The anti-inflammatory compound curcumin inhibits Neisseria gonorrhoeae-induced NF-κB signaling, release of pro-inflammatory cytokines/chemokines and attenuates adhesion in late infection
-
Silja Wessler
Abstract
Neisseria gonorrhoeae (Ngo) is a Gram-negative pathogenic bacterium responsible for an array of diseases ranging from urethritis to disseminated gonococcal infections. Early events in the establishment of infection involve interactions between Ngo and the mucosal epithelium, which induce a local inflammatory response. Here we analyzed the molecular mechanism involved in the Ngo-induced induction of the proinflammatory cytokines tumor necrosis factor α (TNFα), interleukin-6 (IL-6), and IL-8. We identified the immediate early response transcription factor nuclear factor κB (NF-κB) as a key molecule for the induction of cytokine release. Ngo-induced activation of direct upstream signaling molecules was demonstrated for IκB kinase α and β (IKKα and IKKβ) by phosphorylation of IκBα as a substrate and IKK autophosphorylation. Using dominant negative cDNAs encoding kinase-dead IKKα, IKKβ, and NF-κB-inducing kinase (NIK), Ngo-induced NF-κB activity was significantly inhibited. Curcumin, the yellow pigment derived from Curcuma longa, inhibited IKKα, IKKβ and NIK, indicating its strong potential to block NF-κB-mediated cytokine release and the innate immune response. In addition to the inhibition of Ngo-induced signaling, curcumin treatment of cells completely abolished the adherence of bacteria to cells in late infection, underlining the high potential of curcumin as an anti-microbial compound without cytotoxic side effects.
References
Belland, R.J., Chen, T., Swanson, J., and Fischer, S.H. (1992). Human neutrophil response to recombinant neisserial Opa proteins. Mol. Microbiol.6, 1729–1737.10.1111/j.1365-2958.1992.tb01345.xSearch in Google Scholar PubMed
Bharti, A.C., Donato, N., Singh, S., and Aggarwal, B.B. (2003). Curcumin (diferuloylmethane) down-regulates the constitutive activation of nuclear factor-κB and IκBα kinase in human multiple myeloma cells, leading to suppression of proliferation and induction of apoptosis. Blood101, 1053–1062.10.1182/blood-2002-05-1320Search in Google Scholar PubMed
Bharti, A.C., Takada, Y., and Aggarwal, B.B. (2004). Curcumin (diferuloylmethane) inhibits receptor activator of NF-kappa B ligand-induced NF-kappa B activation in osteoclast precursors and suppresses osteoclastogenesis. J. Immunol.172, 5940–5947.10.4049/jimmunol.172.10.5940Search in Google Scholar PubMed
Blackwell, T.S. and Christman, J.W. (1997). The role of nuclear factor-kappa B in cytokine gene regulation. Am. J. Respir. Cell. Mol. Biol.17, 3–9.10.1165/ajrcmb.17.1.f132Search in Google Scholar PubMed
Blom, A.M., Rytkonen, A., Vasquez, P., Lindahl, G., Dahlback, B., and Jonsson, A.B. (2001). A novel interaction between type IV pili of Neisseria gonorrhoeae and the human complement regulator C4B-binding protein. J. Immunol.166, 6764–6770.10.4049/jimmunol.166.11.6764Search in Google Scholar PubMed
