Interleukin-8 Overexpression Is Present in Pyoderma Gangrenosum Ulcers and Leads to Ulcer Formation in Human Skin Xenografts

Oka, Masahiro; Berking, Carola; Nesbit, Mark E.; Satyamoorthy, Kapaettu; Schaider, Helmut; Murphy, Gëorge F.; Ichihashi, Masamitsu; Sauter, Edward R.; Herlyn, Meenhard

doi:10.1038/labinvest.3780064

Cited by 113 publications

(85 citation statements)

References 47 publications

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“…We also observed overexpression of IL-8 in the cytoplasm of macrophages scattered among the inflammatory infiltrate; it is well known that this cytokine is a potent chemotactic polypeptide for neutrophils and may also be involved in angiogenesis [14,17]. In the literature, there is evidence for a role of IL-8 in the pathogenesis of pyoderma gangrenosum, since overexpression of this chemotactic cytokine has been found immunohistochemically in dermal fibroblast from ulcers of patients affected by this disease [18,19]. We provide evidence for abundant expression of TNF-a in both epithelial cells and the inflammatory infiltrate suggesting that this potent pro-inflammatory cytokine, which leads to recruitment of inflammatory cells to areas of inflammation, could synergistically contribute to the proinflammatory pathogenetic mechanism of PV.…”

Section: Discussionsupporting

confidence: 67%

Pyostomatitis Vegetans: Cellular Immune Profile and Expression of IL-6, IL-8 and TNF-α

Ficarra

Baroni

Massi

2009

Head and Neck Pathol

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The aim of this study was to investigate the cellular immune profile and the expression of IL-6, IL-8 and TNF-a in tissue biopsies of pyostomatitis vegetans (PV). Working hypothesis was that knowledge of the cellular immune profile and role of mediators such as IL-6, IL-8 AND TNF-alpha may contribute to a better understanding of the pathogenesis of this rare entity. Archival tissues from three patients with clinically and histologically confirmed PV were studied. Analysis of the immune profile of the cellular infiltrate and expression of IL-6 and IL-8 were evaluated by immunohistochemistry. ISH was performed to evaluate the expression of TNF-a. Biopsy tissues from erythema multiforme, recurrent aphthous stomatitis, lichen planus and normal buccal mucosa were analyzed as controls. All patients were affected by multiple mucosal ulcerations and yellow pustules mainly located in the vestibular, gingival and palatal mucosa. Histopathologically, all specimens showed ulcerated epithelium with characteristic intraepithelial and/or subepithelial microabscesses containing abundant eosinophils plus a mixed infiltrate composed of lymphocytes and neutrophils. Cellular immune profile of the inflammatory infiltrate revealed a predominance of T-lymphocytes, mainly of cytotoxic (CD3?/CD8?) phenotype, over B-cells. CD20? B-lymphocytes were also identified to a lesser degree among the lymphoid cells present in the lamina propria. Overexpression of IL-6 and TNF-a was found in both epithelial and inflammatory mononuclear cells. IL-8 expression was shown in the mononuclear cells scattered among the inflammatory infiltrate. Similar findings of overexpression of IL-6, IL-8 and TNF-a were, however, found in control tissues. In PV lesions, the inflammatory infiltrate shows a predominance of cytotoxic lymphocytes. Expression of IL-6, IL-8 and TNF-a, although not specific to PV, appears up-regulated thus these cytokines would represent a suitable therapeutic target. However, the complexity of the cytokine network and their numerous functions require further studies in order to confirm our findings.

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Section: Discussionsupporting

confidence: 67%

Pyostomatitis Vegetans: Cellular Immune Profile and Expression of IL-6, IL-8 and TNF-α

Ficarra

Baroni

Massi

2009

Head and Neck Pathol

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“…45 We previously showed that IL-8 is overexpressed in the skin of patients with pyoderma gangrenosum, a representative of neutrophilc dermatoses. 46 We also showed that overexpression of IL-8 using adenovirus vector in human skin grafted on severe combined immunodeficiency mice resulted in neutrophil-associated skin ulcer resembling pyoderma gangrenosum. 46 These findings indicate that IL-8-induced neutrophil infiltration has a role either directly or indirectly in the pathogenesis of several inflammatory skin diseases.…”

Section: Discussionmentioning

confidence: 95%

“…46 We also showed that overexpression of IL-8 using adenovirus vector in human skin grafted on severe combined immunodeficiency mice resulted in neutrophil-associated skin ulcer resembling pyoderma gangrenosum. 46 These findings indicate that IL-8-induced neutrophil infiltration has a role either directly or indirectly in the pathogenesis of several inflammatory skin diseases. As IL-8 is not produced in normal conditions, an increased amount of IL-8 in these diseases must result from dysregulation of IL-8 production.…”

