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Dysregulation of inflammatory cytokines in keratinocytes promote the pathogenesis of the skin inflammation, such as allergic contact dermatitis (ACD). High-mobility group box 1 protein (HMGB1) has been implicated in the promotion of skin inflammation upon its extracellular release as a damage-associated molecular pattern molecule. However, whether and how HMGB1 in keratinocytes contributes to ACD and other skin disorders remain elusive. In this study, we generated conditional knockout mice in which the Hmgb1 gene is specifically deleted in keratinocytes, and examined its role in ACD models. Interestingly, the mutant mice showed exacerbated skin inflammation, accompanied by increased ear thickening in 2,4-dinitrofluorobenezene-induced ACDs. The mRNA expression of interleukin-24 (IL-24), a cytokine known to critically contribute to ACD pathogenesis, was elevated in skin lesions of the mutant mice. As with constitutively expressed, IL-4-induced Il24 mRNA, expression was also augmented in the Hmgb1 -deficient keratinocytes, which would account for the exacerbation of ACD in the mutant mice. Mechanistically, we observed an increased binding of trimethyl histone H3 (lys4) (H3K4me3), a hallmark of transcriptionally active genes, to the promoter region of the Il24 gene in the hmgb1 -deficient cells. Thus, the nuclear HMGB1 is a critical "gate keeper" in that the dermal homeostasis is contingent to its function in chromatin remodeling. Our study revealed a facet of nuclear HMGB1, namely its antiinflammatory function in keratinocytes for the skin homeostasis., Competing Interests: The authors declare no competing interest.

Interferon regulatory factors (IRFs) play diverse roles in the regulation of the innate and adaptive immune responses in various diseases. In psoriasis, IRF2 is known to be involved in pathogenesis, while studies on other IRFs are limited. In this study, we investigated the role of IRF5 in psoriasis using imiquimod-induced psoriasis-like dermatitis. Although IRF5 is known to play a critical role in the induction of proinflammatory cytokines by immune cells, such as dendritic cells (DCs), macrophages, and monocytes, IRF5 deficiency unexpectedly exacerbated psoriasiform skin inflammation. The interferon-α and tumor necrosis factor-α mRNA expression levels were decreased, while levels of Th17 cytokines including IL-17, IL-22, and IL-23 were increased in IRF5-deficient mice. Furthermore, IL-23 expression in DCs from IRF5-deficient mice was upregulated both in steady state and after toll-like receptor 7/8 agonist stimulation. Importantly, the expression of IRF4, which is also important for the IL-23 production in DCs, was augmented in DCs from IRF5-deficient mice. Taken together, our results suggest that IRF5 deficiency induces the upregulation of IRF4 in DCs followed by augmented IL-23 production, resulting in the amplification of Th17 responses and the exacerbation of imiquimod-induced psoriasis-like skin inflammation. The regulation of IRF4 or IRF5 expression may be a novel therapeutic approach to psoriasis.

Whereas atopic dermatitis (AD) is considered as a T helper 2 (Th2)-centered disease, IL-17-producing Th (Th17) cells are also activated in AD lesional skin. However, the relationship between Th17 responses and Th2 responses in AD is still to be elucidated. Although Th17 cells are increased in AD skin, the expression and function of IL-26, which is also produced by Th17 cells, in AD are still unknown. In this report, we demonstrated that IL-26 mRNA expression levels were elevated in AD lesional skin compared with healthy controls and that IL-26-producing cells were increased in AD lesional skin by immunohistochemistry. Furthermore, IL-26 promoted IL-8, IL-1β, chemokine (C-C motif) ligand 20, IL-33, and β-defensin 2 production in keratinocytes through phosphorylation of signal transducer and activator of transcription 1 and signal transducer and activator of transcription 3. Selective JAK inhibitors for JAK1, JAK2, and tyrosine kinase 2 blocked IL-26-induced cytokine production in keratinocytes. We also showed that injection of IL-26 exacerbated an oxazolone-induced AD mouse model and upregulated Th2 and Th17 cytokine expression in vivo. Because previous studies indicate that the above molecules induced by IL-26 can promote Th17 and/or Th2 immune responses, IL-26 may play an important role for bridging between Th17 and Th2 responses, resulting in the development of AD., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Interleukin-19 (IL-19), a pro-inflammatory cytokine known to stimulate the production of T helper type 2 (Th2) cytokines, is induced by IL-17A and highly expressed in the lesional skin of psoriasis and atopic dermatitis (AD). This aim of this study was to investigate whether IL-19 is involved in cutaneous T-cell lym-phoma (CTCL) and AD. IL-19 levels were significantly higher in the sera of patients with AD and those with advanced-stage CTCL than in normal controls, correlating significantly with clinical disease markers. IL-19 mRNA levels in lesional skin of both diseases were significantly elevated. Immunohistochemical staining revealed that IL-19 was expressed in the epidermis of AD skin and CTCL skin. In vitro, IL-17A and IL-4 increased IL-19 mRNA expression in human keratinocytes. Thus, IL-19 was increased in the sera and skin of AD and CTCL. These results suggest that IL-19 is important for bridging Th17 to Th2 in these diseases.

