Tumor necrosis factor-alpha and interleukin-17 differently affects Langerhans cell distribution and activation in an innovative three-dimensional model of normal human skin

Three-dimensional models of skin and epidermis imitate the structure of real tissues and provide accurate information about certain skin conditions, such as psoriasis. A three-dimensional model of mouse epidermis was generated from the epidermal keratinocytes of newborn mice and treated with cytokines. The aim of this study was to evaluate this model as an experimental model of psoriasis and to assess the changes occurring in its structure and gene expression after the exposure to proinflammatory cytokines. Treatment of the three-dimensional model with either interleukin 17 or a combination of tumor necrosis factor and interferon was shown to produce morphological changes, which were similar to acanthosis in psoriatic skin. The observed changes in gene expression of metalloproteinases and certain psoriasis biomarkers, such as mki67, krt16 and fosl1, were similar to the changes in patients skin. Notably, changes caused by interleukin 17 were less evident than those caused by the combination of interferon and tumor necrosis factor. On the contrary, HaCaT cells exhibited no significant changes in the expression of fosl1 and had decreased levels of mki67 after being treated with a combination of TNF and IFNG. Moreover, treatment with IL17 had no significant effect on krt16 and mki67 expression and even reduced the fosl1 levels. The findings suggest that artificially generated three-dimensional models of murine skin can be used to study psoriasis.

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Tumour necrosis factor alpha is pro-inflammatory in normal human skin and modulates cutaneous adhesion molecule expression

British Journal of Dermatology ◽

10.1111/j.1365-2133.1995.tb08666.x ◽

1995 ◽

Vol 132 (3) ◽

pp. 345-352 ◽

Cited By ~ 124

Author(s):

R. W. GROVES ◽

M. H. ALLEN ◽

E. L. ROSS ◽

J. N. W. N. BARKER ◽

D. M. MACDONALD

Keyword(s):

Tumour Necrosis Factor ◽

Adhesion Molecule ◽

Tumour Necrosis ◽

Tumour Necrosis Factor Alpha ◽

Adhesion Molecule Expression ◽

Normal Human Skin ◽

Necrosis Factor Alpha ◽

Normal Human ◽

Factor Alpha ◽

Necrosis Factor

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Inflammatory cytokines induce synthesis and secretion of gro protein and a neutrophil chemotactic factor but not β2-microglobulin in human synovial cells and fibroblasts

Biochemical Journal ◽

10.1042/bj2590585 ◽

1989 ◽

Vol 259 (2) ◽

pp. 585-588 ◽

Cited By ~ 54

Author(s):

E E Golds ◽

P Mason ◽

P Nyirkos

Keyword(s):

Interleukin 1 ◽

Human Fibroblasts ◽

Chemotactic Factor ◽

Synovial Cells ◽

Necrosis Factor Alpha ◽

Normal Human ◽

Neutrophil Chemotactic Factor ◽

Factor Alpha ◽

Beta 2 Microglobulin ◽

Necrosis Factor

Exposure of human synovial cells and fibroblasts in monolayer culture to interleukin 1 results in prominent secretion of proteins with Mr values of 6000 and 7000. By N-terminal sequence analysis, the Mr-6000 protein is identified as the protein encoded by a recently described gro mRNA. The Mr-7000 protein is identical to a neutrophil chemotactic factor released from monocytes. Stimulation of normal human fibroblasts with tumour necrosis factor alpha also results in expression and secretion of these two proteins. In addition to these cytokine-induced proteins, we have identified beta 2-microglobulin as an Mr-8000 protein constitutively secreted by synovial cells.

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The Role of Nuclear Factor-kappaB and Melanogenesis in Tumor Necrosis Factor-Alpha-Induced Apoptosis of Normal Human Melanocytes

Skin Pharmacology and Physiology ◽

10.1159/000064536 ◽

2002 ◽

Vol 15 (5) ◽

pp. 321-329 ◽

Cited By ~ 11

Author(s):

Jing Shang ◽

Jürgen Eberle ◽

Christoph C. Geilen ◽

Amir M. Hossini ◽

Lothar F. Fecker ◽

...

Keyword(s):

Tumor Necrosis ◽

Nuclear Factor Kappab ◽

Nuclear Factor ◽

Necrosis Factor Alpha ◽

Human Melanocytes ◽

Normal Human ◽

Factor Alpha ◽

Induced Apoptosis ◽

Necrosis Factor

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NF-IL6 and AP-1 cooperatively modulate the activation of the TSG-6 gene by tumor necrosis factor alpha and interleukin-1

Molecular and Cellular Biology ◽

10.1128/mcb.14.10.6561-6569.1994 ◽

1994 ◽

Vol 14 (10) ◽

pp. 6561-6569

Author(s):

L Klampfer ◽

T H Lee ◽

W Hsu ◽

J Vilcek ◽

S Chen-Kiang

Keyword(s):

Tumor Necrosis Factor ◽

Tumor Necrosis Factor Alpha ◽

Tumor Necrosis ◽

Interleukin 1 ◽

Human Fibroblasts ◽

Tnf Alpha ◽

Necrosis Factor Alpha ◽

Normal Human ◽

Factor Alpha ◽

Necrosis Factor

Tumor necrosis factor alpha (TNF-alpha) and interleukin-1 (IL-1) activate transcription of the TSG-6 gene in normal human fibroblasts through a promoter region (-165 to -58) that encompasses an AP-1 and a NF-IL6 site. We show by deletion analysis and substitution mutagenesis that both sites are necessary for activation by TNF-alpha. Activation by IL-1 requires the NF-IL6 site and is enhanced by the AP-1 site. These results suggest that the NF-IL6 and AP-1 family transcription factors functionally cooperate to mediate TNF-alpha and IL-1 signals. Consistent with this possibility, IL-1 and TNF-alpha markedly increase the binding of Fos and Jun to the AP-1 site, and NF-IL6 activates the native TSG-6 promoter. Activation by NF-IL6 requires an intact NF-IL6 site and is modulated by the ratio of activator to inhibitor NF-IL6 isoforms that are translated from different in-frame AUGs. However, the inhibitor isoform can also bind to the AP-1 site and repress AP-1 site-mediated transcription. The finding that the inhibitor isoform antagonizes activation of the native TSG-6 promoter by IL-1 and TNF-alpha suggests that NF-IL6 has a physiologic role in these cytokine responses. Thus, the functionally distinct NF-IL6 isoforms cooperate with Fos and Jun to positively and negatively regulate the native TSG-6 promoter by TNF-alpha and IL-1.

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