Bos, M.P., Grunert, F., and Belland, R.J. (1997). Differential recognition of members of the carcinoembryonic antigen family by Opa variants of Neisseria gonorrhoeae. Infect. Immun.65, 2353–2361.10.1128/iai.65.6.2353-2361.1997Search in Google Scholar PubMed PubMed Central
Boulton, I.C. and Gray-Owen, S.D. (2002). Neisserial binding to CEACAM1 arrests the activation and proliferation of CD4+ T lymphocytes. Nat. Immunol.3, 229–236.10.1038/ni769Search in Google Scholar PubMed
Chen, T. and Gotschlich, E.C. (1996). CGM1a antigen of neutrophils, a receptor of gonococcal opacity proteins. Proc. Natl. Acad. Sci. USA93, 14851–14856.10.1073/pnas.93.25.14851Search in Google Scholar PubMed PubMed Central
Chen, T., Belland, R.J., Wilson, J., and Swanson, J. (1995). Adherence of pilus– Opa+ gonococci to epithelial cells in vitro involves heparan sulfate. J. Exp. Med.182, 511–517.10.1084/jem.182.2.511Search in Google Scholar PubMed PubMed Central
Chen, T., Grunert, F., Medina-Marino, A., and Gotschlich, E.C. (1997). Several carcinoembryonic antigens (CD66) serve as receptors for gonococcal opacity proteins. J. Exp. Med.185, 1557–1564.10.1084/jem.185.9.1557Search in Google Scholar PubMed PubMed Central
Chen, Y.R. and Tan, T.H. (1998). Inhibition of the c-Jun N-terminal kinase (JNK) signaling pathway by curcumin. Oncogene17, 173–178.10.1038/sj.onc.1201941Search in Google Scholar PubMed
Cheng, A.L., Hsu, C.H., Lin, J.K., Hsu, M.M., Ho, Y.F., Shen, T.S., Ko, J.Y., Lin, J.T., Lin, B.R., Ming-Shiang, W., et al. (2001). Phase I clinical trial of curcumin, a chemopreventive agent, in patients with high-risk or pre-malignant lesions. Anticancer Res.21, 2895–2900.Search in Google Scholar
Dignam, J.D., LeBovitz, R.M., and Roeder, R.G. (1983). Accurate transcription initiation by RNA polymerase II in a soluble extract from isolated mammalian nuclei. Nucleic Acids Res.11, 1475–1489.10.1093/nar/11.5.1475Search in Google Scholar PubMed PubMed Central
Edwards, J.L., Brown, E.J., Uk-Nham, S., Cannon, J.G., Blake, M.S., and Apicella, M.A. (2002). A co-operative interaction between Neisseria gonorrhoeae and complement receptor 3 mediates infection of primary cervical epithelial cells. Cell. Microbiol.4, 571–584.10.1046/j.1462-5822.2002.t01-1-00215.xSearch in Google Scholar PubMed
Egan, M.E., Pearson, M., Weiner, S.A., Rajendran, V., Rubin, D., Glöckner-Pagel, J., Canny, S., Du, K., Lukacs, G.L., and Caplan, M.J. (2004). Curcumin, a major constituent of turmeric, corrects cystic fibrosis defects. Science304, 600–602.10.1126/science.1093941Search in Google Scholar PubMed
Faure, E., Equils, O., Sieling, P.A., Thomas, L., Zhang, F.X., Kirschning, C.J., Polentarutti, N., Muzio, M., and Arditi, M. (2000). Bacterial lipopolysaccharide activates NF-κB through toll-like receptor 4 (TLR-4) in cultured human dermal endothelial cells. Differential expression of TLR-4 and TLR-2 in endothelial cells. J. Biol. Chem.275, 11058–11063.10.1074/jbc.275.15.11058Search in Google Scholar PubMed
Foryst-Ludwig, A., Neumann, M., Schneider-Brachert, W., and Naumann, M. (2004). Curcumin blocks NF-κB and the mitogenic response in Helicobacter pylori-infected epithelial cells. Biochem. Biophys. Res. Commun.316, 1065–1072.10.1016/j.bbrc.2004.02.158Search in Google Scholar PubMed
