Transcriptional regulation of the 230-kDa bullous pemphigoid antigen gene expression by interferon regulatory factor 1 and interferon regulatory factor 2 in normal human epidermal keratinocytes.
Interferon regulatory factors (IRFs) are a family of transcriptional factors induced by interferon-gamma (IFN-gamma). Recent studies have indicated that the deregulation of IRF system in keratinocytes is responsible, at least in part, for aberrant proliferation and the differentiation of the psoriatic epidermis. Previously, we reported that the expression of 230-kDa bullous pemphigoid antigen (BPAG1) gene, which is strictly restricted to basal keratinocytes, is transcriptionally suppressed by IFN-gamma, but the contribution of IRFs in such suppression is still unclear. In this study, we investigated the role of IRFs in the regulation of BPAG1 gene expression. Computer analysis identified IRF1 and IRF2 consensus sequences between -135 and -123 on BPAG1 promoter region. Transient transfection studies with BPAG1 promoter-luciferase reporter gene plasmids and IRF1 and IRF2 expression plasmids revealed that IRF1 and IRF2 directly down-regulated BPAG1 gene transcription in cultured normal human epidermal keratinocytes. Several sets of gel retardation assays with the BPAG1-IRF binding sequence as a probe indicated that IRF1 and IRF2 could bind to the BPAG1-IRF sequence, but some other protein(s), which was induced by IFN-gamma stimulation and possessed binding activity to IRF consensus sequence, showed preferential binding to the BPAG1-IRF sequence. Our results suggest that IFN-gamma-IRF system is involved in BPAG1 gene regulation in type-1 helper T-cell inflammatory skin conditions, such as psoriasis vulgaris.
Odanagi
Maiko
M
Department of Dermatology, Hirosaki University School of Medicine, Aomori, Japan. derma@cc.hirosaki-u.ac.jp
Kikuchi
Yasushi
Y
Yamazaki
Takehiko
T
Kaneko
Takahide
T
Nakano
Hajime
H
Tamai
Katsuto
K
Uitto
Jouni
J
Vitto
Joani
J
Hanada
Katsumi
K
D001324:Autoantigens / Q000096:biosynthesis* / Q000235:genetics*; D001665:Binding Sites; D015152:Blotting, Northern; D002352:Carrier Proteins; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins / Q000096:biosynthesis*; D015536:Down-Regulation; D000071821:Dystonin; D004817:Epidermis / Q000378:metabolism*; D017353:Gene Deletion; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation; D050856:Interferon Regulatory Factor-1; D050836:Interferon Regulatory Factor-2; D007371:Interferon-gamma / Q000378:metabolism; D007372:Interferons / Q000378:metabolism; D015603:Keratinocytes / Q000378:metabolism*; D008156:Luciferases / Q000378:metabolism; D008957:Models, Genetic; D009419:Nerve Tissue Proteins; D024041:Non-Fibrillar Collagens / Q000096:biosynthesis* / Q000235:genetics*; D010750:Phosphoproteins / Q000096:biosynthesis*; D011401:Promoter Regions, Genetic; D011565:Psoriasis / Q000276:immunology; D012313:RNA / Q000378:metabolism; D012097:Repressor Proteins / Q000096:biosynthesis*; D012984:Software; D013997:Time Factors; D014157:Transcription Factors / Q000096:biosynthesis*; D014158:Transcription, Genetic; D000097805:Collagen Type XVII
D001324:Autoantigens; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D000071821:Dystonin; D050856:Interferon Regulatory Factor-1; D050836:Interferon Regulatory Factor-2; D007371:Interferon-gamma; D007372:Interferons; D008156:Luciferases; D009419:Nerve Tissue Proteins; D024041:Non-Fibrillar Collagens; D010750:Phosphoproteins; D012313:RNA; D012097:Repressor Proteins; D014157:Transcription Factors; D000097805:Collagen Type XVII; C486268:DST protein, human; C494257:IRF1 protein, human; C494229:IRF2 protein, human