Cited by 647Inflammatory mediators and NSAID effectsNF-κB Signaling PathwaysSignaling Pathways in Disease

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Transcriptional roles of nuclear factor κB and nuclear factor-interleukin-6 in the tumor necrosis factor α-dependent induction of cyclooxygenase-2 in MC3T3-E1 cells.

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Yamamoto, Kei, Arakawa, Toshiya, Ueda, Natsuo, Yamamoto, Shozo·1995·Journal of Biological Chemistry

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Abstract

When a mouse osteoblastic cell line MC3T3-E1 was cultured in the presence of tumor necrosis factor alpha (TNF alpha), the release of prostaglandin E2 and the cyclooxygenase activity increased in a dose- and time-dependent manner. The increase of the enzyme activity was attributed mostly to the induction of cyclooxygenase-2 rather than cyclooxygenase-1 as judged by the inhibitory effect of NS398, Western blotting, and Northern blotting. In this system we attempted to elucidate the transcriptional regulation of the cyclooxygenase-2 gene. As examined by the luciferase assay, two positive regulatory regions (-186 to -131 and -512 to -385 base pairs) were found in the 5'-flanking promoter region of the mouse cyclooxygenase-2 gene in the TNF alpha-stimulated cells. The former included putative NF-IL6 (C/EBP beta) and AP2 elements, and the latter contained the NF kappa B motif. A DNA probe including the NF-IL6 and AP2 sites gave positive bands upon electrophoretic mobility shift assay using the nuclear extracts of MC3T3-E1 cells. The bands were supershifted by the addition of anti-NF-IL6 antibody but not by anti-AP2 antibody. A probe including the NF kappa B site also gave positive bands, which were supershifted by anti-NF kappa B p50 and p65 antibodies. Furthermore, when the motif of NF-IL6 or NF kappa B or both was subjected to point mutation, the luciferase activity was markedly reduced. These data suggested a potential role of both NF-IL6 and NF kappa B in the induction of cyclooxygenase-2 by TNF alpha.

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Background
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Picado, C., Bioque, G., Roca‐Ferrer, J., Pujols, L., Mullol, J., Benítez, P., & Bulbena, O. (2003) · Allergy · doi:10.1034/j.1398-9995.2003.23792.x · Cited by 44
Gα13 Stimulates Rho-dependent Activation of the Cyclooxygenase-2 Promoter
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Cyclooxygenase-2 Induction in Congestive Heart Failure
Wu, K. K. (1998) · Circulation · doi:10.1161/01.cir.98.2.95 · Cited by 44
o,p′-DDT induces cyclooxygenase-2 gene expression in murine macrophages: Role of AP-1 and CRE promoter elements and PI3-kinase/Akt/MAPK signaling pathways
Han, E. H., Kim, J. Y., Kim, H.-K., Hwang, Y. P., & Jeong, H. G. (2008) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2008.09.003 · Cited by 43
“To date, NF-κB, AP-1, NF-IL6, CRE and the E-box transcriptional elements have been reported to be involved in COX-2 expression (Yamamoto et al., 1995; Guo et al., 2001; Zhou et al., 2003).”
Background
Upregulation of cyclooxygenase-2 is associated with activation of the alternative nuclear factor kappa B signaling pathway in colonic adenocarcinoma.
Shi, G., Li, D., Fu, J., Sun, Y. P., Li, Y., Qu, R., Jin, X., & Li, D. (2015) · PubMed · Cited by 43
Characterization of human cyclooxygenase 2 gene promoter localization of a TGF-β response element
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RETRACTED: Suppression of pro-inflammatory and proliferative pathways by diferuloylmethane (curcumin) and its analogues dibenzoylmethane, dibenzoylpropane, and dibenzylideneacetone: Role of Michael acceptors and Michael donors
Anand, P., Sung, B., Kunnumakkara, A. B., Rajasekharan, K. N., & Aggarwal, B. B. (2011) · Biochemical Pharmacology · doi:10.1016/j.bcp.2011.09.001 · Cited by 42
“NF-κB activation has been shown to regulate the expression of COX-2, cyclin D1, and VEGF [23–25].”
