Masaru Karakawa

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

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Expression of IL-33 in the epidermis: The mechanism of induction by IL-17

BACKGROUND Interleukin (IL)-33 is a dual functional, IL-1 family member cytokine, whose exact roles in inflammatory skin diseases are still unknown. IL-17A is a key cytokine in the pathogenesis of psoriasis. OBJECTIVES We investigated if IL-17A could induce IL-33 in epidermal keratinocytes, and the signaling mechanisms involved. METHODS IL-33 levels were evaluated by RT-PCR and western blot in human keratinocytes following IL-17A simulation. IL-33 immunohistochemical staining of psoriatic skin samples was also performed and compared with that of control tissues. The role of signaling pathways downstream of IL-17A was investigated using small molecule inhibitors of EGFR, ERK, p38, and JAK. Adenovirus vector expressing dominant negative STAT1 was also utilized. RESULTS IL-33 and its receptor, ST2L, were expressed in the psoriatic epidermis, and the associated infiltrating cells. IL-17A induced IL-33 expression at mRNA and protein levels in a time- and concentration-dependent manner. IL-17A caused phosphorylation of EGFR, ERK, p38, and STAT1. IL-17A-induced IL-33 expression was blocked by the addition of EGFR, ERK, p38, and JAK inhibitors, and dominant negative STAT1-expressing adenovirus vector. CONCLUSION IL-17A induced IL-33 in NHEKs through EGFR, ERK, p38, and JAK/STAT1 pathways, which were necessary for the induction of IL-33. IL-33, induced by IL-17A in epidermal keratinocytes, may be involved in the pathophysiology of inflammatory skin diseases, including psoriasis.

Novel Splice Variants of IL-33: Differential Expression in Normal and Transformed Cells

TO THE EDITOR IL-33 is a newly discovered member of the IL-1 family and is constitutively expressed in the epithelial and endothelial cells of various organs (Moussion et al., 2008). IL-33 is important to the T helper 2 (Th2) immune reaction because its receptor, ST2L, is expressed on Th2 lymphocytes, basophils, eosinophils, and mast cells (Schmitz et al., 2005). It may also function independently of the immune reaction (Sanada et al., 2007). IL-33 is usually found in the nucleus, produced as pro-form IL-33 (pro-IL-33), and is digested into a mature form with a lower molecular weight when it is secreted from the cells. Mature IL-33 was first thought to be the active form (Schmitz et al., 2005). However, recent reports have shown that the active pro-form of IL-33 is digested into an inactive mature form (Cayrol and Girard, 2009). Neonatal foreskin normal human epidermal keratinocytes (NHEKs) were purchased from Kurabo (Osaka, Japan) and cultured in keratinocyte serum-free medium (Invitrogen, Carlsbad, CA) supplemented with bovine pituitary extract (Kyokuto Seiyaku, Tokyo, Japan) and epidermal growth factor (R&D Systems, Minneapolis, MN). HaCaT keratinocytes were a generous gift from Dr Kuroki (Showa University) with the permission of Dr Fusenig (Institute Fur

Histamine differentially regulates the production of Th1 and Th2 chemokines by keratinocytes through histamine H1 receptor.

Histamine is a biological amine that plays an important role in allergic responses. However, the involvement of histamine signaling in late allergic responses in the skin is poorly understood. Therefore, we attempted to investigate the involvement of histamine signaling in late allergic responses, especially in keratinocytes (KCs). HaCaT KCs and normal human KCs (NHKs) predominantly expressed histamine H1 receptor (H1R) and H2 receptor (H2R). Histamine suppressed tumor necrosis factor α (TNF-α)- and interferon-γ (IFN-γ)-induced production of CC chemokine ligand 17(CCL17), a type 2 T-helper (Th2) chemokine, by HaCaT KCs. It suppressed the phosphorylation of p38 mitogen-activated protein (MAP) kinase, but not that of extracellular signal-regulated kinases (ERKs), and TNF-α- and IFN-γ-induced nuclear factor κB (NFκB) activity. In contrast, histamine enhanced the production of CXC chemokine ligand 10 (CXCL10), a Th1 chemokine, by TNF-α- and IFN-γ-stimulated HaCaT KCs and NHKs. TNF-α- and IFN-γ-induced CXCL10 production was upregulated by suppression of p38 MAP kinase or NF-κB activity, which could explain histamine involvement. We concluded that histamine suppresses CCL17 production by KCs by suppressing p38 MAP kinase and NF-κB activity through H1R and may act as a negative-feedback signal for existing Th2-dominant inflammation by suppressing CCL17 and enhancing CXCL10 production.

