Inverse regulation of the nuclear factor-kappaB binding to the p53 and interleukin-8 kappaB response elements in lesional psoriatic skin

Claus Johansen; Esben Flindt; Knud Kragballe; Jeanette Henningsen; Majken Westergaard; Karsten Kristiansen; Lars Iversen

doi:10.1111/j.0022-202X.2005.23749.x

Inverse regulation of the nuclear factor-kappaB binding to the p53 and interleukin-8 kappaB response elements in lesional psoriatic skin

Claus Johansen, Esben Flindt, Knud Kragballe, Jeanette Henningsen, Majken Westergaard, Karsten Kristiansen, Lars Iversen

52 Citations (Scopus)

Abstract

Nuclear factor-kappaB (NF-kappaB) is an inducible nuclear transcription factor regulating a range of cellular processes. An imbalance of the DNA binding activity of NF-kappaB may, therefore, be part of the pathophysiological mechanisms in psoriasis. The purpose of this study was to determine the NF-kappaB DNA binding activity in psoriatic skin using three different kappaB sites and to determine how DNA binding activity was modulated by the anti-psoriatic drug calcipotriol. By electrophoretic mobility shift assay, we demonstrated that the NF-kappaB DNA binding to the p53 kappaB site was decreased, whereas the NF-kappaB DNA binding to the interleukin-8 (IL-8) kappaB site was increased in lesional psoriatic skin compared with non-lesional psoriatic skin. No regulation was seen on the NF-kappaB DNA binding to the major histocompatibility complex class I kappaB site. These changes were paralleled by a similar decrease in p53 expression and an increase in IL-8 expression in involved psoriatic skin compared with uninvolved skin as determined by quantitative RT-PCR. The alteration in NF-kappaB DNA binding activity was neither accompanied by any change in the expression of the inhibitor kappaB (IkappaB) kinases, IKKalpha, IKKbeta, and IKKgamma nor in the expression of the NF-kappaB inhibitor proteins, IkappaBalpha and IkappaBbeta. Immunofluorescence analysis revealed that p65 was sequestered in the cytoplasm of keratinocytes, whereas p50 exhibited a cytoplasmic as well as a nuclear localization. Interestingly, this distribution of p50 and p65 was similar in lesional and non-lesional psoriatic skin. Topical application of calcipotriol to lesional psoriatic skin for 4 d resulted in increased NF-kappaB binding to the p53 kappaB site and decreased NF-kappaB binding to the IL-8 kappaB site. Taken together, our data demonstrate that the NF-kappaB DNA binding activity is regulated in a specific manner in psoriatic skin depending on the kappaB sites investigated, and that topical treatment of psoriatic skin normalizes the abnormal NF-kappaB binding activity seen in lesional psoriatic skin.

Original language	English
Journal	Journal of Investigative Dermatology
Volume	124
Issue number	6
Pages (from-to)	1284-92
Number of pages	8
ISSN	0022-202X
DOIs	https://doi.org/10.1111/j.0022-202X.2005.23749.x
Publication status	Published - 2005
Externally published	Yes

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10.1111/j.0022-202X.2005.23749.x

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@article{706199200efe11de8478000ea68e967b,

title = "Inverse regulation of the nuclear factor-kappaB binding to the p53 and interleukin-8 kappaB response elements in lesional psoriatic skin",

