Differential suppression of dendritic cell cytokine production by anti-inflammatory drugs.

BACKGROUND: Various anti-inflammatory drugs are available for the treatment of skin disorders. In these diseases, untoward immune responses to endogenous and/or environmental antigens are initiated by maturation and polarization of dendritic cells (DC). OBJECTIVE: To explore the suppressive effects of anti-inflammatory drugs on DC maturation and, in particular, polarization. METHODS: Exposure of DC to nickel in vitro results in DC maturation and secretion of both type 1 and type 2 cytokines, thereby providing a model to study the effects of anti-inflammatory drugs on DC responses. The inhibitory effects of anti-inflammatory drugs (ciclosporin, dexamethasone, diclofenac, dimethylfumarate, hydrocortisone, lactoferrin, 1-alpha,25-dihydroxyvitamin D3) on DC maturation (CD83, CD86, HLA-DR, CXCL8) and polarization (type 1: IL-12p70, TNF-alpha; type 2: IL-10, CCL17) were studied. RESULTS: All anti-inflammatory drugs, except for lactoferrin, had inhibitory effects on DC maturation. Hydrocortisone and dexamethasone exclusively suppressed the release of type 1 cytokines. A less pronounced, but similar profile was observed for dimethylfumarate and 1-alpha,25-dihydroxyvitamin D3. Ciclosporin suppressed both type 1 and 2 cytokines. In contrast, diclofenac suppressed only type 2 DC cytokine secretion. CONCLUSION: The present results give more insight into the pharmacological effects of immunosuppressive drugs on the immune system, and can thereby contribute to a more rational selection of anti-inflammatory drugs for the treatment of inflammatory skin disorders.

CXCL8 secretion by dendritic cells predicts contact allergens from irritants.

Monocyte-derived dendritic cell functions have been explored for identification of contact allergens in vitro. Current methods, including measurement of changes in cell surface marker expression (e.g. CD83, CD86) do not provide a sensitive method for detecting the sensitising potential of a chemical. In this study, we investigated whether chemokine production by monocyte-derived dendritic cells is increased upon maturation and whether chemokine production can provide methodology for the detection of allergens. Monocyte-derived dendritic cells were exposed to allergens (nickel sulphate, cobalt chloride, palladium chloride, copper sulphate, chrome-(III)-chloride, potassium dichromate, p-phenylenediamine and dinitrochlorobenzene) and irritants (sodium dodecyl sulphate, dimethylsulphoxide, benzalkoniumchloride and propane-1-ol). CD83 and CD86 expression was analysed by flow cytometry and chemokine production (CXCL8, CCL5, CCL17, CCL18, CCL19, CCL20, CCL22) was determined by ELISA. Significant up regulation of CD83 and CD86 expression could only be induced by three out of seven and five out of seven allergens, respectively. In contrast, CXCL8 production was significantly increased after stimulation with all allergens tested, whereas irritant exposure led to decreased CXCL8 production. All other chemokines tested, failed in identifying contact allergens. In conclusion, CXCL8 production, next to CD83 and CD86 up regulation, by monocyte-derived dendritic cells provides a promising in vitro tool for discrimination between allergens and irritants.

Induction of cytokine (interleukin-1alpha and tumor necrosis factor-alpha) and chemokine (CCL20, CCL27, and CXCL8) alarm signals after allergen and irritant exposure.

The immune system is called into action by alarm signals generated from injured tissues. We examined the nature of these alarm signals after exposure of skin residential cells to contact allergens (nickel sulfate and potassium dichromate) and a contact irritant [sodium dodecyl sulfate (SDS)]. Nickel sulfate, potassium dichromate, and SDS were applied topically to the stratum corneum of human skin equivalents. A similar concentration-dependent increase in chemokine (CCL20, CCL27, and CXCL8) secretion was observed for all three chemicals. Exposure to nickel sulfate and SDS was investigated in more detail: similar to chemokine secretion, no difference was observed in the time- and concentration-dependent increase in pro-inflammatory cytokine [interleukin-1alpha (IL-1alpha) and tumor necrosis factor-alpha (TNF-alpha)] secretion. Maximal increase in IL-1alpha secretion occurred within 2 h after exposure to both nickel sulfate and SDS and prior to increased chemokine secretion. TNF-alpha secretion was detectable 8 h after chemical exposure. After allergen or irritant exposure, increased CCL20 and CXCL8, but not CCL27, secretion was inhibited by neutralizing human antibodies to either IL-1alpha or TNF-alpha. Our data show that alarm signals consist of primary and secondary signals. IL-1alpha and TNF-alpha are released as primary alarm signals, which trigger the release of secondary chemokine (CCL20 and CXCL8) alarm signals. However, some chemokines, for example, CCL27 can be secreted in an IL-1alpha and TNF-alpha independent manner. Our data suggest that skin residential cells respond to both allergen and irritant exposure by releasing mediators that initiate infiltration of immune responsive cells into the skin.