Naoko Kanda

IL‐18 enhances IFN‐γ‐induced production of CXCL9, CXCL10, and CXCL11 in human keratinocytes

IL‐18 is involved in the pathogenesis of atopic dermatitis, psoriasis, and allergic contact dermatitis. CXCL9, CXCL10, and CXCL11 recruit type 1 T cells, and the production of these chemokines by keratinocytes is enhanced in these dermatoses. We examined the in vitro effects of IL‐18 on IFN‐γ‐induced CXCL9, CXCL10, and CXCL11 production in human keratinocytes. IL‐18 enhanced the IFN‐γ‐induced secretion and mRNA expression of CXCL9, CXCL10, and CXCL11 in parallel to the activation of NF‐κB, STAT1, and IFN‐regulatory factor (IRF)‐1. Antisense oligonucleotides against NF‐κB p50, p65, or STAT1 suppressed CXCL9, CXCL10, and CXCL11 production, and antisense IRF‐1 suppressed CXCL11 production. Inhibitors of PI3 K, p38 MAPK, and MEK suppressed IL‐18 plus IFN‐γ‐induced CXCL9, CXCL10, and CXCL11 production and NF‐κB, STAT1, and IRF‐1 activities. IL‐18 induced phosphorylation of ERK and Akt, while IFN‐γ induced phosphorylation of p38 MAPK. These results suggest that IL‐18 may potentiate IFN‐γ‐induced CXCL9, CXCL10, and CXCL11 production in keratinocytes by activating NF‐κB, STAT1, or IRF‐1 through PI3 K/Akt and MEK/ERK pathways. These effects of IL‐18 may promote the infiltration of type 1 T cells into lesions with inflammatory dermatoses and amplify the skin inflammation. IL‐18 may act as a pro‐inflammatory cytokine in these dermatoses and thus is a candidate therapeutic target.

The skin fungus-induced Th1- and Th2-related cytokine, chemokine and prostaglandin E2 production in peripheral blood mononuclear cells from patients with atopic dermatitis and psoriasis vulgaris

Background It is suggested that skin fungi may be involved in the development of atopic dermatitis (AD) and psoriasis vulgaris (PV).

IL‐12, IL‐23, and IL‐27 enhance human β‐defensin‐2 production in human keratinocytes

IL‐12, IL‐23, and IL‐27, which are produced by APC, modulate innate and adaptive immunities. Human β‐defensin‐2 (hBD‐2) produced by epidermal keratinocytes promotes cutaneous antimicrobial defense and inflammation. We examined the in vitro effects of IL‐12, IL‐23, and IL‐27 on hBD‐2 production in human keratinocytes. IL‐12, IL‐23, and IL‐27 enhanced IL‐1β‐induced hBD‐2 secretion and mRNA expression in keratinocytes. The stimulatory effects of IL‐12, IL‐23, and IL‐27 were suppressed by antisense oligonucleotides against NF‐κB p50 and p65. In addition, the effects of IL‐12 and IL‐27 were suppressed by antisense STAT3 and STAT1, respectively. All the three IL enhanced the basal and IL‐1β‐induced transcriptional activities of NF‐κB, while IL‐12 and IL‐27 enhanced STAT3 and STAT1 activities, respectively. Further, IL‐12, IL‐23, and IL‐27 promoted basal and IL‐1β‐induced phosphorylation of IκBα. IL‐12 and IL‐23 tyrosine phosphorylated STAT3 and STAT1, respectively; IL‐12, IL‐23, and IL‐27 tyrosine phosphorylated JAK2 and tyrosine kinase‐2; and IL‐27 tyrosine phosphorylated JAK1. These results suggest that IL‐12, IL‐23, and IL‐27 may enhance IL‐1β‐induced hBD‐2 production in keratinocytes by activating NF‐κB. STAT3 and STAT1 are involved in the effects of IL‐12 and IL‐27, respectively. Thus, IL‐12, IL‐23, and IL‐27 may promote cutaneous antimicrobial defense and inflammation via hBD‐2.