abstract = "Nuclear factor-kappaB (NF-kappaB) is an inducible nuclear transcription factor regulating a range of cellular processes. An imbalance of the DNA binding activity of NF-kappaB may, therefore, be part of the pathophysiological mechanisms in psoriasis. The purpose of this study was to determine the NF-kappaB DNA binding activity in psoriatic skin using three different kappaB sites and to determine how DNA binding activity was modulated by the anti-psoriatic drug calcipotriol. By electrophoretic mobility shift assay, we demonstrated that the NF-kappaB DNA binding to the p53 kappaB site was decreased, whereas the NF-kappaB DNA binding to the interleukin-8 (IL-8) kappaB site was increased in lesional psoriatic skin compared with non-lesional psoriatic skin. No regulation was seen on the NF-kappaB DNA binding to the major histocompatibility complex class I kappaB site. These changes were paralleled by a similar decrease in p53 expression and an increase in IL-8 expression in involved psoriatic skin compared with uninvolved skin as determined by quantitative RT-PCR. The alteration in NF-kappaB DNA binding activity was neither accompanied by any change in the expression of the inhibitor kappaB (IkappaB) kinases, IKKalpha, IKKbeta, and IKKgamma nor in the expression of the NF-kappaB inhibitor proteins, IkappaBalpha and IkappaBbeta. Immunofluorescence analysis revealed that p65 was sequestered in the cytoplasm of keratinocytes, whereas p50 exhibited a cytoplasmic as well as a nuclear localization. Interestingly, this distribution of p50 and p65 was similar in lesional and non-lesional psoriatic skin. Topical application of calcipotriol to lesional psoriatic skin for 4 d resulted in increased NF-kappaB binding to the p53 kappaB site and decreased NF-kappaB binding to the IL-8 kappaB site. Taken together, our data demonstrate that the NF-kappaB DNA binding activity is regulated in a specific manner in psoriatic skin depending on the kappaB sites investigated, and that topical treatment of psoriatic skin normalizes the abnormal NF-kappaB binding activity seen in lesional psoriatic skin.",

author = "Claus Johansen and Esben Flindt and Knud Kragballe and Jeanette Henningsen and Majken Westergaard and Karsten Kristiansen and Lars Iversen",

note = "Keywords: Administration, Cutaneous; Adult; Blotting, Western; Calcitriol; Cells, Cultured; DNA; Dermatologic Agents; Electrophoretic Mobility Shift Assay; Fluorescent Antibody Technique; Gene Expression Regulation; Humans; I-kappa B Kinase; I-kappa B Proteins; Interleukin-8; Keratinocytes; NF-kappa B; Protein Isoforms; Protein-Serine-Threonine Kinases; Psoriasis; RNA, Messenger; Response Elements; Reverse Transcriptase Polymerase Chain Reaction; Skin; Tumor Suppressor Protein p53",

year = "2005",

doi = "10.1111/j.0022-202X.2005.23749.x",

language = "English",

volume = "124",

pages = "1284--92",

journal = "Journal of Investigative Dermatology",

issn = "0022-202X",

publisher = "nature publishing group",

number = "6",

}

TY - JOUR

T1 - Inverse regulation of the nuclear factor-kappaB binding to the p53 and interleukin-8 kappaB response elements in lesional psoriatic skin

AU - Johansen, Claus

AU - Flindt, Esben

AU - Kragballe, Knud

AU - Henningsen, Jeanette

AU - Westergaard, Majken

AU - Kristiansen, Karsten

AU - Iversen, Lars

N1 - Keywords: Administration, Cutaneous; Adult; Blotting, Western; Calcitriol; Cells, Cultured; DNA; Dermatologic Agents; Electrophoretic Mobility Shift Assay; Fluorescent Antibody Technique; Gene Expression Regulation; Humans; I-kappa B Kinase; I-kappa B Proteins; Interleukin-8; Keratinocytes; NF-kappa B; Protein Isoforms; Protein-Serine-Threonine Kinases; Psoriasis; RNA, Messenger; Response Elements; Reverse Transcriptase Polymerase Chain Reaction; Skin; Tumor Suppressor Protein p53

