Dexpanthenol modulates gene expression in skin wound healing in vivo.

Topical application of dexpanthenol is widely used in clinical practice for the improvement of wound healing. Previous in vitro experiments identified a stimulatory effect of pantothenate on migration, proliferation and gene regulation in cultured human dermal fibroblasts. To correlate these in vitro findings with the more complex in vivo situation of wound healing, a clinical trial was performed in which the dexpanthenol-induced gene expression profile in punch biopsies of previously injured and dexpanthenol-treated skin in comparison to placebo-treated skin was analyzed at the molecular level by Affymetrix® GeneChip analysis. Upregulation of IL-6, IL-1ß, CYP1B1, CXCL1, CCL18 and KAP 4-2 gene expression and downregulation of psorasin mRNA and protein expression were identified in samples treated topically with dexpanthenol. This in vivo study might provide new insight into the molecular mechanisms responsible for the effect of dexpanthenol in wound healing and shows strong correlations to previous in vitro data using cultured dermal fibroblasts.

Ultraviolet B radiation and reactive oxygen species modulate interleukin-31 expression in T lymphocytes, monocytes and dendritic cells.

BACKGROUND: Interleukin (IL)-31 is a novel Th2 T-cell cytokine that induces pruritus and dermatitis in transgenic mice. While enhanced mRNA expression of this cytokine is detected in skin samples of inflammatory skin diseases, the regulation of IL-31 expression is poorly understood. OBJECTIVES: To assess the effects of ultraviolet (UV) B radiation and H2O2 on IL-31 mRNA and protein expression in skin and different peripheral blood mononuclear cells (PBMCs). METHODS: The effects of UVB radiation and H2O2, as a prototypic reactive oxygen species, on IL-31 mRNA and protein expression were analysed in various inflammation-related cells and murine skin tissue. RESULTSTreatment of cells with UVB radiation and H2 O2 strongly induced IL-31 mRNA and protein expression in human PBMCs and in the skin of SKH-1 mice. Following exposure to UVB or H2O2, we observed increased expression of IL-31 mRNA in T cells, monocytes, macrophages, and immature and especially mature dendritic cells. H2O2 treatment but not UVB radiation led to a moderate upregulation of IL-31 mRNA expression in epidermal keratinocytes and dermal fibroblasts. Pretreatment of T lymphocytes with the MAPK p38 inhibitor SB203580 or the MEK1 inhibitor U0126 reduced the stimulatory effect of H2O2. These experiments suggest that p38 is involved in the regulation of IL-31 expression in human skin. CONCLUSIONS: Our studies reveal that UVB and reactive oxygen species stimulate the expression of IL-31 in PBMCs and skin, especially in T cells, monocytes and monocyte-derived dendritic cells.

High-resolution transcriptional profiling of chemical-stimulated dendritic cells identifies immunogenic contact allergens, but not prohaptens.

Allergic contact dermatitis is a complex syndrome and knowledge about the in vitro detection of small-molecular-weight compounds, particularly prohaptens, is limited. Therefore, we investigated chemical-induced gene expression changes in human antigen-presenting cells upon stimulation with immunogenic contact allergens, prohaptens and irritants. Monocyte-derived dendritic cells (moDCs) and THP-1 cells were stimulated with the prohapten cinnamic alcohol (CAlc), the hapten cinnamic aldehyde (CAld), an irritant and an obligatory sensitizer in vitro. Whole-genome screening and consecutive PCR analysis of differential gene expression in moDCs stimulated with either CAld or the obligatory sensitizer revealed coregulation of 11 marker genes which were related to immunological reactions (IL-8, CD1e, CD200R1, PLA2G5, TNFRSF11A), oxidative or metabolic stress responses (AKR1C3, SLC7A11, GCLM) or other processes (DPYLS3, TFPI, TRIM16). In contrast, the prohapten CAlc and the irritant did not change marker gene expression. In THP-1 cells, CAld and the positive control elicited similar expression changes in only 4 of the previously identified genes (IL-8, TRIM16, CD200R1, GCLM). In conclusion, we provide important insights into the pathophysiological basis of allergic contact dermatitis, identify marker genes suitable for skin hazard assessment and demonstrate that contact-allergenic prohaptens escape in in vitro detection if their skin metabolism is not taken into account.

Tacrolimus modulates dendritic cell activation in the sensitization phase of allergic contact dermatitis.

BACKGROUND: Knowledge of the effect of topically applied calcineurin antagonists such as tacrolimus on the sensitization phase of allergic contact dermatitis is currently limited. OBJECTIVE: To investigate tacrolimus-dependent immunomodulation on gene expression alterations in human antigen-presenting cells which are stimulated with small-molecular-weight contact allergens. METHODS: Monocyte-derived dendritic cells (moDC) and THP-1 cells were stimulated with the contact sensitizer cinnamic aldehyde (CAld) and compared with the very strong experimental sensitizer 2,4,6-trinitrobenzene sulfonic acid (TNBS) in vitro. Quantitative PCR analysis was used to detect gene expression changes, particularly of interleukin (IL) 8, as an indicator of differential dendritic cell (DC) gene expression after sensitizer stimulation in the absence or presence of tacrolimus and betamethasone at two different concentrations. RESULTS: DC activation was clearly demonstrated by a significant IL-8 upregulation after 24 h, whereas tacrolimus or betamethasone alone did not affect IL-8 baseline expression. Betamethasone and, to a lesser extent, tacrolimus led to a marked reduction of chemical-induced IL-8 expression by TNBS and CAld. CONCLUSION: The results of the present study support the hypothesis that the calcineurin inhibitor tacrolimus has modulatory effects on human antigen-presenting cells during the sensitization phase of allergic contact dermatitis. In addition, moDC as well as THP-1 cells may serve as a system to study immune-modulating effects of drugs such as glucocorticoids or calcineurin antagonists.

[Sensitisation to p-Phenylenediamine. Effects of metabolism and individual susceptibility]. / Sensibilisierung auf p-Phenylendiamin. Einfluss von Metabolisierung und individuellen Risikofaktoren.

Due to its constant exposure to small molecular weight compounds, the skin is a major target for allergic reactions. Para-phenylenediamine (PPD) is a common and strong contact allergen. Recent studies have revealed new aspects of steps involved in sensitization and allergic contact dermatitis to PPD, giving insight into the cutaneous metabolism of small molecular compounds and its effect on activation and deactivation of immunogenic substances. Molecular epidemiological studies have suggested that polymorphisms in genes encoding cytokines (e.g. TNF-alpha) or metabolizing enzymes (e.g. N-acetyltransferase) may have influence on these mechanisms and the individual susceptibility for sensitization.