Grassmé, H.U.C., Ireland, R.M., and van Putten, J.P.M. (1996). Gonococcal opacity protein promotes bacterial entry-associated rearrangements of the epithelial cell actin cytoskeleton. Infect. Immun.64, 1621–1630.10.1128/iai.64.5.1621-1630.1996Search in Google Scholar PubMed PubMed Central
Gray-Owen, S.D., Lorenzen, D.R., Haude, A., Meyer, T.F., and Dehio, C. (1997a). Differential Opa specificities for CD66 receptors influence tissue interactions and cellular response to Neisseria gonorrhoeae. Mol. Microbiol.26, 971–980.10.1046/j.1365-2958.1997.6342006.xSearch in Google Scholar PubMed
Gray-Owen, S.D., Dehio, C., Haude, A., Grunert, F., and Meyer, T.F. (1997b). CD66 carcinoembryonic antigens mediate interactions between Opa-expressing Neisseria gonorrhoeae and human polymorphonuclear phagocytes. EMBO J.16, 3435–3445.10.1093/emboj/16.12.3435Search in Google Scholar PubMed PubMed Central
Haas, R., Schwarz, H., and Meyer, T.F. (1987). Release of soluble pilin antigen coupled with gene conversion in Neisseria gonorrhoeae. Proc. Natl. Acad. Sci. USA84, 9079–9083.10.1073/pnas.84.24.9079Search in Google Scholar PubMed PubMed Central
Hayashi, F., Smith, K.D., Ozinsky, A., Hawn, T.R., Yi, E.C., Goodlett, D.R., Eng, J.K., Akira, S., Underhill, D.M., and Aderem, A. (2001). The innate immune response to bacterial flagellin is mediated by Toll-like receptor 5. Nature410, 1099–1103.10.1038/35074106Search in Google Scholar PubMed
Hobbie, S., Chen, L.M., Davis, R.J., and Galan, J.E. (1997). Involvement of mitogen-activated protein kinase pathways in the nuclear responses and cytokine production induced by Salmonella typhimurium in cultured intestinal epithelial cells. J. Immunol.159, 5550–5559.10.4049/jimmunol.159.11.5550Search in Google Scholar
Huang, M.T., Lou, Y.R., Ma, W., Newmark, H.L., Reuhl, K.R., and Conney, A.H. (1994). Inhibitory effects of dietary curcumin on forestomach, duodenal, and colon carcinogenesis in mice. Cancer Res.54, 5841–5847.Search in Google Scholar
Jee, S.H., Shen, S.C., Tseng, C.R., Chiu, H.C., and Kuo, M.L. (1998). Curcumin induces a p53-dependent apoptosis in human basal cell carcinoma cells. J. Invest. Dermatol.111, 656–661.10.1046/j.1523-1747.1998.00352.xSearch in Google Scholar PubMed
Jiang, M.C., Yang Yen, H.F, Yen, J.J., and Lin, J.K. (1996). Curcumin induces apoptosis in immortalized NIH 3T3 and malignant cancer cell lines. Nutr. Cancer26, 111–120.10.1080/01635589609514468Search in Google Scholar PubMed
Kahrs, A.F., Bihlmaier, A., Facius, D., and Meyer, T.F. (1994). Generalized transposon shuttle mutagenesis in Neisseria gonorrhoeae: a method for isolating epithelial cell invasion-defective mutants. Mol. Microbiol.12, 819–832.10.1111/j.1365-2958.1994.tb01068.xSearch in Google Scholar PubMed
Kallstrom, H., Liszewski, M.K., Atkinson, J.P., and Jonsson, A.B. (1997). Membrane cofactor protein (MCP or CD46) is a cellular pilus receptor for pathogenic Neisseria. Mol. Microbiol.25, 639–647.10.1046/j.1365-2958.1997.4841857.xSearch in Google Scholar PubMed
Kawamori, T., Lubet, R., Steele, V.E., Kellof, G.J., Kaskey, R.B., Rao, C.V., and Reddy, B.S. (1999). Chemopreventive effect of curcumin, a naturally occurring anti-inflammatory agent, during the promotion/progression stages of colon cancer. Cancer Res.59, 597–601.Search in Google Scholar