Interleukin (IL)-21 is regarded as a potent antitumor agent, which increases the cytotoxicity of both natural killer (NK) and CD8(+) T cells. In this study, we investigated the role of IL-21 in mycosis fungoides (MF). IL-21 mRNA expression levels in patch and plaque MF were significantly higher than those in normal skin. IL-21 mRNA expression levels in tumor MF were significantly decreased compared with those in patch and plaque MF. Interestingly, mRNA expression levels of IL-21 in MF lesional skin significantly correlated with those of T-helper type-1 cytokines/chemokines such as CXCL10, CXCL11 and γ-interferon. Immunohistochemistry showed that IL-21 was expressed by keratinocytes in patch and plaque MF. Furthermore, serum IL-21 levels in patients with tumor MF were significantly lower than those of healthy controls and plaque MF. Thus, IL-21 expression was significantly downregulated in skin and blood of patients with tumor MF, which may contribute to progression of MF. Our study suggests that recombinant IL-21 would be a promising therapy for MF., (© 2016 Japanese Dermatological Association.)

IL-32 is a pro-inflammatory cytokine expressed by activated natural killer cells, T cells, keratinocytes, and fibroblasts. In this study, we examined the role of IL-32 in cutaneous T-cell lymphoma (CTCL), including mycosis fungoides (MF) and Sézary syndrome (SS). IL-32 mRNA expression levels in lesional skin of MF patch, plaque, and tumor were increased compared with those of normal skin, which positively correlated with CCL17 and CCL18 mRNA expression levels. Serum IL-32 levels positively correlated with disease activity within each patient. Immunostaining showed that keratinocytes expressed IL-32 in the lesional skin of MF patch and plaque, whereas in MF tumor, atypical T cells in the dermis strongly expressed IL-32. We also showed that IL-32 dose-dependently accelerated the proliferation of MF and SS cell lines in vitro, which was inhibited by blocking mitogen-activated protein kinase and NF-κB-mediated signaling. The addition of anti-IL-32 antibodies in culture decreased the proliferation of SS cells and the viability of MF cells, suggesting that IL-32 serves as an autocrine growth factor. In conclusion, our results suggest that IL-32 has a role in the formation and maintenance of CTCL lesions, providing a possible therapeutic target for patients with this disease.

B cells regulate immune responses by producing antigen-specific antibodies. However, specific B-cell subsets can also negatively regulate T-cell immune responses, and have been termed regulatory B cells. Human and mouse regulatory B cells (B10 cells) with the ability to express the inhibitory cytokine interleukin-10 (IL-10) have been identified. Although rare, B10 cells are potent negative regulators of antigen-specific inflammation and T-cell-dependent autoimmune diseases in mice. How B10-cell IL-10 production and regulation of antigen-specific immune responses are controlled in vivo without inducing systemic immunosuppression is unknown. Using a mouse model for multiple sclerosis, here we show that B10-cell maturation into functional IL-10-secreting effector cells that inhibit in vivo autoimmune disease requires IL-21 and CD40-dependent cognate interactions with T cells. Moreover, the ex vivo provision of CD40 and IL-21 receptor signals can drive B10-cell development and expansion by four-million-fold, and generate B10 effector cells producing IL-10 that markedly inhibit disease symptoms when transferred into mice with established autoimmune disease. The ex vivo expansion and reinfusion of autologous B10 cells may provide a novel and effective in vivo treatment for severe autoimmune diseases that are resistant to current therapies.

