CCL27 and CCL17 are chemokines believed to be involved in the process of establishing the inflammatory infiltrate, characteristic for the various inflammatory skin diseases. The skinspecific CCL27 binds the chemokine receptor-10 (CCR10), and CCL17 is a chemokine receptor-4 (CCR4) ligand. The purpose of our study was to characterize the expression of CCL27 and CCL17 in the inflammatory skin diseases: psoriasis, atopic dermatitis (AD) and acute allergic contact dermatitis (ACD) induced in nickel-sensitive individuals. Surprisingly, our studies revealed a markedly decreased CCL27 mRNA and protein expression in psoriatic lesions compared with non-lesional psoriatic skin. A minor CCL17 mRNA increase was measured in lesional psoriatic skin. No alterations were found in AD. In ACD, we found a pronounced (90-fold) raise in CCL17 mRNA and a 50-fold increase in CCL17 protein compared with normal skin. A kinetic ACD study of CCL17 expression showed the highest mean value 24 h after hapten application. Furthermore, we found the mRNA levels of CCR10 and CCR4 paralleling the results of their corresponding ligands. Overall, our principal findings were a distinct decrease in CCL27 in lesional psoriatic skin and a marked upregulation of CCL17 in ACD. These findings underscore the differential cutaneous T-cell recruitment in different inflammatory diseases.

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NF-kappaB is a dimeric transcription factor which regulates transcription of a number of different genes including IL-8 and p53. In resting cells NF-kappaB is usually retained in an inactive state in the cytoplasm through binding to a member of the inhibitory kappaB (IkappaB) protein family. The purpose of this study was to determine the effect of 1alpha,25(OH)(2)D(3) on NF-kappaB activation in both unstimulated and stimulated (IL-1alpha) cultured normal human keratinocytes. NF-kappaB DNA binding activity was determined by EMSA using two different oligonucleotides containing the kappaB sequence from either the IL-8 or the p53 promoter. IkappaBalpha and p53 expression was determined by Western blotting and IL-8 expression by ELISA. In unstimulated keratinocytes no NF-kappaB binding to the IL-8 kappaB binding sequence was detectable, whereas stimulation with IL-1alpha (10 ng/ml) led to a significant ( P<0.05) induction of NF-kappaB binding. In contrast NF-kappaB binding to the p53 kappaB binding sequence was detectable in unstimulated cells, although it was significantly increased after IL-1alpha (10 ng/ml) stimulation. Incubation with 1alpha,25(OH)(2)D(3) (10(-8)-10(-7) M) was shown to significantly ( P<0.05) stimulate the expression of IkappaBalpha and in parallel experiments with normal human keratinocytes stimulated with IL-1alpha (10 ng/ml) a significant ( P<0.05) time and dose-dependent decrease in NF-kappaB binding to the IL-8 kappaB binding sequence and in IL-8 expression were seen. A less-pronounced decrease in NF-kappaB binding to the p53 kappaB response element was seen after preincubation with 1alpha,25(OH)(2)D(3) and IL-1alpha stimulation, and it did not result in any change in p53 expression. These results demonstrate that 1alpha,25(OH)(2)D(3) inhibits NF-kappaB binding to the IL-8 kappaB binding sequence more potently than binding to the p53 kappaB binding sequence. We propose that this selectivity may be mediated through an increased expression of IkappaBalpha which leads to an inhibition of specific NF-kappaB subunits resulting in a selective regulation of NF-kappaB-induced gene transcription.

Nijsten T, Meads DM, de Korte J, et al. Cross-cultural inequivalence of dermatology-specific health-related quality of life instruments in psoriasis patients.

ObjectiveAtopic dermatitis (AD) is an inflammatory skin disorder with a childhood prevalence reaching 20%. An estimated 50% of patients have a life-long chronic course. The purpose of this study was to estimate the risk of first-time myocardial infarction (MI) in patients with AD compared with a general population cohort.DesignCohort study.SettingDenmark.ParticipantsUsing population-based medical registries, we identified individuals born in Denmark from 1947 to 1983 with at least two hospital-diagnoses of AD following inpatient admissions or hospital-based outpatient visits at any age from 1977 to 2013. Individuals with AD were matched with general population controls (10:1) for birth-year and gender. Unique personal identifiers permitted unambiguous data linkage.Primary outcome measuresFollow-up began on the date of AD diagnosis (index date for general population controls) and continued until death, emigration, MI or the year 2013. We computed the 15-year-cumulative incidence of MI following a diagnosis of AD. Comparing patients with AD with the general population cohort, we computed HRs of MI presented with 95% CIs and adjusted for history of diabetes mellitus, hypertension, hyperlipidaemia or stroke, educational level, birth-year and sex.ResultsWe identified 4814 patients diagnosed with AD. The cumulative incidence of MI was 0.6% for patients with AD and 0.4% for their matched controls. The corresponding adjusted HR was 1.74 (1.21 to 2.49). The HR for patients who were not in need of systemic treatment was 1.58 (1.02 to 2.45) and it was 2.40 (1.27 to 4.45) for those who were treated with azathioprine, methotrexate or cyclosporine.ConclusionsHospital-diagnosed AD was associated with increased risk of MI compared with the general population.