Serena Lembo

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.

Dermoscopic patterns of superficial basal cell carcinoma

Background  Superficial basal cell carcinoma (BCC) presents as a scaly, pink to red–brown patch and is predominantly located on the trunk. Clinical diagnosis may not be always easy and implicates a variety of differential diagnoses; in this situation dermoscopy has been reported improving the diagnostic accuracy. This study investigated dermoscopic patterns of superficial BCC focalizing the most specific and frequent structures in order to improve the diagnostic accuracy.

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‐1β, IL‐1Ra, IL‐36α, IL‐36β, 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‐36β, 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.

Mechanistic target of rapamycin (mTOR) expression is increased in acne patients' skin.

Abbreviations: mTOR, Mechanistic target of rapamycin; mTORC, mTOR signalling complex; BCAA, branched-chain essential amino acid; 4E-BP1, the eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1; SREBP-1, sterol response element-binding protein-1; S6K1, ribosomal protein S6 kinase 1; FOXO1, forkhead box protein O1; HOMAIR, homoeostatic model assessment of insulin resistance; GAGS, global acne grading system; HS, healthy skin; LS, lesional skin; NLS, non-lesional skin; RT-PCR, real-time polymerase chain reaction; IHC, immunohistochemistry; IF, immunofluorescence; ELISA, enzyme-linked immunosorbent assay; P-S6K1, phospho-S6-ribosomal protein.

Effects of adalimumab therapy in adult subjects with moderate-to-severe psoriasis on Th17 pathway

Until relatively recently, psoriasis has been considered to be a mainly T helper (Th)1‐driven inflammatory disease; however, several findings have now assessed a major role for Th17 cells in its pathogenesis. Adalimumab is a biological agent that inhibits TNF‐α, a pro‐inflammatory cytokine with a pivotal role in the mechanisms of the disease.

Crosstalk between skin inflammation and adipose tissue-derived products: pathogenic evidence linking psoriasis to increased adiposity.

ABSTRACT Introduction: Psoriasis is a chronic skin disorder associated with several comorbid conditions. In psoriasis pathogenesis, the role of some cytokines, including TNF-α and IL-17, has been elucidated. Beside their pro-inflammatory activity, they may also affect glucose and lipid metabolism, possibly promoting insulin resistance and obesity. On the other hand, adipose tissue, secreting adipokines such as chemerin, visfatin, leptin, and adiponectin, not only regulates glucose and lipid metabolism, and endothelial cell function regulation, but it may contribute to inflammation. Areas covered: This review provides an updated ‘state-of-the-art’ about the reciprocal contribution of a small subset of conventional cytokines and adipokines involved in chronic inflammatory pathways, upregulated in both psoriasis and increased adiposity. A systematic search was conducted using the PubMed Medline database for primary articles. Expert commentary: Because psoriasis is associated with increased adiposity, it would be important to define the contribution of chronic skin inflammation to the onset of obesity and vice versa. Clarifying the pathogenic mechanism underlying this association, a therapeutic strategy having favorable effects on both psoriasis and increased adiposity could be identified.

Nicotinamide downregulates gene expression of interleukin-6, interleukin-10, monocyte chemoattractant protein-1, and tumour necrosis factor-α gene expression in HaCaT keratinocytes after ultraviolet B irradiation.

Ultraviolet (UV) radiation has profound effects on human skin, causing sunburn, inflammation, cellular‐tissue injury, cell death, and skin cancer. Most of these effects are mediated by a number of cytokines produced by keratinocytes. In this study we investigated whether nicotinamide (NCT), the amide form of vitamin B3, might have a protective function in reducing the expression of interleukin (IL)‐1β, IL‐6, IL‐8, IL‐10, monocyte chemoattractant protein (MCP)‐1 and tumour necrosis factor (TNF)‐α in UV‐irradiated keratinocytes. HaCaT cells were treated with UVB in the presence or absence of NCT, and cytokine mRNA levels were examined by quantitative real‐time PCR. NCT significantly downregulated IL‐6, IL‐10, MCP‐1 and TNF‐α mRNA expression, whereas it did not exert any significant effect on IL‐1β or IL‐8 expression. Because of its ability to decrease these cytokine mediators after UV exposure, NCT is a possible therapy to improve or prevent conditions induced or aggravated by UV light.