Background
Retracted
Calpain inhibitor I reduces colon injury caused by dinitrobenzene sulphonic acid in the rat
Cuzzocrea, S., McDonald, M. C., Mazzon, E., Mota‐Filipe, H., Centorrino, T., Terranova, M. L., Ciccolo, A., Britti, D., Caputi, A. P., & Thiemermann, C. (2001) · Gut · doi:10.1136/gut.48.4.478 · Cited by 41
Regulation of Lipocalin-type Prostaglandin D Synthase Gene Expression by Hes-1 through E-box and Interleukin-1β via Two NF-κB Elements in Rat Leptomeningeal Cells
Fujimori, K., Fujitani, Y., Kadoyama, K., Kumanogoh, H., Ishikawa, K., & Urade, Y. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m208288200 · Cited by 42
Regulation of Cyclo-oxygenase Gene Expression in Rat Smooth Muscle Cells by Catalase
Chen, G., Kamal, M., Hannon, R., & Warner, T. D. (1998) · Biochemical Pharmacology · doi:10.1016/s0006-2952(98)00021-5 · Cited by 42
The Anti-Inflammatory Effect of Ripasudil (K-115), a Rho Kinase (ROCK) Inhibitor, on Endotoxin-Induced Uveitis in Rats
Uchida, T., Honjo, M., Yamagishi, R., & Aihara, M. (2017) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.17-22679 · Cited by 41
Stimulus‐specific defect in the phagocytic pathways of annexin 1 null macrophages
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“…of annexin 1, lipopolysaccharide activation led to a marked upregulation of COX-2 and iNOS protein expression, and this was associated with a prolonged and more pronounced release of PGE2, this may be due to overactivity at the NFkB promoter, that regulates COX-2 expression (Yamamoto et al., 1995).”
Background
Are the anti-inflammatory effects of dexamethasone responsible for inhibition of the induction of enzymes involved in prostanoid formation in rat carrageenin-induced pleurisy?
Kawamura, M., Hatanaka, K., Saito, M., Ogino, M., Ono, T., Ogino, K., Matsuo, S., & Harada, Y. (2000) · European Journal of Pharmacology · doi:10.1016/s0014-2999(00)00377-0 · Cited by 40
Involvement of Rel/NF-κB transcription factors in senescence
Gosselin, K., & Abbadie, C. (2003) · Experimental Gerontology · doi:10.1016/j.exger.2003.09.007 · Cited by 41
Differential Regulation of COX-2 Transcription by Ras- and Rho-Family of GTPases
Slice, L. W., Bui, L., Mak, C., & Walsh, J. H. (2000) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.2000.3487 · Cited by 41
Hypoxia induces ROS-resistant memory upon reoxygenation in vivo promoting metastasis in part via MUC1-C
Godet, I., Oza, H. H., Shi, Y., Joe, N., Weinstein, A. G., Johnson, J., Considine, M., Talluri, S., Zhang, J., Xu, R., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-51995-2 · Cited by 45
Curcumin attenuates cyclooxygenase‐2 expression via inhibition of the NF‐κB pathway in lipopolysaccharide‐stimulated human gingival fibroblasts
Hu, P., Huang, P., & Chen, M. W. (2013) · Cell Biology International · doi:10.1002/cbin.10050 · Cited by 42
“Curcumin negatively regulates LPS-stimulated NF-kB activation NF-kB is a major regulatory component of COX-2 mediated by LPS as COX-2 promoter regions contain NF-kB sites which are necessary for inducing expression of these genes (Yamamoto et al., 1995).”
