Ultraviolet light induces Stat3 activation in human keratinocytes and fibroblasts through reactive oxygen species and DNA damage

Please cite this paper as: Ultraviolet light induces Stat3 activation in human keratinocytes and fibroblasts through reactive oxygen species and DNA damage. Experimental Dermatology 2010; 19: 654–660. Abstract: Stat3 is activated by the outer stressors, such as ultraviolet (UV) exposure. In this study, we investigated the Stat3 response to UV irradiation in human epidermal keratinocytes and dermal fibroblasts. Results indicated that UVB and UVC differentially activate Stat3 in these cells. The UV‐induced Stat3 activation was mediated by both reactive oxygen species (ROS) and DNA damage, and the dominancy of ROS and DNA damage to activate Stat3 depended on the wavelength of UV. By using fibroblasts from a patient with xeroderma pigmentosum A (XP‐A) and those transfected with human XPA gene, we found that UVB activates Stat3 via both ROS and DNA damage, while UVC does so mainly via DNA damage. The present data suggest that Stat3 activation in UV‐exposed human skin is one of the initial events where DNA damage and ROS are involved.     

IL-15 and IL-23 synergize to trigger Th17 response by CLA+ T cells in psoriasis

IL-15 has emerged as a potentially relevant target in the IL-17 response in psoriasis. However, its mechanism is poorly characterized in humans. IL-15 and IL-23 are constitutively expressed in the psoriatic lesion. Also, IL-15 is considered a susceptibility-associated gene in psoriasis, as are IL-23R, and HLACW6. Here, we studied the effect of IL-15 and IL-23 stimulation on the cytokine response of CLA+/CLA- T cells from 9 psoriasis patients and 3 healthy control subjects. To this end, CLA + and CLA- T cells from blood samples were cultured with epidermal cells from skin biopsies and treated with IL-15 and IL-23. After five days of culture, cytokines in supernatant were measured by ELISA or fluorescent bead-based immunoassay. There was a statistically significant increase in IL-17F and IL-17A production (P < .001) in cocultures of psoriasis skin-homing CLA + T cells with epidermal cells when stimulated with IL-15 and IL-23, but this effect was not observed in the cells of healthy controls. Interestingly, this response was reduced by around 50 to 80% by blocking HLA class I and II molecules. Our results point to the synergic action of IL-15 and IL-23 selectively for CLA + cells in psoriasis, leading to the induction of Th17 cell-related cytokines.     

IL-12B和IL-23R基因多态性与中国汉族人银屑病易感性关联研究

目的 探讨中国汉族人群中IL-12B和IL-23R基因多态性与银屑病易感性的关系。方法 在217例银屑病患者和288例正常人对照中,采用DNA直接测序法对IL-12B和IL-23R基因的多态性位点进行基因分型,并将阳性结果在一个更大的包括578例银屑病患者和1422例正常人对照的整合样本群中,使用Taqman探针荧光PCR技术进行重复检验。实验数据进行Hardy-Weinberg平衡检验、卡方检验、单倍型分析和Logistic回归模型分析。结果 IL-12B rs6887695位点等位基因频率在病例组与对照组之间差异有统计学意义,OR = 1.33（95% CI 1.03 ~ 1.73）,P = 0.028;IL-23R rs11465817和rs1343152位点等位基因频率在病例组与对照组之间差异无统计学意义（P > 0.05）。连锁不平衡分析发现,rs11465817和rs1343152位点之间有一定的连锁不平衡（D′ = 0.744,r2 = 0.281）。对2个位点进行单倍型分析发现,A-A ∶ OR = 2.890,P = 0.0018,提示这一单倍型具有显著的发病风险。结论 IL-12B基因rs6887695多态性与中国汉族人群银屑病易感性相关;IL-23R基因rs11465817、IL-23R基因rs1343152位点多态性与中国汉族人群银屑病易感性无显著相关性,但是,IL-23R基因rs11465817-rs1343152位点A-A单倍型的中国汉族人具有更高的银屑病发病风险。     

Modulation of MHC class II+ Langerhans cell numbers in corticosteroid treated epidermis by GM-CSF in combination with TNF-α

Abstract It is important to understand how dendritic cells (DC) are recruited, maintained and stimulated to migrate from tissues to lymph nodes. This is because DC are potent initiators of primary immune responses and candidates for vaccine development. Identification of factors which could lead to increased numbers of DC in tissues could affect immune responses by modulating their interaction with antigen which penetrates the tissue. To identify cytokines which could increase DC in tissues we tested the ability of GM-CSF, TNF-α and IL-6 to partially prevent steroid depletion of Langerhans cells (LC) from the epidermis. Cytokines diluted in serum-containing medium were compared with cytokines diluted in albumin-containing, serum-free medium in order to determine a minimum combination of cytokines required to increase LC and the effect of serum on the LC-increasing activity of cytokines. In the presence of serum, GM-CSF or TNF-α could increase LC frequency compared to the control; but in the absence of serum neither of these cytokines were effective unless they were combined with each other. In the presence of serum the combination of GM-CSF with TNF-α was ineffective. The data support the hypotheses that GM-CSF and TNF-α are both important in regulating LC numbers in the epidermis in vivo. Serum may modulate how each of these cytokines, separately or in combination, affect LC frequency in the epidermis–GM-CSF and TNF-α separately probably interact with other factors present in serum to increase LC frequency, whereas in combination it is possible that these separate effects are cancelled in the presence of serum. TNF-α and GM-CSF together, in the absence of serum, form one combination of a minimum number of cytokines which can regulate LC frequency in the epidermis; and IL-6 alone, or in combination with GM-CSF, does not increase LC frequency.     