Purpose: Both patients with cutaneous T-cell lymphoma (CTCL) and those with atopic dermatitis (AD) have pruritus, T(H)2-biased T cells, and a tendency to have bacterial infections, suggesting a common pathologic basis for these two diseases. Recently, interleukin (IL)-22-producing T cells were reported in skin of patients with AD. In this study, we investigated expression levels of T(H)22- and T(H)17-related molecules in lesional skin and sera isolated from patients with CTCL., Experimental Design: Skin biopsies and sera were collected from patients with CTCL or psoriasis and from healthy volunteers. Protein and mRNA expression levels of IL-22, IL-17A, IL-17F, IL-23p19, IL-10, IL-4, CCL20, CCR6, IL-8, and IL-20 were examined in lesional tissue and a subset of these molecules in sera. Phosphorylation of STAT3 was also assessed in lesional skin of CTCL and psoriasis by immunohistochemistry., Results: IL-22, IL-10, IL-4, CCL20, and CCR6 mRNA and protein levels, but not IL-17A, IL-17F, IL-23p19, IL-8, or IL-20, were significantly elevated in lesional skin of CTCL. Phosphorylation of STAT3 was detected in epidermis of CTCL skin. Moreover, serum IL-22, IL-10, and CCL20 levels were increased in CTCL and correlated with disease severity., Conclusions: Our results suggest that IL-22 is important in establishing the tumor microenvironment for CTCL. Enhanced expression of CCL20 may explain epidermal hyperplasia and migration of CCR6(+) cells, such as Langerhans cells, into lesional skin. Relatively low expression of IL-17 may explain the lack of neutrophils in lesions of CTCL, which correlates with bacterial infections that commonly occur in skin affected by CTCL., (©2011 AACR.)

The immunological significance of IL-27 has been reported and discussed in various Th1/Th17-mediated inflammatory diseases. However, its importance in psoriasis is unknown. We investigated pathophysiological roles of IL-27 in psoriasis in this study. Serum IL-27 levels in psoriatic patients were significantly higher than those in healthy controls, and correlated with disease severity and serum IFN-gamma levels. An immunohistochemical analysis revealed the infiltration of IL-27-secreting cells in the papillary dermis of psoriatic skin lesions but not in skin lesions with atopic dermatitis or normal skin. Furthermore, IL-27 alone greatly induced in vitro CXCL9, CXCL10, and CXCL11 production and tyrosine phosphorylation of signal transducer and activator of transcription 1 in normal human keratinocytes, while it suppressed the tumor necrosis factor-alpha-induced production of IL-1alpha and CCL20. These results indicate that IL-27 may promote the onset of psoriasis, while it may simultaneously attenuate the expanded inflammation in this disease. Our results implicate potential therapeutic effects of IL-27 for psoriasis.

Summary: Background: Interleukin (IL)‐25 is a member of the IL‐17 family, which can promote and augment T‐helper (Th) type 2 responses. The expression of IL‐25 and its cognate receptor, IL‐25 receptor (IL‐25R), is upregulated and correlated with disease activity in Th2‐associated diseases. Objectives: To examine the expression and function of IL‐25 in cutaneous T‐cell lymphoma (CTCL). Methods: Expression and location of IL‐25 in lesional skin was investigated with immunohistochemistry. The effect of various cytokines on IL‐25 production from normal human epidermal keratinocytes was assessed by quantitative reverse‐transcription real‐time polymerase chain reaction. Serum IL‐25 levels were measured by enzyme‐linked immunosorbent assay. The direct effect of IL‐25 on tumour cells was also examined using CTCL cell lines and peripheral blood mononuclear cells in patients with Sézary syndrome. Results: IL‐25 expression was increased in epidermal keratinocytes in lesional skin of CTCL. Th2 cytokines, IL‐4 and IL‐13, and periostin induced IL‐25 expression by normal human epidermal keratinocytes. Serum IL‐25 levels were increased in patients with advanced CTCL and correlated with serum lactate dehydrogenase levels. MyLa cells expressed IL‐25R and its expression was augmented by stimulation with IL‐25. IL‐25 enhanced IL‐13 production from MyLa cells via phosphorylation of signal transducer and activator of transcription 6. Peripheral blood mononuclear cells from one patient with Sézary syndrome expressed IL‐25R and showed increase of IL‐13 production by IL‐25. Conclusions: Th2 cytokines highly expressed in CTCL lesional skin induce IL‐25 production by epidermal keratinocytes, which may, in turn, lead to formation of a Th2‐dominant microenvironment through the direct induction of IL‐13 by tumour cells. [ABSTRACT FROM AUTHOR]

The article presents a study which investigates the Interleukin (IL)-27 levels in sera of 27 patients with cutaneous T-cell lymphoma (CTCL). The patients were classified according to the types of skin lesions into early stage and advance stage. It notes that the two groups were analyzed using statistical tools through which serum samples were taken from the patients. Results found out that patients with advance stage group of CTCL are considered in malignant stage and resistant for treatment.