Background
Ginsenoside Rg3 Sensitizes Colorectal Cancer to Radiotherapy through Downregulation of Proliferative and Angiogenic Biomarkers
Liu, T., Duo, L., & Duan, P. (2018) · Evidence-based Complementary and Alternative Medicine · doi:10.1155/2018/1580427 · Cited by 40
Adaptive immune regulation of glial homeostasis as an immunization strategy for neurodegenerative diseases
Kosloski, L. M., Ha, D. M., Hutter-Saunders, J. A. L., Stone, D. K., Pichler, M. R., Reynolds, A. D., Gendelman, H. E., & Mosley, R. L. (2010) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2010.06834.x · Cited by 40
“Abbreviations used: a-syn, alpha-synuclein; Ab, beta-amyloid; AD, Alzheimer’s disease; APC, antigen presenting cell; BBB, blood brain barrier; BDNF, brain-derived neurotrophic factor; COX, cyclooxygenase; DTBZ, [11C]-dihydrotetrabenazine; FD, [18F]-fluoroDOPA; Foxp3, forkhead homeobox p3; GA, glatiramer acetate; GDNF,…”
BackgroundInfluential
Identification of a novel blocker of IκBα kinase activation that enhances apoptosis and inhibits proliferation and invasion by suppressing nuclear factor-κB
Sung, B., Pandey, M. K., Nakajima, Y., Nishida, H., Konishi, T., Chaturvedi, M. M., & Aggarwal, B. B. (2008) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-07-0406 · Cited by 39
Essential role of c-Jun induction and coactivator p300 in epidermal growth factor-induced gene expression of cyclooxygenase-2 in human epidermoid carcinoma A431 cells
Chen, L.-C., Chen, B., Chang, J.-M., & Chang, W. (2004) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2004.04.003 · Cited by 40
Clinical implication of expression of cyclooxygenase-2 and peroxisome proliferator activated-receptor γ in epithelial ovarian tumours
Sakamoto, A., Yokoyama, Y., UMEMOTO, M., Futagami, M., Sakamoto, T., Bing, X., & Mizunuma, H. (2004) · British Journal of Cancer · doi:10.1038/sj.bjc.6602009 · Cited by 39
“Tumour necrosis factor-alpha is a strong inducer of COX-2 expression by stimulating the NFkB system (Yamamoto et al, 1995).”
Background
p65 Homodimer activity in distal airway cells determines lung dysfunction in equine heaves
Sandersen, C., Bureau, F., Turlej, R. K., Fiévez, L., Dogné, S., Kirschvink, N. A., & Lekeux, P. M. (2001) · Veterinary Immunology and Immunopathology · doi:10.1016/s0165-2427(01)00329-4 · Cited by 39
Effect of PPAR Activators on Cytokine-Stimulated Cyclooxygenase-2 Expression in Human Colorectal Carcinoma Cells
Ikawa, H., Kameda, H., Kamitani, H., Baek, S. J., Nixon, J. B., Hsi, L. C., & Eling, T. E. (2001) · Experimental Cell Research · doi:10.1006/excr.2001.5233 · Cited by 39
Induction of Prostaglandin H Synthase 2 in Human Airway Epithelial Cells Exposed to Residual Oil Fly Ash
Samet, J. M., REED, W., Ghio, A. J., Devlin, R. B., Carter, J. D., Dailey, L. A., Bromberg, P. A., & Madden, M. C. (1996) · Toxicology and Applied Pharmacology · doi:10.1016/s0041-008x(96)80021-4 · Cited by 39
Renin-Angiotensin System and Renal Damage: Emerging Data on Angiotensin II as a Proinflammatory Mediator
Ruiz‐Ortega, M., Lorenzo, Ó., Rup�rez, M., Esteban, V., Mezzano, S. A., & Egido, J. (2001) · KARGER eBooks · doi:10.1159/000060153 · Cited by 37
TNFR1 Promotes Tumor Necrosis Factor-mediated Mouse Colon Epithelial Cell Survival through RAF Activation of NF-κB
Edelblum, K. L., Goettel, J. A., Koyama, T., McElroy, S. J., Yan, F., & Polk, D. B. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m801269200 · Cited by 38