白芍总苷联合NB-UVB对中重度银屑病血清IL-17、IL-23和皮损PAR-2表达的影响

目的: 明确白芍总苷联合NB-UVB治疗中重度银屑病的疗效及对血清IL-17、IL-23及皮损蛋白酶活化受体2(PRA-2)表达的影响.方法: 选取2019年5月至2020年6月来我院皮肤科就诊的中重度银屑病患者,随机分为NB-UVB组、白芍总苷组、白芍总苷联合NB-UVB组.治疗3个月,计算PASI评分.ELISA法...     

Downregulation of integrin‐αvβ6 on keratinocytes in the scar of lichen planopilaris and folliculitis decalvans: Relevance for the disappearance of epidermal Langerhans cells

Primary cicatricial alopecia (PCA) is a group of poorly understood mechanisms in which the destruction of hair follicles leads to permanent hair loss. Lichen planopilaris (LPP) is a type of lymphocytic PCA and it has been known for epidermal Langerhans cells (LC) to disappear in the scar of LPP. We also found that epidermal LC also disappeared in the scar of folliculitis decalvans (FD), a type of neutrophilic PCA. Of note was that epidermal LC did not disappear in the scar of discoid lupus erythematosus, another type of lymphocytic PCA, suggesting that LC disappearance in the scar was not always a common feature of PCA. We found that the expression of integrin (ITG)‐αvβ6 in scar epidermis was significantly diminished in LPP and FD, but not in other PCA and disorders accompanied with scar formation. We also found that exogenous interleukin‐1β and α‐interferon downregulated ITG‐αvβ6 expression in normal human epidermal keratinocytes. These data suggest that downregulation of ITG‐αvβ6 may be one of the causes of LC disappearance in the scar of LPP and FD.     

Cutaneous squamous cell carcinoma,thyroid cancer and Langerhans cell histiocytosis in a patient with X‐linked recessive Mendelian susceptibility to mycobacterial diseases with a nuclear factor‐κB essential modifier mutation

Nuclear factor (NF)‐κB essential modifier (NEMO), also known as IκB kinase subunit‐γ (IKKγ), is a pivotal molecule in the NF‐κB signaling pathway. Mutations of NEMO cause incontinentia pigmenti and X‐linked ectodermal dysplasia with immunodeficiency. Mendelian susceptibility to mycobacterial diseases (MSMD), which confers an almost selective predisposition to mycobacterial infection, is also caused by NEMO mutations. We herein report the first case of a patient with X‐linked recessive (XR) MSMD who developed cutaneous squamous cell carcinoma, thyroid cancer and Langerhans cell histiocytosis. The relationship between NEMO mutation and oncogenesis is discussed.     

Guselkumab,an anti‐interleukin‐23 monoclonal antibody,for the treatment of moderate to severe plaque‐type psoriasis in Japanese patients: Efficacy and safety results from a phase 3, randomized,double‐blind,placebo‐controlled study

Previous global studies of guselkumab have demonstrated clinical benefits in patients with psoriasis. The aim of this 52‐week, phase 3 study was to evaluate efficacy and safety of guselkumab in Japanese patients with moderate to severe plaque‐type psoriasis. Patients randomly received guselkumab 50 mg or 100 mg at weeks 0, 4 and every 8 weeks, or placebo with cross‐over to guselkumab 50 mg or 100 mg at week 16. Co‐primary end‐points were the proportion of patients achieving Investigator's Global Assessment (IGA) cleared/minimal (0/1) and 90% or more improvement in Psoriasis Area and Severity Index (PASI‐90) at week 16. Overall, 192 patients were randomized to placebo, guselkumab 50 mg or 100 mg. At week 16, patients in the placebo group were crossed over to guselkumab 50 mg or 100 mg. At week 16, a significantly (P < 0.001) higher proportion of patients receiving guselkumab 50 mg and 100 mg versus placebo achieved IGA 0/1 (92.3% and 88.9% vs 7.8%) and PASI‐90 (70.8% and 69.8% vs 0%). Patients in guselkumab 50 mg and 100 mg groups achieved significant improvement versus placebo in PASI‐75 (89.2% and 84.1% vs 6.3%, P < 0.001) at week 16; improvement was maintained through week 52. Incidences of treatment‐emergent adverse events were comparable among the groups through week 16; the most commonly reported was nasopharyngitis. No new safety concerns were observed until week 52. In conclusion, guselkumab treatment demonstrated superior efficacy over placebo and was well tolerated in Japanese patients with moderate to severe plaque‐type psoriasis.