Paraoxonases and psoriasis: negative imbalance of antioxidant endogenous mechanisms.

BACKGROUND: Numerous reports have shown that psoriasis patients are more exposed to lipoprotein peroxidation and to a decrease in the activity of paraoxonase (PON)1, an antioxidant and anti-inflammatory enzyme. Thus, it has been suggested that malfunction of the antioxidant system and an increased production of reactive oxygen species drive immune inflammatory events, that result in progressive skin cell damage in patients with psoriasis. The PON protein family, including PON1, PON2 and PON3, is one of the most important endogenous defense mechanisms against oxidative stress. In the present study, we investigated PON gene expression in psoriasis and in cutaneous oxidative stress. METHODS: The study population included 10 patients affected by moderate-to-severe plaque psoriasis and 15 healthy donors who have undergone to plastic surgery, were used as control. Skin punch biopsies of lesional and non lesional psoriatic skin were performed for analysis of PON2 and PON3 gene expression. In addition, oxidation assays in ex vivo full-thickness healthy skin organ cultures were performed. RESULTS: No significant differences were observed between PON2 and PON3 gene expression in psoriatic lesional and non lesional skin compared with healthy controls. H2O2 treatment induced a significant decrease of PON2 and PON3 expression in ex vivo full-thickness healthy skin organ cultures; conversely the pretreatment of samples with the antioxidant reagent N-acetyl-L-cysteine (NAC) induced a significant increase. Interestingly, no significant alterations were reported for PON2 and PON3 expression in ex vivo full-thickness healthy skin organ cultures stimulated with IL-17. CONCLUSIONS: Taken together our findings have revealed that a strong pro-oxidative activity is not effectively countered by antioxidant endogenous mechanisms both in psoriatic skin and in ex vivo experimental model.

Chronic hand eczema: is IL-36α helpful in diagnosis and classification?

BACKGROUND: Chronic hand eczema (CHE) is not a homogenous disease, necessitating complex differential diagnostics. Interleukin (IL) -1 family members are significantly up-regulated in ACD and psoriasis patients skin. METHODS: The present study aims to deepen the knowledge about clinical assessment and characterization of patients affected by chronic hand dermatitis (CHD) as well as to investigate the role of possible biomarkers which may help in the diagnostic process. An observational case-control study was performed enrolling 30 CHD patients and 20 healthy controls. Each patient underwent detailed medical history, clinical examination, epicutaneous patch test, and lesional skin biopsies for histological and immunohistochemical analysis. RESULTS: Patient history, clinical examination and patch testing led us to a final CHD characterization in only 8/30 subjects (26.7%). In the remaining subjects, clinical and histological features suggested a diagnosis of psoriasis in 9/22 (30%) and idiopathic chronic hand eczema (CHE) in 13/22 (43.3%). Trying to find a possible marker for the latter dermatosis, we analyzed IL-1 family in all the recruited subjects. IL-1 members were increased in all conditions, but IL-36α was the only analyzed cytokine able to characterize patients who end up with a diagnosis of idiopathic CHE. CONCLUSIONS: In conclusion, we can assess that medical history and patch testing remain essential investigations in CHD patients even if not always sufficient to perform a final diagnosis. Moreover, IL-1 members are probably involved in CHE skin inflammation, with IL-36α being a possible future biomarker which might help in the complex diagnostic process of CHE.

IL-33 is regulated by TNF-α in normal and psoriatic skin.

Interleukin-33 (IL-33) is the most recently discovered IL-1 family member. Considered an endogenous "alarmin" released by necrotic cells in response to tissue injury or damage, IL-33 is constitutively expressed in tissues exposed to the environment, where endothelial and epithelial cells constitute its major sources. Several findings reported that pro-inflammatory stimuli, such as IFN-γ and TNF-α, as well as IL-17, can induce IL-33 expression in normal human epidermal keratinocytes. In the present study, we deeply investigated the relation between IL-33 and TNF-α, by employing the whole skin as study model. TNF-α dose- and time-dependently induced IL-33 gene expression in ex vivo healthy skin organ culture. Similarly, TNF-α significantly increased IL-33 mRNA expression in normal human epidermal sheets. Moreover, IL-33 was enhanced in psoriatic skin and anti-TNF-α therapy was able to significantly reduce it. The biology of IL-33 is gaining in complexity, and this molecule is now known to have additional roles beyond its original description. In particular, we can assess that IL-33 is regulated by TNF-α in normal and psoriatic skin.