Adalimumab administration after infliximab therapy is a successful treatment strategy for generalized pustular psoriasis

We report a case of a 70‐year‐old woman with generalized pustular psoriasis (GPP) who responded well to infliximab therapy and adalimumab therapy after secondary failure of infliximab therapy, but did not respond to ustekinumab therapy. We speculate that the pathogenic factor in this case favored anti‐tumor necrosis factor (TNF)‐α therapy to anti‐interleukin‐12/23 therapy. Herein, we also briefly present three additional cases of treatment with adalimumab after secondary failure of infliximab. GPP is often difficult to treat, and no placebo‐controlled trials have been conducted to guide the use of biologics against it because of a paucity of cases. Infliximab and adalimumab are anti‐TNF‐α antibodies that specifically block the interaction of TNF‐α with its receptors. Infliximab has been reported to be effective, with a rapid clearance of symptoms, even in cases of severe GPP. Adalimumab could be a good biologic candidate that can be administrated after secondary failure of infliximab therapy.

CCL27 Is Downregulated by Interferon Gamma via Epidermal Growth Factor Receptor in Normal Human Epidermal Keratinocytes

The cutaneous T cell‐attracting chemokine (CTACK)/CCL27 is indispensable in skin inflammation. CTACK/CCL27 is exclusively produced by epidermal keratinocytes to attract CCR10‐expressing T lymphocytes to the skin. We investigated the mechanism of CTACK/CCL27 production from normal human epidermal keratinocytes (NHEKs) by the proinflammatory cytokines TNFα and IFNγ. CTACK/CCL27 production was induced by TNFα via ERK, JNK, p38, and NFκB. The induction of CTACK/CCL27 by TNFα was suppressed by IFNγ via a pathway dependent on JAK, STAT1, and STAT3. Our results also demonstrated that IFNγ and TNFα induced the phosphorylation of EGFR and the following phosphorylation of ERK, which is partly responsible for the suppressive effect of IFNγ on TNFα‐induced production of CTACK/CCL27. Peri‐lesional skin of psoriasis demonstrates early inflammatory changes as we have previously reported. CTACK/CCL27 expression was diffuse in the peri‐lesional epidermis, while it was restricted to basal layer in lesional epidermis, suggesting that CTACK/CCL27 expression was induced in the early stage of psoriatic plaque formation, and IFNγ could participate in the suppression of CTACK/CCL27 expression in the lesional epidermis, reflecting the later stage of psoriatic plaque formation. Our study suggests that CTACK/CCL27 may have a pivotal role in the early stage of psoriasis plaque formation, but should be downregulated in the later stage to induce inflammation characteristic for chronic psoriasis plaques. J. Cell. Physiol. 229: 1935–1945, 2014.

Possible involvement of SDF-1/CXCL12 in the pathogenesis of Degos disease.

BACKGROUND Degos disease or malignant atrophic papulosis is a rare occlusive vasculopathic disease characterized by pathognomonic cutaneous lesions and frequently fatal systemic involvement. The etiology of malignant atrophic papulosis remains unclear, and there is currently no effective treatment for malignant atrophic papulosis. Several chemokines can potentiate and expand the platelet response to increase thrombus formation. Among these chemokines, this study examined the expression of stromal cell-derived factor (SDF)-1/CXCL12, which is secreted by bone-marrow stromal and endothelial cells, activates megakaryocyte precursors, and costimulates platelet activation. OBJECTIVE We sought to investigate and compare the expression of SDF-1/CXCL12 in tissue sections taken from 2 patients with Degos disease, 2 patients with other vaso-occlusive diseases, and 2 healthy control subjects. METHODS Immunohistochemical staining involving antibodies to SDF-1/CXCL12 was performed on 3 skin biopsy specimens taken from 2 patients with Degos disease, 1 from a patient with antiphospholipid syndrome, 1 from a patient with cryoglobulinemia, and 2 from healthy control subjects. RESULTS Strong SDF-1/CXCL12 staining was observed in the infiltrating inflammatory cells in the perivascular, intravascular, and perineural areas in tissue samples from patients with Degos disease. No staining was observed in samples from patients with antiphospholipid syndrome or cryoglobulinemia or from healthy control subjects. LIMITATIONS The number of cases available for evaluation was small. The findings were based primarily on the immunohistochemical results and were not confirmed using other techniques. CONCLUSIONS The intense staining of SDF-1/CXCL12 in lesions attributed to Degos disease, demonstrated for the first time to our knowledge in this study, suggests SDF-1/CXCL12 involvement in the pathogenesis of the disease.