PY - 2005

Y1 - 2005

N2 - Nuclear factor-kappaB (NF-kappaB) is an inducible nuclear transcription factor regulating a range of cellular processes. An imbalance of the DNA binding activity of NF-kappaB may, therefore, be part of the pathophysiological mechanisms in psoriasis. The purpose of this study was to determine the NF-kappaB DNA binding activity in psoriatic skin using three different kappaB sites and to determine how DNA binding activity was modulated by the anti-psoriatic drug calcipotriol. By electrophoretic mobility shift assay, we demonstrated that the NF-kappaB DNA binding to the p53 kappaB site was decreased, whereas the NF-kappaB DNA binding to the interleukin-8 (IL-8) kappaB site was increased in lesional psoriatic skin compared with non-lesional psoriatic skin. No regulation was seen on the NF-kappaB DNA binding to the major histocompatibility complex class I kappaB site. These changes were paralleled by a similar decrease in p53 expression and an increase in IL-8 expression in involved psoriatic skin compared with uninvolved skin as determined by quantitative RT-PCR. The alteration in NF-kappaB DNA binding activity was neither accompanied by any change in the expression of the inhibitor kappaB (IkappaB) kinases, IKKalpha, IKKbeta, and IKKgamma nor in the expression of the NF-kappaB inhibitor proteins, IkappaBalpha and IkappaBbeta. Immunofluorescence analysis revealed that p65 was sequestered in the cytoplasm of keratinocytes, whereas p50 exhibited a cytoplasmic as well as a nuclear localization. Interestingly, this distribution of p50 and p65 was similar in lesional and non-lesional psoriatic skin. Topical application of calcipotriol to lesional psoriatic skin for 4 d resulted in increased NF-kappaB binding to the p53 kappaB site and decreased NF-kappaB binding to the IL-8 kappaB site. Taken together, our data demonstrate that the NF-kappaB DNA binding activity is regulated in a specific manner in psoriatic skin depending on the kappaB sites investigated, and that topical treatment of psoriatic skin normalizes the abnormal NF-kappaB binding activity seen in lesional psoriatic skin.

AB - Nuclear factor-kappaB (NF-kappaB) is an inducible nuclear transcription factor regulating a range of cellular processes. An imbalance of the DNA binding activity of NF-kappaB may, therefore, be part of the pathophysiological mechanisms in psoriasis. The purpose of this study was to determine the NF-kappaB DNA binding activity in psoriatic skin using three different kappaB sites and to determine how DNA binding activity was modulated by the anti-psoriatic drug calcipotriol. By electrophoretic mobility shift assay, we demonstrated that the NF-kappaB DNA binding to the p53 kappaB site was decreased, whereas the NF-kappaB DNA binding to the interleukin-8 (IL-8) kappaB site was increased in lesional psoriatic skin compared with non-lesional psoriatic skin. No regulation was seen on the NF-kappaB DNA binding to the major histocompatibility complex class I kappaB site. These changes were paralleled by a similar decrease in p53 expression and an increase in IL-8 expression in involved psoriatic skin compared with uninvolved skin as determined by quantitative RT-PCR. The alteration in NF-kappaB DNA binding activity was neither accompanied by any change in the expression of the inhibitor kappaB (IkappaB) kinases, IKKalpha, IKKbeta, and IKKgamma nor in the expression of the NF-kappaB inhibitor proteins, IkappaBalpha and IkappaBbeta. Immunofluorescence analysis revealed that p65 was sequestered in the cytoplasm of keratinocytes, whereas p50 exhibited a cytoplasmic as well as a nuclear localization. Interestingly, this distribution of p50 and p65 was similar in lesional and non-lesional psoriatic skin. Topical application of calcipotriol to lesional psoriatic skin for 4 d resulted in increased NF-kappaB binding to the p53 kappaB site and decreased NF-kappaB binding to the IL-8 kappaB site. Taken together, our data demonstrate that the NF-kappaB DNA binding activity is regulated in a specific manner in psoriatic skin depending on the kappaB sites investigated, and that topical treatment of psoriatic skin normalizes the abnormal NF-kappaB binding activity seen in lesional psoriatic skin.

U2 - 10.1111/j.0022-202X.2005.23749.x

DO - 10.1111/j.0022-202X.2005.23749.x

M3 - Journal article

C2 - 15955105

SN - 0022-202X

VL - 124

SP - 1284

EP - 1292

JO - Journal of Investigative Dermatology

JF - Journal of Investigative Dermatology

IS - 6

ER -

Inverse regulation of the nuclear factor-kappaB binding to the p53 and interleukin-8 kappaB response elements in lesional psoriatic skin

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