Mammalian target of rapamycin, insulin resistance and hidradenitis suppurativa: a possible metabolic loop

mosomal STS was detectable by fluorescent in situ hybridization analysis, suggesting no gross deletion of the STS locus. Suspecting the possible involvement of minor mutation(s), all the 10 exons of STS were sequenced, revealing that each patient had different single nucleotide substitutions in close proximity within exon 7. Patient 1 had a T>G substitution at nucleotide 1049, changing a valine to a glycine (c.1049T>G, p.V350G; Fig. 1e), whereas patient 2 had a G>A substitution at nucleotide 1075, changing a glycine to an arginine (c.1075G>A, p.G359R; Fig. 1f). The possibility of polymorphism was excluded using a world-wide SNPs database. To date, 20 point mutations of STS, including those reported here, have been identified in XLRI (Fig. 2b). Of these, 15 (75%) were missense mutations and the remaining 5 (25%) were nonsense mutations. The majority of these mutations (18/20, 90%) were localized exclusively within the downstream of exon 7, supporting the hypothesis that this region is essential for in vivo enzyme activity. More precisely, STS protein has 26 substrate binding and 10 catalytic sites that are highly homologous to those in other sulfatase family members, aryl sulfatase A and B. These characteristic amino acids are indispensable for maintenance of the tertiary structure, substrate binding/scaffolding and catalytic activity. Nevertheless, none of these functional amino acids, except two substrate binding sites (T165 and E349), relate to the 20 STS point mutations. Combining these assumptions with the considerably high incidence of complete STS deletion in XLRI, it is conceivable that STS point mutations sufficiently affect the baseline enzymatic activity to elicit the development of the disease. To look for mutation-specific conformational alterations, we aligned the secondary and tertiary structures of STS (Fig. 2c,d). It comprises tandem transmembrane domains across the cytoplasmic domain within exon 5, two post-translational glycosylation sites, five Ca binding sites and six disulphide bonds, thereby forming the ‘mushroom-like’ configuration embedded into the lumenal membrane of the endoplasmic reticulum. Interestingly, all mutations were clustered within the lumen side, but not within the transmembrane or cytoplasmic domains (Fig. 2d), indicating that the lumenal portion of STS is highly sensitive to the transversion of a single amino acid, albeit to a lesser extent with basic secondary structures (e.g. a-helices; Fig. 2b). Collectively, STS point mutations demonstrate restricted localization, causing efficient impairment of the corresponding enzyme activity, and are more unlikely to be responsible for the phenotypic heterogeneity in XLRI subjects.

Anti-inflammatory properties of low and high doxycycline doses: an in vitro study.

Doxycycline is used to treat infective diseases because of its broadspectrum efficacy. High dose administration (100 or 200 mg/day) is often responsible for development of bacterial resistances and endogenous flora alterations, whereas low doses (20–40 mg/day) do not alter bacteria susceptibility to antibiotics and exert anti-inflammatory activities. In this study, we wanted to assess the efficacy of both low and high doxycycline doses in modulating IL-8, TNF-α, and IL-6 gene expression in HaCaT cells stimulated with LPS. Three experimental settings were used, differing in the timing of doxycycline treatment in respect to the insult induced by LPS: pretreatment, concomitant, and posttreatment. Low doses were more effective than high doses in modulating gene expression of LPS-induced proinflammatory cytokines (IL-8, TNF-α, and IL-6), when added before (pretreatment) or after (posttreatment) LPS stimulation. This effect was not appreciated when LPS and doxycycline were simultaneously added to cell cultures: in this case high doses were more effective. In conclusion, our in vitro study suggests that low doxycycline doses could be safely used in chronic or acute skin diseases in which the inflammatory process, either constantly in progress or periodically recurring, has to be prevented or controlled.