Elevated skin surface pH has been reported in patients with atopic dermatitis (AD). Here we explored the role of skin pH in the pathogenesis of AD using the NC/Tnd murine AD model. Alkalinization of the skin of asymptomatic NC/Tnd mice housed in specific pathogen-free (SPF) conditions induced KLK5 and activated the protease-activated receptor 2 (PAR2), resulting in thymic stromal lymphopoietin (TSLP) secretion and a cutaneous T-helper 2 allergic response. This was associated with increased trans-epidermal water loss and development of eczematous lesions in these SPF NC/Tnd mice, which normally do not suffer from AD. Injection of recombinant TSLP also induced scratching behavior in the SPF NC/Tnd mice. TSLP production and dermatitis induced by alkalinization of the skin could be blocked by the PAR2 antagonist ENMD-1068. In contrast, weak acidification of eczematous skin in conventionally housed NC/Tnd mice reduced kallikrein (KLK) 5　activity and ameliorated the dermatitis. Onset of the dermatitis was associated with increased epidermal filaggrin expression and impaired activity of the sodium/hydrogen exchanger NHE1, a known regulator of skin pH. We conclude that alterations in skin pH directly modulate KLK5 activity leading to skin barrier dysfunction, itch, and dermatitis via the PAR2-TSLP pathway.Journal of Investigative Dermatology accepted article preview online, 22 September 2015. doi:10.1038/jid.2015.363.

Since more than 75% of breast cancers overexpress estrogen receptors (ER), endocrine therapy targeting ER has significantly improved the survival rate. Nonetheless, breast cancer still afflicts women worldwide and the major problem behind it is resistance to endocrine therapy. We have previously shown the involvement of nuclear factor-κB (NF-κB) in neoplastic proliferation of human breast cancer cells; however, the association with the transformation of ER-positive cells remains unclear. In the current study, we focused on roles of NF-κB in the hormone dependency of breast cancers by means of ER-positive MCF-7 cells. Blocking of NF-κB signals in ER-negative cells stopped proliferation by downregulation of D-type cyclins. In contrast, the MCF-7 cells were resistant to NF-κB inhibition. Under estrogen-free conditions, the ER levels were reduced when compared with the original MCF-7 cells and the established cell subline exhibited tamoxifen resistance. Additionally, NF-κB participated in cell growth instead of the estrogen-ER axis in the subline and consequently, interfering with the NF-κB signals induced additive anticancer effects with tamoxifen. MMP-9 production responsible for cell migration, as well as the cell expansion in vivo, were suppressed by NF-κB inhibition. Therefore, we suggest that NF-κB is a master switch in both ER-positive and ER-negative breast cancers.

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