Novel effects of diosgenin on skin aging

Extracts of Dioscorea coomposita or Dioscorea villosa are consumed as supplemental health foods at the time of climacteric. The extracts contain large amounts of the plant steroid, diosgenin. Here, we studied the safety and efficacy of diosgenin against skin aging at the time of climacteric. In vitro, diosgenin enhanced DNA synthesis in a human 3D skin equivalent model, and increased bromodeoxyuridine uptake and intracellular cAMP level in adult human keratinocytes. The increase of bromodeoxyuridine uptake by diosgenin was blocked by an adenylate cyclase inhibitor, but not by antisense oligonucleotides against estrogen receptor alpha, estrogen receptor beta or an orphan G-protein-coupled receptor, GPR30, indicating the involvement of cAMP but not estrogen receptor alpha, estrogen receptor beta or GPR30. In vivo, administration of diosgenin improved the epidermal thickness in the ovariectomized mice, a climacteric model, without altering the degree of fat accumulation. In order to examine the safety of diosgenin, diosgenin and 17beta-estradiol were administered to breast cancer-burdened mice. The results revealed that while 17beta-estradiol accelerated the tumor growth, diosgenin did not show this effect. Our finding, a restoration of keratinocyte proliferation in aged skin, suggests that diosgenin may have potential as a safe health food for climacteric.

Adiponectin as an anti-inflammatory factor in the pathogenesis of psoriasis: induction of elevated serum adiponectin levels following therapy

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Prolactin enhances basal and IL-17-induced CCL20 production by human keratinocytes.

Psoriasis vulgaris is an autoimmune dermatosis with Th17 infiltration. Prolactin (PRL) may participate in the pathogenesis of psoriasis. The chemokine CCL20 recruits Th17 cells, and CCL20 production by epidermal keratinocytes is enhanced in psoriatic lesions. We examined the in vitro effects of PRL on CCL20 production in human keratinocytes. PRL increased basal and IL‐17‐induced CCL20 secretion, and mRNA expression in keratinocytes. CCL20 production by PRL was suppressed by antisense oligonucleotides against the AP‐1 components c‐Fos and c‐Jun, whereas that by IL‐17 was suppressed by antisense NF‐κB p50 and p65. CCL20 production induced by PRL plus IL‐17 was suppressed by antisense c‐Fos, c‐Jun, p50, and p65. PRL alone increased the transcriptional activity of AP‐1, and c‐Fos and c‐Jun expression; moderately enhanced NF‐κB activity and IκBα phosphorylation; and potently increased IL‐17‐induced NF‐κB activity. MEK and JNK inhibitors suppressed PRL‐ or PRL‐plus‐IL‐17‐induced CCL20 production and AP‐1 activities. MEK inhibitor suppressed PRL‐induced c‐Fos expression, whereas JNK inhibitor suppressed c‐Jun expression. PRL induced ERK and JNK phosphorylation. These results suggest that PRL may enhance basal and IL‐17‐induced CCL20 production in keratinocytes by AP‐1 and NF‐κB activation, which is partially mediated via MEK/ERK and JNK. PRL may promote Th17 infiltration into psoriatic lesions via CCL20.

Human β-defensin-2 enhances IFN-γ and IL-10 production and suppresses IL-17 production in T cells

Psoriasis is an inflammatory dermatosis with enhanced expression of hBD‐2 in keratinocytes and infiltration of cytokine‐producing T cells, which in turn, up‐ or down‐regulate hBD‐2 expression. We determined the serum levels of hBD‐2 and cytokines in psoriasis patients and analyzed the effects of hBD‐2 on cytokine production in human peripheral blood T cells. Serum hBD‐2 levels in patients were higher than those in controls and correlated with PASI, serum IFN‐γ, and IL‐10 levels and correlated inversely with serum IL‐17 levels. IFN‐γ, IL‐17, IL‐22, TNF‐α, IL‐1β, and IL‐6 enhanced, and IL‐10, IL‐4, and IL‐13 suppressed hBD‐2 secretion from keratinocytes. hBD‐2 enhanced secretion and mRNA levels of IFN‐γ, TNF‐α, IL‐10, IL‐1β, IL‐6, and IL‐22 and reduced those of IL‐17 in CD3/28‐stimulated T cells. These effects of hBD‐2 were counteracted by PTX. hBD‐2 induced phosphorylation of JNK, ERK, and Akt in T cells. Inhibitors of these signals attenuated hBD‐2‐induced production of IFN‐γ, TNF‐α, IL‐10, IL‐1β, IL‐6, and IL‐22. hBD‐2 suppressed phosphorylation of STAT3 and enhanced expression of SOCS3 in CD3/28‐stimulated T cells. siRNA against SOCS3 reversed hBD‐2‐induced suppression of IL‐17 production and STAT3 phosphorylation. JNK and MEK inhibitors suppressed hBD‐2‐induced expression of SOCS3. In conclusion, hBD‐2 may bind PTX‐sensitive GPCR(s) on T cells and act as a stimulator by enhancing IFN‐γ, TNF‐α, IL‐1β, IL‐6, and IL‐22 production via JNK, MEK/ERK, and PI3K/Akt and as a regulator by suppressing IL‐17 production via SOCS3 or by stimulating IL‐10 production.