Section: Discussionmentioning

confidence: 95%

Phospholipase Cɛ has a crucial role in ultraviolet B-induced neutrophil-associated skin inflammation by regulating the expression of CXCL1/KC

Oka

Edamatsu

Kunisada

et al. 2011

Laboratory Investigation

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Phospholipase C (PLC) e is a phosphoinositide-specific PLC regulated by small GTPases including Ras and Rap. We previously demonstrated that PLCe has an important role in the development of phorbol ester-induced skin inflammation. In this study, we investigated the role of PLCe in ultraviolet (UV) B-induced acute inflammatory reactions in the skin. Wild-type (PLCe þ / þ ) and PLCe gene knockout (PLCe À/À ) mice were irradiated with a single dose of UVB at 1, 2.5, and 10 kJ/m 2 on the dorsal area of the skin, and inflammatory reactions in the skin were histologically evaluated up to 168 h after irradiation. In PLCe þ / þ mice, irradiation with 1 and 2.5 kJ/m 2 UVB resulted in dose-dependent neutrophil infiltration in the epidermis at 24 and 48 h after irradiation. When mice were irradiated with 10 kJ/m 2 of UVB, most mice developed skin ulcers by 48 h and these ulcers became more severe at 168 h. In PLCe À/À mice, UVB (1 or 2.5 kJ/m 2 )-induced neutrophil infiltration was markedly suppressed compared with PLCe þ / þ mice. The suppression of neutrophil infiltration in PLCe À/À mice was accompanied by attenuation of UVB-induced production of CXCL1/keratinocyte-derived chemokine (KC), a potent chemokine for neutrophils, in the whole skin. Cultured epidermal keratinocytes and dermal fibroblasts produced CXCL1/KC in a PLCe-dependent manner after UVB irradiation, and the UVB-induced upregulation of CXCL1/KC in these cells was significantly abolished by a PLC inhibitor. Furthermore, UVB-induced epidermal thickening was noticeably reduced in the skin of PLCe À/À mice. These results indicate that PLCe has a crucial role in UVB-induced acute inflammatory reactions such as neutrophil infiltration and epidermal thickening by at least in part regulating the expression of CXCL1/KC in skin cells such as keratinocytes and fibroblasts.

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“…In human skin xenografts, IL-8 overexpression induced subepidermal neutrophil accumulation and formation of ulcers resembling PG clinically and histologically. 11 Furthermore, cultured fibroblasts isolated from a PG ulcer produced high levels of IL-8, while fibroblasts from surrounding unaffected skin produced no detectable IL-8, 12 indicating local production from cells within the lesion. Raised serum concentrations of IL-8 have been reported in patients with active PG, 12 as have raised serum concentrations of cytokines IL-6, 13 and granulocyte colony-stimulating factor (G-CSF), which stimulates proliferation, differentiation and survival of neutrophils.…”

Section: Aetiopathogenesismentioning

confidence: 99%

Management of pyoderma gangrenosum

Teagle

Hargest

2014

J R Soc Med

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Pyoderma gangrenosum (PG) is an uncommon ulcerative skin disease often associated with underlying systemic diseases. Its pathogenesis is unknown, although immune pathways have been implicated. Targeted therapy is therefore lacking and currently treatment is largely empirical and consists of corticosteroids and ciclosporin first line. This paper reviews the current and emerging knowledge about PG. PG occurs with an incidence of 3–10 per million per year. The ulcers are exquisitely painful and characteristically have a necrotic centre with irregular overhanging bluish borders. Around half of cases are associated with underlying systemic disease, most commonly inflammatory bowel disease, rheumatoid arthritis and haematological malignancies; the remaining cases are idiopathic. The pathogenesis is unknown, but the most widely supported theory is immunological, and biopsies of lesions show a predominantly neutrophilic infiltrate. Several aberrant immune processes have been described, with neutrophils and their recruitment to sites of inflammation by cytokines taking an apparently important role. Topical and systemic therapies are both vital aspects of treatment, and in recent years, immune modulators have been used with increasing success, with an emerging role for anti-tumour necrosis factor alpha agents such as the monoclonal antibody infliximab. Although uncommon, PG causes significant morbidity to those it affects. Further research is needed into the disease pathogenesis, and adequate targeted treatment.

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Interleukin-8 Overexpression Is Present in Pyoderma Gangrenosum Ulcers and Leads to Ulcer Formation in Human Skin Xenografts

Cited by 113 publications

References 47 publications

Pyostomatitis Vegetans: Cellular Immune Profile and Expression of IL-6, IL-8 and TNF-α

Pyostomatitis Vegetans: Cellular Immune Profile and Expression of IL-6, IL-8 and TNF-α

Phospholipase Cɛ has a crucial role in ultraviolet B-induced neutrophil-associated skin inflammation by regulating the expression of CXCL1/KC

Management of pyoderma gangrenosum

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