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Many exogenous factors including excessive alcohol consumption have been associated with psoriasis, but the underlying mechanisms still remain elusive. Drinking worsens therapeutic compliance, and decreases the efficacy and increases the toxicity of systemic antipsoriatic treatments. Excess alcohol intake results in compromised immunity and increased risk of infections, but alcohol can induce proinflammatory cytokine production in various cell types and can increase mitogen-derived lymphocyte proliferation and lymphocyte activation. As we have previously reported, alcohol and one of its metabolites, acetone, induce keratinocyte proliferation and increase the mRNA levels of genes characteristic for proliferating keratinocytes, such as alpha5 integrin, cyclin D1 and keratinocyte growth factor receptor. Recently the correlation between blood and skin ethanol levels in humans was determined by a transdermal alcohol monitoring device, against the 'gold standard' breath alcohol readings. Based on transdermal alcohol measurements it can be concluded that cutaneous alcohol concentrations can reach levels that induce proinflammatory cytokine production and lymphocyte and keratinocyte proliferation in vitro. It is expected that the development of methodologies measuring transdermal ethanol will provide additional tools to evaluate how alcohol influences skin physiology and different dermatological conditions including psoriasis. Our review focuses on the possible link between alcohol misuse and psoriasis, particularly on the possible role of cutaneous ethanol in precipitating the disease.

SUMMARYPsoriasis is a chronic, inflammatory, hyperproliferative skin disease, in which autoimmunity plays a great role. Natural killer T cells (NK T cells), are suggested to be involved in the pathogenesis of different autoimmune diseases. To examine the involvement of CD3 + CD56 + NK T cells in the pathogenesis of psoriasis, we investigated the lymphocyte subpopulations obtained from blood samples of psoriatic patients before and after treatment, and of healthy controls, using two-colour flow cytometry. We found no significant differences between total T cells, total B cells, T helper cells, T cytotoxic cells and NK cells in patients with psoriasis before and after treatment and in controls. Increased percentage of memory T cells and decreased percentage of naive T cells was detected in psoriatic patients compared to controls, but these changes were not statistically significant. The CD3 + CD56 + cells of psoriatic patients were significantly decreased relative to controls. The percentage of CD3 + CD56 + cells increased after different antipsoriatic therapies, but remained significantly lower than those found in controls. CD3 + CD56 + cells of healthy controls were capable of rapid activation, while in psoriatic patients activated NK T cells were almost absent. The decrease in the number of CD3 + CD56 + cells may represent an intrinsic characteristic feature of patients with psoriasis, which is supported by the fact that after treatment NK T cells do not reach the values found in controls. In conclusion our results suggest that CD3 + CD56 + NK T cells could be actively involved in the development of Th1 mediated autoimmune diseases.

SummaryBackground-Type I interferons (IFNs) play an important role in the pathogenesis of many autoimmune disorders including psoriasis. In the presence of IFN-α and granulocyte/macrophage colony-stimulating factor (GM-CSF), monocytes differentiate into dendritic cells (DCs) referred to as IFN-DCs. IFN-DCs potentially mimic DC populations involved in psoriasis and express a wide range of Toll-like receptor (TLR) subtypes.

Alcohol has been reported to be a risk factor in psoriasis mainly based on the observation that there is a higher prevalence of alcohol abuse in individuals with psoriasis. The mechanism by which alcohol affects this disease is still elusive. So far there are no reports describing the effects of metabolites relevant to alcohol metabolism on the growth of human keratinocytes. In the present study we examined the effects of ethanol and acetone, which exceeds its normal endogenous level in the blood of heavy drinkers, on the proliferation of HaCaT keratinocytes. HaCaT cells were incubated for 30 min in the presence of various concentrations of ethanol (2.14 m M-1.71 M) and acetone (1.7 mM-1.36 M). The numbers of viable and proliferating cells were determined at different times after ethanol and acetone treatment. The effects of ethanol and acetone on the mRNA levels of genes characteristic for proliferating keratinocytes such as alpha5 integrin, keratinocyte growth factor receptor and cyclin D1 were studied by reverse-transcriptase polymerase chain reaction. Both ethanol and acetone induced proliferation of HaCaT cells. The maximum increase in the number of viable cells and the maximum proliferative response was observed with 4.28 m M ethanol and 13.6 m M acetone. The alpha5 integrin, keratinocyte growth factor receptor and cyclin D1 mRNA levels were higher compared to the controls as early as 2 h after ethanol and 30 min after acetone treatment of the cells. The stimulatory effect of ethanol and acetone on human keratinocytes may be one of the reasons why psoriasis can be precipitated by alcohol misuse.

Emerging evidence suggests that excessive alcohol consumption is associated with psoriasis. In alcoholics, antipsoriatic treatments are less efficient, but more toxic and an additional challenge is poor therapeutic compliance. There is a correlation between excess alcohol intake and increased risk of infections, but on the other hand alcohol and its metabolites can trigger a persistent systemic inflammation, mediated by pro-inflammatory cytokines released from activated Kupffer cells in the liver and from monocytes in the circulation. Ethanol and its metabolites can also enhance lymphocyte and keratinocyte activation and proliferation and can increase the mRNA levels of genes characteristic for proliferating keratinocytes. In this review, we discuss the mechanisms by which alcohol contributes to psoriasis development focusing on liver, systemic inflammation and skin.

Dendritic cells (DCs) have a critical role in antiviral responses, in autoimmune disease pathogenesis and in initiating and maintaining inflammatory skin disorders, and are candidates for cell-based immunotherapeutic approaches for tumours. Recent studies have shown the important role of type I interferons (IFNs) in DC differentiation and activation. In the presence of IFN-α and granulocyte/macrophage colony-stimulating factor monocytes differentiate into DCs referred to as IFN-DCs. In vitro generated IFN-DCs show a partially mature phenotype, are effective in taking up antigens, share features of myeloid DCs, plasmacytoid DCs and natural killer cells, exhibit an enhanced chemotactic response and are capable of migrating to the lymph nodes. IFN-DCs produce several chemokines and cytokines, including T-helper 1 (Th1) mediators belonging to the interleukin-12 family. IFN-DCs stimulate T- and B-cell responses and the production of IFN-γ in mixed lymphocyte reactions and have a capacity to produce IFN-γ themselves. IFN-DCs express several toll-like receptor (TLR) subtypes and TLR ligand stimulation improves their costimulatory molecule expression, increases their Th1 cytokine production and enhances their capacity to stimulate naive T-cell proliferation. Here we review the interaction of IFN-α and monocytes and the role of IFN-DCs in infections, in autoimmunity, in inflammation and in cancer immunotherapy focusing on dermatological conditions.

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