[Show abstract][Hide abstract] ABSTRACT: The tyrosine kinase inhibitor (TKI) imatinib has been shown to promote psoriasis in some patients with chronic myelogenous leukaemia (CML); but it remained unclear whether second-generation TKIs such as nilotinib and dasatinib had a similar potential. Here, we present a patient, in whom psoriatic erythema appeared at 26 months after initiation of nilotinib treatment. Topical ointments of activated vitamin D3 derivative and corticosteroid were applied; whereupon, the erythema gradually improved. During the clinical course, nilotinib administration continued without reduction of its dose. This is the first report of psoriasis that developed during nilotinib treatment. We also discuss the mechanisms of nilotinib-mediated progression of psoriasis. This article is protected by copyright. All rights reserved.
No preview · Article · Jun 2013 · European Journal Of Haematology
[Show abstract][Hide abstract] ABSTRACT: 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.
[Show abstract][Hide abstract] ABSTRACT: 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.
Full-text · Article · Aug 2012 · Journal of the American Academy of Dermatology
[Show abstract][Hide abstract] ABSTRACT: 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.
[Show abstract][Hide abstract] ABSTRACT: 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.
No preview · Article · Dec 2010 · Archives for Dermatological Research
[Show abstract][Hide abstract] ABSTRACT: The remission period of psoriasis vulgaris following narrowband ultraviolet B (NB-UVB) light therapy with topical vitamin D(3) 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.
No preview · Article · Oct 2010 · The Journal of Dermatology
[Show abstract][Hide abstract] ABSTRACT: 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.
Preview · Article · Nov 2009 · Journal of Investigative Dermatology
[Show abstract][Hide abstract] ABSTRACT: Early inflammatory changes in psoriatic plaques were investigated immunohistochemically by studying the normal-appearing skin adjacent to the plaques (perilesional skin), lesional skin, and distant uninvolved skin from psoriasis patients. Perilesional epidermis contained numerous CD1a-positive Langerhans cells, some of which expressed HLA-DR, CD83, CD80, and CD86, at the same time expressing Langerin. There were also numerous CD83-positive, CD11c-positive, Langerin-negative dendritic cells (DCs) in the epidermal-dermal junction of perilesional skin. CD3-positive T lymphocytes were sparse in the perilesional skin. Perilesional epidermis expressed keratin K6 and K16, inflammatory keratins, and C/EBPbeta, a transcription factor related to inflammatory cytokines. Our results demonstrated the abundant distribution of activated DCs in the perilesional skin of psoriatic plaques, where early inflammatory changes occur in the epidermal keratinocytes, which suggests their involvement in the provocation of epidermal inflammation in the perilesional epidermis and further pathogenic roles in the formation of psoriatic plaques.