Annular erythema associated with lupus erythematosus/Sjögren's syndrome

BACKGROUND Annular-polycyclic and papulosquamous lesions are associated with subacute cutaneous lupus erythematosus (SCLE). In some Asian cases, annular erythema has been associated with Sjögrens syndrome (SS). However, the relation between the two is unclear. OBJECTIVE Our purpose was to clarify the clinical manifestations and immunologic features of patients with annular erythema. METHODS This study included 15 patients with annular erythema. Systemic, serologic, and genetic findings were analyzed. RESULTS Histologic examination showed perivascular and periappendageal lymphocytic infiltrates in all patients. However, LE-specific epidermal changes were observed in only three (20%). Although all patients at least partially demonstrated features of LE or SS, eight (53%) fulfilled the American Rheumatism Association criteria for systemic LE (SLE) and five (33%) were diagnosed with SS. Renal (20%) and central nervous system (7%) involvement was observed. Anti-Ro(SS-A) and anti-La(SS-B) antibodies were detected in nine (60%) and seven (47%) patients, respectively. There were no histocompatibility antigen (HLA) haplotype differences. CONCLUSION Annular erythema in Asian patients is the counterpart of subacute skin lesions of LE in whites, except for the paucity of LE-specific histopathologic findings and HLA-DR3 tissue type.

IL-27 Activates Th1-Mediated Responses in Imiquimod-Induced Psoriasis-Like Skin Lesions

IL-27, a member of the IL-12 cytokine family, primes Th1 cell differentiation, whereas it suppresses Th17 cell development. We have previously reported that serum IL-27 levels are elevated in psoriatic patients and that IL-27 greatly induces in vitro production of Th1-type chemokines through STAT1 activation. In this study, to further investigate the in vivo role of IL-27 in the pathogenesis of psoriasis, we induced psoriasis-like inflammation on mouse back skin with topical application of imiquimod (IMQ), and continuously injected IL-27 or PBS subcutaneously. IMQ-treated skin showed an increase of IL-27 mRNA levels and the infiltration of IL-27-producing cells in the papillary dermis. The injection of IL-27 to the IMQ-treated skin exacerbated the disease compared with PBS injection. The IL-27 injection further augmented mRNA levels of IFN-γ, CXCL9, CXCL10, CXCL11, and TNF-α, without altering those of IL-17A, IL-17F, IL-22, and CCL20. Finally, IL-27 antagonism attenuated the upregulation of IFN-γ, CXCL9, CXCL10, CXCL11, and TNF-α mRNA levels, and induced clinical and histological improvement in the IMQ-treated skin. These results indicate that IL-27 would act in a proinflammatory manner, and thereby exacerbate the psoriasis-like skin inflammation induced by IMQ.

Decreased serum LL-37 and vitamin D3 levels in atopic dermatitis: relationship between IL-31 and oncostatin M.

Skin lesions with atopic dermatitis (AD) are associated with dysregulated expression of LL‐37 and enhanced expression of IL‐22, thymic stromal lymphopoietin (TSLP), IL‐25, IL‐31, and oncostatin M. Vitamin D3 enhances LL‐37 production in keratinocytes. This study aimed to examine the serum levels of LL‐37 and vitamin D3 and their regulation of cytokine production in patients with AD.