MOLECULAR ANALYSIS OF CONSTITUTIVE IL-1α GENE EXPRESSION IN HUMAN MELANOMA CELLS: AUTHOCRINE STIMULATION THROUGH NF-κB ACTIVATION BY ENDOGENOUS IL-1α

Kimura, Hiroaki; Inukai, Yoshitaka; Takii, Takemasa; Furutani, Yoshio; Shibata, Yasuhiro; Hayashi, Hidetoshi; Sakurada, Shinsaku; Okamoto, Takashi; Inoue, Jun‐ichiro; Oomoto, Yasukazu; Onozaki, Kikuo

doi:10.1006/cyto.1998.0369

Cited by 21 publications

(19 citation statements)

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“…1A). As has been reported [26], in A375-R8 cells, deletion of the upstream sequence to the nucleotide position from -421 to -103 resulted in an augmentation of the activity. By further deletion to -70, the transcriptional activity was decreased substantially as compared with -103.…”

Section: Resultssupporting

confidence: 76%

The interaction with Sp1 and reduction in the activity of histone deacetylase 1 are critical for the constitutive gene expression of IL-1α in human melanoma cells

Enya

Hayashi

Takii

et al. 2007

Journal of Leukocyte Biology

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A375-6 human melanoma cells are sensitive to the antiproliferative effect of IL-1. After a long period of culturing, we have obtained cells resistant to IL-1. The resistant clone A375-R8 constitutively produced IL-1 alpha. In this study, we identified a sequence, CGCC, located at -48 to -45 upstream of the transcription start site, to be essential for the constitutive IL-1 alpha gene activation. Specificity protein 1 (Sp1) and Sp3 bound to the nucleotide containing the sequence. Although the binding level to the nucleotide and expression level of Sp1 and Sp3 are comparable in A375-R8 and A375-6 cells, transactivation activity of Sp1 is higher in A375-R8 cells as compared with A375-6 cells. Sp3 could not transactivate the IL-1 alpha promoter. These results suggest that Sp1 but not Sp3 is important for IL-1 alpha gene activation. Trichostatin A (TSA), an inhibitor of histone deacetylase (HDAC), greatly augmented the IL-1 alpha promoter activity in A375-6 cells to the level comparable with that in A375-R8 cells. TSA also induced IL-1 alpha mRNA expression in A375-6 cells. Sp1 and Sp3 bound to HDAC1 in A375-R8 and A375-6 cells. The chromatin immunoprecipitation assay revealed the binding of Sp1 and HDAC1 to the promoter region of the IL-1 alpha gene. The activities of HDAC bound to Sp1 and Sp3, and that of HDAC1 was lower in A375-R8 cells as compared with A375-6 cells. These results indicate that the reduction in the activity and interaction of HDAC1 with Sp1 are critical for the constitutive IL-1 alpha gene expression.

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Section: Resultssupporting

confidence: 76%

The interaction with Sp1 and reduction in the activity of histone deacetylase 1 are critical for the constitutive gene expression of IL-1α in human melanoma cells

Enya

Hayashi

Takii

et al. 2007

Journal of Leukocyte Biology

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“…As a competitive inhibitor of ligands that bind IL-1R, rIL-1ra prevented IL-1␣ (and IL-1␤) from binding IL-1Rs. This interference disrupted the autocrine, receptor-mediated, positive feedback loop that entails IL-1␣ stimulating its own expression through activation of NF-B (45). This autocrine production of IL-1␣ was halted by IL-1ra.…”

Section: Discussionmentioning

confidence: 99%

“…IL-1␣ is known to stimulate IL-6/IL-8 expression through NF-B (26,45). In addition, C/EBP␤ was recently shown to be important for IL-6/IL-8 expression by senescent cells (15,16).…”

Section: Discussionmentioning

confidence: 99%

Cell surface-bound IL-1α is an upstream regulator of the senescence-associated IL-6/IL-8 cytokine network

Orjalo

Bhaumik

Gengler

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

538

508

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Inflammation underlies most age-related diseases, including cancer, but the etiology is poorly understood. One proposed factor is the presence of senescent cells, which increase with age. The senescence response arrests the proliferation of potentially oncogenic cells, and most senescent cells secrete high levels of proinflammatory cytokines and other proteins. The complex senescenceassociated secretory phenotype is likely regulated at multiple levels, most of which are unknown. We show that cell surfacebound IL-1␣ is essential for signaling the senescence-associated secretion of IL-6 and IL-8, 2 proinflammatory cytokines that also reinforce the senescence growth arrest. Senescent human fibroblasts expressed high levels of IL-1␣ mRNA, intracellular protein, and cell surface-associated protein, but secreted very little protein. aging ͉ cancer ͉ inflammation ͉ invasion ͉ IRAK1

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“…NF-kB is a critical transcription factor for activation of the IL-1a gene. 22) These results suggest that the inhibitory effect of DHT is due to the inhibition of NF-kB activation by TNFa via AR, although we do not rule out the possibility that other transcription factors are also affected by DHT/AR.…”

Section: Discussionmentioning

confidence: 66%

“…22) To determine whether DHT inhibits the NF-kB activation by TNFa via the AR, MH7A cells were transfected with the NF-kB-dependent reporter plasmid with or without the expression vector of AR, and treated with TNFa in the presence or absence of DHT. As shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

Dihydrotestosterone Inhibits Tumor Necrosis Factor .ALPHA. Induced Interleukin-1.ALPHA. mRNA Expression in Rheumatoid Fibroblast-Like Synovial Cells

Itoh

Hayashi

et al. 2007

Biological & Pharmaceutical Bulletin

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Rheumatoid arthritis (RA) is a chronic inflammatory disease that affects multiple synovial joints. Proinflammatory cytokines, such as interleukin-1 (IL-1) and tumor necrosis factor (TNF)a a play important roles as principle inflammatory and destructive components of the disease. RA is known to be associated with significant gender differences in its prevalence and clinical features. We found that a potent androgen, 5a a-dihydrotestosterone (DHT) inhibits IL-1a a mRNA expression induced by TNFa a and the DHT effect was inhibited by an androgen receptor antagonist, hydroxyflutamide (OHF). DHT inhibited the NF-k kB activation induced by TNFa a in a manner dependent on the androgen receptor (AR). These results suggest that DHT inhibits the TNFa a-induced IL-1a a mRNA expression by inhibiting NF-k kB activation, and contributes to the gender differences of the disease.

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MOLECULAR ANALYSIS OF CONSTITUTIVE IL-1α GENE EXPRESSION IN HUMAN MELANOMA CELLS: AUTHOCRINE STIMULATION THROUGH NF-κB ACTIVATION BY ENDOGENOUS IL-1α

Cited by 21 publications

References 0 publications

The interaction with Sp1 and reduction in the activity of histone deacetylase 1 are critical for the constitutive gene expression of IL-1α in human melanoma cells

The interaction with Sp1 and reduction in the activity of histone deacetylase 1 are critical for the constitutive gene expression of IL-1α in human melanoma cells

Cell surface-bound IL-1α is an upstream regulator of the senescence-associated IL-6/IL-8 cytokine network

Dihydrotestosterone Inhibits Tumor Necrosis Factor .ALPHA. Induced Interleukin-1.ALPHA. mRNA Expression in Rheumatoid Fibroblast-Like Synovial Cells

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