. Finally, the transfection with c-Jun and c-Fos siRNA in human keratinocytes effectively blocked the HBD-2 expression induced by AV119, confirming that AP-1 was involved in the transductional pathway activated by AV119. In conclusion, this is the first report on AV119 transductional pathway, in which the activation of PTKs and PKC leads to AP-1 and HBD-2 gene activation.

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