Krull, M., Klucken, A.C., Wuppermann, F.N., Fuhrmann, O., Magerl, C., Seybold, J., Hippenstiel, S., Hegemann, J.H., Jantos, C.A., and Suttorp, N. (1999). Signal transduction pathways activated in endothelial cells following infection with Chlamydia pneumoniae. J. Immunol.162, 4834–4841.10.4049/jimmunol.162.8.4834Search in Google Scholar
Kunsch, C., Ruben, S.M., and Rosen, C.A. (1992). Selection of optimal kappa B/Rel DNA-binding motifs: interaction of both subunits of NF-κB with DNA is required for transcriptional activation. Mol. Cell. Biol.12, 4412–4421.Search in Google Scholar
Leu, T.H., Su, S.L., Chuang, Y.C., and Maa, M.C. (2003). Direct inhibitory effect of curcumin on Src and focal adhesion kinase activity. Biochem. Pharmacol.66, 2323–2331.10.1016/j.bcp.2003.08.017Search in Google Scholar PubMed
Ling, L., Cao, Z., and Goeddel, D.V. (1998). NF-κB-inducing kinase activates IKK-α by phosphorylation of Ser-176. Proc. Natl. Acad. Sci. USA95, 3792–3797.10.1073/pnas.95.7.3792Search in Google Scholar PubMed PubMed Central
Mahmoud, N.N., Carothers, A.M., Grunberger, D., Bilinski, R.T., Churchill, M.R., Martucci, C., Newmark, H.L., and Bertagnolli, M.M. (2000). Plant phenolics decrease intestinal tumors in an animal model of familial adenomatous polyposis. Carcinogenesis21, 921–927.10.1093/carcin/21.5.921Search in Google Scholar PubMed
Malinin, N.L., Boldin, M.P., Kovalenko, A.V., and Wallach, D. (1997). MAP3K-related kinase involved in NF-κB induction by TNF, CD95 and IL-1. Nature385, 540–544.10.1038/385540a0Search in Google Scholar PubMed
Matsushima, A., Kaisho, T., Rennert, P.D., Nakano, H., Kurosawa, K., Uchida, D., Takeda, K., Akira, S., and Matsumoto, M. (2001). Essential role of nuclear factor (NF)-κB-inducing kinase and inhibitor of κB (IκB) kinase α in NF-κB activation through lymphotoxin β receptor, but not through tumor necrosis factor receptor I. J. Exp. Med.193, 631–636.10.1084/jem.193.5.631Search in Google Scholar PubMed PubMed Central
McCaw, S.E., Schneider, J., Liao, E.H., Zimmermann, W., and Gray-Owen, S.D. (2003). Immunoreceptor tyrosine-based activation motif phosphorylation during engulfment of Neisseria gonorrhoeae by the neutrophil-restricted CEACAM3 (CD66d) receptor. Mol. Microbiol.49, 623–637.10.1046/j.1365-2958.2003.03591.xSearch in Google Scholar
Muenzner, P., Dehio, C., Fujiwara, T., Achtman, M., Meyer, T.F., and Gray-Owen, S.D. (2000). Carcinoembryonic antigen family receptor specificity of Neisseria meningitidis Opa variants influences adherence to and invasion of proinflammatory cytokine-activated endothelial cells. Infect. Immun.68, 3601–3607.10.1128/IAI.68.6.3601-3607.2000Search in Google Scholar
Muenzner, P., Naumann, M., Meyer, T.F., and Gray-Owen, S.D. (2001). Pathogenic Neisseria trigger expression of their carcinoembryonic antigen-related cellular adhesion molecule 1 (CEACAM1; previously CD66a) receptor on primary endothelial cells by activating the immediate early response transcription factor, nuclear factor-κB. J. Biol. Chem.276, 24331–24340.10.1074/jbc.M006883200Search in Google Scholar