The balance between pro- and anti-inflammatory cytokines is crucial in human allergic contact dermatitis pathogenesis: the role of IL-1 family members.

The interleukin (IL)-1 family includes 11 members that are important in inflammatory processes. It includes various agonists and two antagonists, IL-1Ra and IL-36Ra. Our aim was to investigate whether the IL-1 family is involved in allergic contact dermatitis (ACD). The expression of IL-1 family members was evaluated by PCR and immunohistochemistry in the positive patch test reaction site (involved skin) and in the uninvolved skin of ACD patients. We also examined these cytokines in an ex vivo model of ACD. The antagonistic activity of IL-36Ra was evaluated by injecting recombinant IL-36Ra in uninvolved skin biopsies of ACD patients. IL-1Ra and IL-36Ra expression was quantified in mononuclear cells of nickel-sensitized patients challenged in vitro with nickel. IL-33 involvement in ACD was investigated by intra-dermal injection of anti-IL-33 in the uninvolved skin of patients ex vivo. Results showed that IL-1ß, IL-1Ra, IL-36α, IL-36ß, IL-36γ and IL-33 expression, but not IL-36Ra expression, was enhanced in ACD-involved skin. Immunohistochemical analysis and ex vivo skin cultures confirmed these results. Injection of anti-IL-33 in ACD-uninvolved skin inhibited IL-8 expression, whereas IL-36Ra inhibited IL-36α, IL-36ß, IL-36γ and IL-8 expression. Nickel induced IL-1Ra expression in lymphocytes of nickel-sensitized patients. Hence, various IL-1 agonists and antagonists may be involved in ACD pathogenesis.

Interleukin-1 family members are enhanced in psoriasis and suppressed by vitamin D and retinoic acid.

Interleukin (IL)-1 family comprise 11 members that play an important role in immune regulation and inflammatory process. Retinoids exert complex effects on the immune system, having anti-inflammatory effects in chronic dermatological diseases. Vitamin D (vitD) and analogs have been shown to suppress TNF-α-induced IL-1α in human keratinocytes (KCs). In the present study, we investigated IL-1 family members in psoriasis and the effects of vitD and retinoic acid (RA) on these members. We analyzed IL-1 family members gene expression in psoriatic skin and in ex vivo skin organ culture exposed to TNF-α, IL-17 or broadband UVB; afterwards, treatment with vitD or RA was performed and IL-1 family members mRNA was evaluated. Similarly, KCs were stimulated with IL-17 and subsequently treated with vitD. IL-1 family members were enhanced in psoriatic skin and in ex vivo skin organ cultures after pro-inflammatory stimuli (TNF-α, IL-17 and UVB). RA and vitD were able to suppress this enhancement.

IL-33 is secreted by psoriatic keratinocytes and induces pro-inflammatory cytokines via keratinocyte and mast cell activation.

IL-33 is a novel pro-inflammatory cytokine and ligand for the orphan receptor ST2. Although originally defined as an inducer of Th2-mediated responses, IL-33 was recently found to be involved in arthritis, a Th1/Th17-mediated disease. Here, we assessed the ability of IL-33 to promote inflammation via mast cells (MCs) and keratinocytes (KCs) activation in psoriasis. IL-33 resulted elevated in the skin but not in the serum of psoriasis patients. IL-33 was secreted by psoriasis KCs and HaCaT cells after TNF-α stimulation. In HMC-1, TNF-α, but not IL-17, could induce a robust increase in IL-33 expression. In HaCaT cells, TNF-α was able to induce IL-6, MCP-1 and VEGF, and the addition of IL-33 reinforced these increases. TNF-α + IL-33 combination showed similar results in primary KCs and ex vivo skin organ culture. In conclusion, our study suggests that IL-33 may be involved in psoriasis biology via MCs and KCs.