Skin barrier defects play an important role in atopic dermatitis (AD) pathogenesis. Loricrin, an important barrier protein suppressed in human AD, is down-regulated by IL-4 in keratinocytes. However, the molecular mechanism is unknown. Since loricrin transcription requires p300/CBP, and Stat6 also recruits this common coactivator for its stimulated factors, we hypothesize that IL-4-activated Stat6 competes for the available endogenous p300/CBP, leading to loricrin transcription inhibition. First, we showed that loricrin is suppressed in the skin of IL-4 transgenic mice, an AD mouse model. In human keratinocytes, IL-4 down-regulation of loricrin is abrogated by a pan-Jak inhibitor, suggesting that the Jak-Stat pathway is involved. To further investigate the downstream molecular mechanism, we transfected HaCat cells with a loricrin promoter and then treated them with either IL-4 or vehicle. Not surprisingly, IL-4 greatly suppressed the promoter activity. Interestingly, this suppression was prevented when we knocked down Stat6, indicating that Stat6 participates in IL-4 regulation of loricrin. A Stat6-specific inhibitor confirmed the knockdown study. Finally, IL-4 suppression of loricrin was reversed with transfection of a CBP expression vector in a dose-dependent manner. Taken together, for the first time, we delineate a molecular mechanism for IL-4 down-regulation of loricin expression in human keratinocytes, which may play an important role in AD pathogenesis.

No abstract

No abstract

Cux1 is a transcriptional repressor gene and part of the network controlling G1‐S phase transition. It represses the expression of the cyclin kinase inhibitors (CKI) p21 and p27. To determine the function of Cux1, we generated transgenic mice constitutively expressing Cux1. These mice develop multiorgan hyperplasia resulting from the aberrant repression of p27. We have previously characterized the changes in kidney development, spermatogenesis, and liver development in the Cux1 transgenic mice. In this study we have focused on the changes in the lung resulting from constitutive Cux1 expression. Histological staining of mice lung tissue showed extensive inflammation, localized areas of atelectasis alternated to emphysema, severe bronchiectasis, thickened bronchial basal membrane, and pluristratification of bronchial epithelium interspaced with areas of necrosis. Peribronchial arteries exhibited mild media thickening and enlarged adventitia with significant presence of fibroblasts (trichrome staining). The damage, bronchiectasis, and inflammation in particular were more evident in lungs of Cux1 transgenic mice. In conclusion, our results suggest that increased Cux1 expression results in multiple lung pathologies and may contribute to bronchiectasis.

Prebiotics are substances with well spread use as functional food, which selectively induce the growth or activity of microorganisms that live in a microbiome, conferring benefits upon host well-being and health. Skin microbiome has an important role as host guardian, taking part in several physiological functions including skin turnover, reaction patterns in the immune system and disposition for inflammation-mediated diseases. Several studies have shown the effect of ingestion of prebiotics in improving skin health. However, little is known about the effect of several ingredients used topically in skin microbiome. In this study, we evaluated 4 natural ingredients commonly used in topical formulations for their prebiotic effect towards skin microorganisms. Results showed that Orbignya phalerata polissacarides and a-D-glucopyranosil stimulate S. epidermidis, S. xylosus and S. warneri proliferation in vitro. Besides, Carapa guianensis, Bertholletia excelsa and Mauritia flexuosa vegetal oils also increased S. xylosus and S. epidermidis proliferation in vitro. Finally, Caesaria sylvestris extract also increased S. epidermidis and S. xylosus population in vitro. Understanding the effect of topical formulations on skin microbiome can lead to novel breakthroughs in skin treatment.