Molecular biology of Barrett's cancer
Atherfold, P. A., & Jankowski, J. A. (2006) · Best Practice & Research Clinical Gastroenterology · doi:10.1016/j.bpg.2006.04.003 · Cited by 37
Inflammation in parkinson’s disease
Hald, A., van Beek, J., & Lotharius, J. (2007) · Sub-cellular biochemistry/Subcellular biochemistry · doi:10.1007/1-4020-5688-5_12 · Cited by 37
Garcinone B reduces prostaglandin E2 release and NF-κB-mediated transcription in C6 rat glioma cells
Yamakuni, T., Aoki, K., Nakatani, K., Kondo, N., Oku, H., Ishiguro, K., & Ohizumi, Y. (2005) · Neuroscience Letters · doi:10.1016/j.neulet.2005.10.023 · Cited by 37
Phospholipase D, tumor promoters, proliferation and prostaglandins
Daniel, L. W., Sciorra, V. A., & Ghosh, S. (1999) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/s1388-1981(99)00099-2 · Cited by 37
Anti-inflammatory and anticancer effects of p-methoxycinnamic acid, an active phenylpropanoid, against 1,2-dimethylhydrazine-induced rat colon carcinogenesis
Gunasekaran, S., Venkatachalam, K., & Nalini, N. (2018) · Molecular and Cellular Biochemistry · doi:10.1007/s11010-018-3398-5 · Cited by 36
Regulation of bone biology by prostaglandin endoperoxide H synthases (PGHS): A rose by any other name…
LI, L., Pettit, A. R., Gregory, L. S., & Forwood, M. R. (2006) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2006.01.005 · Cited by 36
Ebselen abrogates TNFα induced pro‐inflammatory response in glioblastoma
Tewari, R., Sharma, V., Koul, N., Ghosh, A., Joseph, C., Sk, U. H., & Sen, E. (2008) · Molecular Oncology · doi:10.1016/j.molonc.2008.10.004 · Cited by 38
“Western blot analysis demonstrates expression of pro-inflammatory mediator COX-2 in cells treated with either TNFa or Ebselen or both.”
BackgroundInfluential
Combined use of insulin and endothelin-1 causes decrease of protein expression of ?-subunit of insulin receptor, insulin receptor substrate-1, and insulin-stimulated glucose uptake in rat adipocytes
Shih, K., Kwok, C., & Ho, L.-T. (2000) · Journal of Cellular Biochemistry · doi:10.1002/(sici)1097-4644(20000801)78:2 · Cited by 13
Induction of Cyclooxygenase-2 Expression by Hepatitis B Virus Depends on Demethylation-associated Recruitment of Transcription Factors to the Promoter
Yue, X., Yang, F., Yang, Y., Mu, Y., Sun, W. Y., Li, W., Xu, D., Wu, J., & Zhu, Y. (2011) · Virology Journal · doi:10.1186/1743-422x-8-118 · Cited by 35
“It has been well established that NF-B, C/EBP, and CREB are the primary transcription factors responsible for the regulation of COX-2 expression [10] [11] [12] [13] .”
BackgroundInfluential
Prostaglandin terminal synthases as novel therapeutic targets
Hara, S. (2017) · Proceedings of the Japan Academy Series B · doi:10.2183/pjab.93.044 · Cited by 35
Identification of an N-terminal Truncation of the NF-κB p65 Subunit That Specifically Modulates Ribosomal Protein S3-dependent NF-κB Gene Expression
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COX-2 gene promoter DNA methylation status in eutopic and ectopic endometrium of Egyptian women with endometriosis
Zidan, H. E., Rezk, N. A., Alnemr, A. A. A., & el Ghany, A. M. A. (2015) · Journal of Reproductive Immunology · doi:10.1016/j.jri.2015.06.093 · Cited by 35
“Within the promoter region of the COX-2 gene, the nuclear factor for the interleukin-6 expression site (NF-IL6) is a CpG site that plays a role in the regulation of COX-2 expression (Yamamoto et al., 1995; Murata et al., 2004).”
