MicroRNAs are a recently discovered class of posttranscriptional regulators of gene expression with critical functions in health and disease. Psoriasis is the most prevalent chronic inflammatory skin disease in adults, with a substantial negative impact on the patients' quality of life. Here we show for the first time that psoriasis-affected skin has a specific microRNA expression profile when compared with healthy human skin or with another chronic inflammatory skin disease, atopic eczema. Among the psoriasis-specific microRNAs, we identified leukocyte-derived microRNAs and one keratinocyte-derived microRNA, miR-203. In a panel of 21 different human organs and tissues, miR-203 showed a highly skin-specific expression profile. Among the cellular constituents of the skin, it was exclusively expressed by keratinocytes. The up-regulation of miR-203 in psoriatic plaques was concurrent with the down-regulation of an evolutionary conserved target of miR-203, suppressor of cytokine signaling 3 (SOCS-3), which is involved in inflammatory responses and keratinocyte functions. Our results suggest that microRNA deregulation is involved in the pathogenesis of psoriasis and contributes to the dysfunction of the cross talk between resident and infiltrating cells. Taken together, a new layer of regulatory mechanisms is involved in the pathogenesis of chronic inflammatory skin diseases.

Keratinocytes have the ability to kill pathogenic fungi and bacteria by producing antimicrobial substances. Recent studies suggest that microbial components use signaling molecules of the human Toll‐like receptor (TLR) family to transduce signals in various cells. Here we provide evidence that keratinocytes express both TLR2 and TLR4 at the mRNA and protein levels, and show that TLR2 and TLR4 are present in the normal human epidermis in vivo and that their expression is regulated by microbial components. The expression of myeloid differentiation protein gene (MyD88), which is involved in the signaling pathway of many TLR, was also demonstrated in keratinocytes. LPS + IFN‐γ increased the expression of TLR2 and TLR4 50‐ and 5‐fold respectively. Treatment of keratinocytes with Candida albicans, mannan, Mycobacterium tuberculosis or LPS with IFN‐γ resulted in the activation and nuclear translocation of NF‐κB. Inhibition of NF‐κB blocked the Candida‐killing activity of keratinocytes, suggesting that the antimicrobial effect of keratinocytes requires NF‐κB activation. LPS + IFN‐γ, C. albicans (4 Candida/KC), peptidoglycan (1 µg/ml) or M. tuberculosis extract significantly increased IL‐8 gene expression after 3 h of treatment (P < 0.05). The increases over the 0‐h level were 15‐, 8‐, 10.8‐ and 7‐fold, respectively. The microbial compound‐induced increase in IL‐8 gene expression could be inhibited by anti‐TLR2 and anti‐TLR4 neutralizing antibodies, suggesting that TLRs are involved in the pathogen‐induced expression of this pro‐inflammatory cytokine. Our findings stress the importance of the role of keratinocytes as a component of innate immunity.