Dithiocarbamates as potent inhibitors of nuclear factor kappa B activation in intact cells

doi:10.1084/jem.175.5.1181

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Dithiocarbamates as potent inhibitors of nuclear factor kappa B activation in intact cells

R Schreck, B Meier, DN Mannel, W Droge and PA Baeuerle
Laboratorium fur Molekulare Biologie, Ludwig-Maximilians-Universitat, Martinsried, Germany.

Dithiocarbamates and iron chelators were recently considered for the treatment of AIDS and neurodegenerative diseases. In this study, we show that dithiocarbamates and metal chelators can potently block the activation of nuclear factor kappa B (NF-kappa B), a transcription factor involved in human immunodeficiency virus type 1 (HIV-1) expression, signaling, and immediate early gene activation during inflammatory processes. Using cell cultures, the pyrrolidine derivative of dithiocarbamate (PDTC) was investigated in detail. Micromolar amounts of PDTC reversibly suppressed the release of the inhibitory subunit I kappa B from the latent cytoplasmic form of NF-kappa B in cells treated with phorbol ester, interleukin 1, and tumor necrosis factor alpha. Other DNA binding activities and the induction of AP-1 by phorbol ester were not affected. The antioxidant PDTC also blocked the activation of NF-kappa B by bacterial lipopolysaccharide (LPS), suggesting a role of oxygen radicals in the intracellular signaling of LPS. This idea was supported by demonstrating that treatment of pre-B and B cells with LPS induced the production of O2- and H2O2. PDTC prevented specifically the kappa B-dependent transactivation of reporter genes under the control of the HIV-1 long terminal repeat and simian virus 40 enhancer. The results from this study lend further support to the idea that oxygen radicals play an important role in the activation of NF-kappa B and HIV-1.
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Kinoshita, K., Sato, K., Hori, M., Ozaki, H., Karaki, H. (2003). Decrease in activity of smooth muscle L-type Ca2+ channels and its reversal by NF-{kappa}B inhibitors in Crohn's colitis model. Am. J. Physiol. Gastrointest. Liver Physiol. 285: G483-G493 [Abstract] [Full Text]
Takada, Y., Mukhopadhyay, A., Kundu, G. C., Mahabeleshwar, G. H., Singh, S., Aggarwal, B. B. (2003). Hydrogen Peroxide Activates NF-{kappa}B through Tyrosine Phosphorylation of I{kappa}B{alpha} and Serine Phosphorylation of p65: EVIDENCE FOR THE INVOLVEMENT OF I{kappa}B{alpha} KINASE AND Syk PROTEIN-TYROSINE KINASE. J. Biol. Chem. 278: 24233-24241 [Abstract] [Full Text]
LI, Y.-P., LECKER, S. H., CHEN, Y., WADDELL, I. D., GOLDBERG, A. L., REID, M. B. (2003). TNF-{alpha} increases ubiquitin-conjugating activity in skeletal muscle by up-regulating UbcH2/E220k. FASEB J. 17: 1048-1057 [Abstract] [Full Text]
La Grutta, S., Gagliardo, R., Mirabella, F., Pajno, G. B., Bonsignore, G., Bousquet, J., Bellia, V., Vignola, A. M. (2003). Clinical and Biological Heterogeneity in Children with Moderate Asthma. Am. J. Respir. Crit. Care Med. 167: 1490-1495 [Abstract] [Full Text]
Galbiati, F., Polastri, L., Thorens, B., Dupraz, P., Fiorina, P., Cavallaro, U., Christofori, G., Davalli, A. M. (2003). Molecular Pathways Involved in the Antineoplastic Effects of Calcitriol on Insulinoma Cells. Endocrinology 144: 1832-1841 [Abstract] [Full Text]
Zhou, J., Meadows, G. G. (2003). Alcohol Consumption Decreases IL-2-Induced NF-{kappa}B Activity in Enriched NK Cells from C57BL/6 Mice. Toxicol Sci 73: 72-79 [Abstract] [Full Text]
Schram, B. R., Rothstein, T. L. (2003). NF-{kappa}B Is Required for Surface Ig-Induced Fas Resistance in B Cells. J. Immunol. 170: 3118-3124 [Abstract] [Full Text]