Background
Inhibition of nitric oxide synthesis by aminoguanidine increases intestinal damage in the acute phase of rat TNB‐colitis
Dikopoulos, N., Nussler, A. K., Liptay, S., Bachem, M. G., Reinshagen, M., Stiegler, M., Schmid, R. M., Adler, G., & Weidenbach, H. (2001) · European Journal of Clinical Investigation · doi:10.1046/j.1365-2362.2001.00802.x · Cited by 35
Contribution of membrane‐associated prostaglandin E2 synthase to bone resorption
Saegusa, M., Murakami, M., Nakatani, Y., Yamakawa, K., Katagiri, M., Matsuda, K., Nakamura, K., Kudo, I., & Kawaguchi, H. (2003) · Journal of Cellular Physiology · doi:10.1002/jcp.10356 · Cited by 35
“In osteoblasts, NF-kB, NF-IL6, AP-1, C/EBP-a, -b, CRE and Runx2 are known to be involved in the transcriptional induction of COX-2 (Yamamoto et al., 1995; Harrison et al., 2000; Okada et al., 2000b; Chikazu et al., 2002).”
Background

Authors: Yamamoto, K., Arakawa, T., Ueda, N., & Yamamoto, S.
Affiliations: Tokushima University (JP)
Corresponding author: Yamamoto, Kei
Yamamoto, Shozo
ORCID: Yamamoto, Kei
Arakawa, Toshiya
Venue: Journal of Biological Chemistry
Publisher: Elsevier BV
Published: 1995-12
Volume: 270
Issue: 52
Pages: 31315-31320
ISSN: 0021-9258 (ISSN-L)
DOI: 10.1074/jbc.270.52.31315
OpenAlex: W2002708977
Cited by: 647
References: 38
Citations by year: 2026: 2 · 2025: 2 · 2024: 7 · 2023: 2 · 2022: 3 · 2021: 17 · 2020: 8 · 2019: 11 · 2018: 12 · 2017: 8 · 2016: 10 · 2015: 8 · 2014: 10 · 2013: 15 · 2012: 14
FWCI: 17.65
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
creativecommons.org/licenses/by/4.0/ (vor, 9116 d)
Locations: Journal of Biological Chemistry (publishedVersion, cc-by)
PubMed (publishedVersion)
Funders: Japan Foundation for Applied Enzymology
Japan Research Foundation for Clinical Pharmacology
Kissei
Ono Pharmaceutical
Japan Society for the Promotion of Science
Daiichi Sankyo Company
Topics: Health Sciences › Medicine › Pharmacology (medical) › Inflammatory mediators and NSAID effects
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
Keywords: cyclooxygenase-2, NF-κB, NF-IL6, C/EBPβ, TNF-α, transcriptional regulation, prostaglandin E2, MC3T3-E1 cells, osteoblasts, promoter regulation, gene induction
MeSH terms: Animals, Base Sequence, DNA-Binding Proteins, Enzyme Induction, Isoenzymes, Molecular Sequence Data, Nuclear Proteins, Oligodeoxyribonucleotides, Promoter Regions, Genetic, Prostaglandin-Endoperoxide Synthases, Regulatory Sequences, Nucleic Acid, Transcription, Genetic, Tumor Necrosis Factor-alpha, NF-kappa B, 3T3 Cells, CCAAT-Enhancer-Binding Proteins, Mice

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Transcriptional roles of nuclear factor κB and nuclear factor-interleukin-6 in the tumor necrosis factor α-dependent induction of cyclooxygenase-2 in MC3T3-E1 cells.

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