Duration of remission period of narrowband ultraviolet B therapy on psoriasis vulgaris.

The remission period of psoriasis vulgaris following narrowband ultraviolet B (NB‐UVB) light therapy with topical vitamin D3 application was evaluated retrospectively to investigate the therapeutic efficacy. Fifty‐two patients (60 cases) were treated with a 5‐day/week protocol of NB‐UVB light irradiation plus topical vitamin D ointment application for 1 month and followed up for at least 12 months. We considered re‐exacerbation as the time when the patients needed treatment other than topical therapy. The remission period was defined as the duration from the end of treatment until re‐exacerbation. Twenty‐seven cases (56%) of psoriasis showed a remission period longer than 12 months. The patients with a past history of systemic therapy or phototherapy had a significantly shorter remission period than those without such a history. No statistically significant differences were observed in sex, age, period before treatment, Psoriasis Area and Severity Index score and total irradiation dose. A previous history of systemic therapy or phototherapy may mean that the disease is severe and sufficiently active to form multiple new lesions requiring these treatments. Our results suggest that the 5‐day/week NB‐UVB light protocol for 4 weeks is an effective and safe treatment for psoriasis vulgaris and can induce long‐term remission.

Roxithromycin downregulates production of CTACK/CCL27 and MIP-3α/CCL20 from epidermal keratinocytes

Cutaneous T cell-attracting chemokine (CTACK)/CCL27 and macrophage inflammatory protein (MIP)-3α/CCL20 are the major inflammatory chemokines involved in skin inflammation. The present study showed that roxithromycin (RXM) suppressed the TNFα-induced production of CCL27 and CCL20 in HaCaT keratinocytes and normal human keratinocytes (NHKs) in a dose-dependent manner. The production of CCL20 induced by TNFα was suppressed by the addition of inhibitors of nuclear factor kappa B (NFκB). RXM suppressed NFκB activity induced by TNFα. RXM, by regulating CCL27 and CCL20, may contribute to the modulation of inflammation.

Psoriasis arthropathica associated with severe obesity showing high serum leptin level

Dear Editor, A 47-year-old man was seen in November 2002 for scaly erythema on the scalp. Three months later, scaly erythema also appeared on the abdomen and gradually spread to the whole body. His father and brother had been diagnosed with psoriasis vulgaris, and he had been diagnosed with hypertension. He and his brother had a body mass index (BMI) of 42.9 and 50.7 kg/m, respectively, and were severely obese. He had multiple erythema with white to silver scales on the back (Fig. 1a), abdomen (Fig. 1b) and extremities. Skin biopsy from the scaly erythema on the upper arm (Fig. 1c) disclosed hyperkeratosis with parakeratosis and elongation of rete ridges (Fig. 2a). In the papillary dermis and partially in the epidermis, there was an infiltration of lymphocytes, mixed with neutrophils, and a subcorneal microabscess (Fig. 2b). General laboratory data showed no particular abnormalities including glucose, glycohemoglobin A1c, total cholesterol and triglyceride except for a slightly elevated level of C-reactive protein (CRP; 0.6 mg/ dL). Serum leptin levels of our patient and his brother were high (20.2 and 28.1 ng/mL, respectively; normal, <5.2 ng/mL). He was diagnosed with psoriasis vulgaris and his Psoriasis Area and Severity Index (PASI) score was 15. He was treated with topical corticosteroid (mometasone furoate) and vitamin D3 (maxacalcitol), resulting in improvement of the skin lesions. When he was 49 years old, he suffered from arthralgia on the fingers and elbows. The distal interphalangeal joints of his right fingers swelled, and the CRP level rose to 5.0 mg/dL. Rheumatoid factor was negative. Thus, he was diagnosed with psoriasis arthropathica and treated with 8 mg/week of methotrexate, resulting in soothing of the arthralgia and a decline in the CRP level (1.0 mg/dL). Obesity is a significant risk factor for psoriasis and BMI is correlated with the severity of the disease. Naldi et al. disclosed that a moderately increased BMI (26–29 kg/m) was associated with a slightly