Tahepold, P., Vaage, J., Starkopf, J., Valen, G. (2003). Hyperoxia elicits myocardial protection through a nuclear factor {kappa}B-dependent mechanism in the rat heart. J. Thorac. Cardiovasc. Surg. 125: 650-660 [Abstract] [Full Text]
Marin-Castano, M. E., Elliot, S. J., Potier, M., Karl, M., Striker, L. J., Striker, G. E., Csaky, K. G., Cousins, S. W. (2003). Regulation of Estrogen Receptors and MMP-2 Expression by Estrogens in Human Retinal Pigment Epithelium. IOVS 44: 50-59 [Abstract] [Full Text]
Carlisle, M. L., King, M. R., Karp, D. R. (2003). {gamma}-Glutamyl transpeptidase activity alters the T cell response to oxidative stress and Fas-induced apoptosis. Int Immunol 15: 17-27 [Abstract] [Full Text]
Sappington, P. L., Han, X., Yang, R., Delude, R. L., Fink, M. P. (2003). Ethyl Pyruvate Ameliorates Intestinal Epithelial Barrier Dysfunction in Endotoxemic Mice and Immunostimulated Caco-2 Enterocytic Monolayers. J. Pharmacol. Exp. Ther. 304: 464-476 [Abstract] [Full Text]
Putnins, E. E., Sanaie, A.-R., Wu, Q., Firth, J. D. (2002). Induction of Keratinocyte Growth Factor 1 Expression by Lipopolysaccharide Is Regulated by CD-14 and Toll-Like Receptors 2 and 4. Infect. Immun. 70: 6541-6548 [Abstract] [Full Text]
Crowley-Weber, C. L., Payne, C. M., Gleason-Guzman, M., Watts, G. S., Futscher, B., Waltmire, C. N., Crowley, C., Dvorakova, K., Bernstein, C., Craven, M., Garewal, H., Bernstein, H. (2002). Development and molecular characterization of HCT-116 cell lines resistant to the tumor promoter and multiple stress-inducer, deoxycholate. Carcinogenesis 23: 2063-2080 [Abstract] [Full Text]
Munzert, G., Kirchner, D., Stobbe, H., Bergmann, L., Schmid, R. M., Dohner, H., Heimpel, H. (2002). Tumor necrosis factor receptor-associated factor 1 gene overexpression in B-cell chronic lymphocytic leukemia: analysis of NF-kappa B/Rel-regulated inhibitors of apoptosis. Blood 100: 3749-3756 [Abstract] [Full Text]
Bian, X., Opipari, A. W. Jr., Ratanaproeksa, A. B., Boitano, A. E., Lucas, P. C., Castle, V. P. (2002). Constitutively Active NFkappa B Is Required for the Survival of S-type Neuroblastoma. J. Biol. Chem. 277: 42144-42150 [Abstract] [Full Text]
Hale-Donze, H., Greenwell-Wild, T., Mizel, D., Doherty, T. M., Chatterjee, D., Orenstein, J. M., Wahl, S. M. (2002). Mycobacterium avium Complex Promotes Recruitment of Monocyte Hosts for HIV-1 and Bacteria. J. Immunol. 169: 3854-3862 [Abstract] [Full Text]
Morel, J. C. M., Park, C. C., Zhu, K., Kumar, P., Ruth, J. H., Koch, A. E. (2002). Signal Transduction Pathways Involved in Rheumatoid Arthritis Synovial Fibroblast Interleukin-18-induced Vascular Cell Adhesion Molecule-1 Expression. J. Biol. Chem. 277: 34679-34691 [Abstract] [Full Text]
Lu, B., Wang, L., Medan, D., Toledo, D., Huang, C., Chen, F., Shi, X., Rojanasakul, Y. (2002). Regulation of Fas (CD95)-induced apoptosis by nuclear factor-kappa B and tumor necrosis factor-alpha in macrophages. Am. J. Physiol. Cell Physiol. 283: C831-C838 [Abstract] [Full Text]
Mershon, J. L., Baker, R. S., Clark, K. E. (2002). Estrogen increases iNOS expression in the ovine coronary artery. Am. J. Physiol. Heart Circ. Physiol. 283: H1169-H1180 [Abstract] [Full Text]
Hellmuth, M., Wetzler, C., Nold, M., Chang, J.-H., Frank, S., Pfeilschifter, J., Muhl, H. (2002). Expression of interleukin-8, heme oxygenase-1 and vascular endothelial growth factor in DLD-1 colon carcinoma cells exposed to pyrrolidine dithiocarbamate. Carcinogenesis 23: 1273-1279 [Abstract] [Full Text]
Zhou, J., Zhang, J., Lichtenheld, M. G., Meadows, G. G. (2002). A Role for NF-{kappa}B Activation in Perforin Expression of NK Cells Upon IL-2 Receptor Signaling. J. Immunol. 169: 1319-1325 [Abstract] [Full Text]