Muenzner, P., Billker, O., Meyer, T.F., and Naumann, M. (2002). Nuclear factor-κB directs carcinoembryonic antigen-related cellular adhesion molecule 1 receptor expression in Neisseria gonorrhoeae-infected epithelial cells. J. Biol. Chem.277, 7438–7446.10.1074/jbc.M108135200Search in Google Scholar
Mukhopadhyay, A., Bueso-Ramos, C., Chatterjee, D., Pantazis, P., and Aggarwal, B.B. (2001). Curcumin downregulates cell survival mechanisms in human prostate cancer cell lines. Oncogene20, 7597–7609.10.1038/sj.onc.1204997Search in Google Scholar
Naumann, M. and Scheidereit, C. (1994). Activation of NF-κB in vivo is regulated by multiple phosphorylations. EMBO J.13, 4597–4607.10.1002/j.1460-2075.1994.tb06781.xSearch in Google Scholar
Naumann, M., Wessler, S., Bartsch, C., Wieland, B., and Meyer, T.F. (1997). Neisseria gonorrhoeae epithelial cell interaction leads to the activation of the transcription factors nuclear factor κB and activator protein 1 and the induction of inflammatory cytokines. J. Exp. Med.186, 247–258.10.1084/jem.186.2.247Search in Google Scholar
Naumann, M., Rudel, T., Wieland, B., Bartsch, C., and Meyer, T.F. (1998). Coordinate activation of activator protein 1 and inflammatory cytokines in response to Neisseria gonorrhoeae epithelial cell contact involves stress response kinases. J. Exp. Med.188, 1277–1286.10.1084/jem.188.7.1277Search in Google Scholar
Naumann, M., Rudel, T., and Meyer, T.F. (1999a). Host cell interactions and signalling with Neisseria gonorrhoeae. Curr. Opin. Microbiol.2, 62–70.10.1016/S1369-5274(99)80011-3Search in Google Scholar
Naumann, M., Weßler, S., Bartsch, C., Wieland, B., Covacci, A., Haas, R., and Meyer, T.F. (1999b). Activation of activator protein 1 and stress response kinases in epithelial cells colonized by Helicobacter pylori encoding the pathogenicity island. J. Biol. Chem.274, 31655–31662.10.1074/jbc.274.44.31655Search in Google Scholar PubMed
Ramsewak, R.S., DeWitt, D.L., and Nair, M.G. (2000). Cytotoxicity, antioxidant and anti-inflammatory activities of curcumins I–III from Curcuma longa. Phytomedicine7, 303–308.10.1016/S0944-7113(00)80048-3Search in Google Scholar
Rao, C.V., Rivenson, A., Simi, B., and Reddy, B.S. (1995). Chemoprevention of colon carcinogenesis by dietary curcumin, a naturally occurring plant phenolic compound. Cancer Res.55, 259–266.Search in Google Scholar
Roebuck, K.A., Carpenter, L.R., Lakshminarayanan, V., Page, S.M., Moy, J.N., and Thomas, L.L. (1999). Stimulus-specific regulation of chemokine expression involves differential activation of the redox-responsive transcription factors AP-1 and NF-κB. J. Leukoc. Biol.65, 291–298.10.1002/jlb.65.3.291Search in Google Scholar
Rothwarf, D., Zandi, E., Natoli, G., and Karin, M. (1998). IKK-gamma is an essential regulatory subunit of the IκB kinase complex. Nature395, 297–300.10.1038/26261Search in Google Scholar
Sood, A., Mathew, R., and Trachtman, H. (2001). Curcumin treatment modulates collagen metabolism in isoproterenol induced myocardial necrosis in rats. Biochem. Biophys. Res. Commun.283, 36–41.10.1006/bbrc.2001.4749Search in Google Scholar
van Putten, J.P. and Paul, S.M. (1995). Binding of syndecan-like cell surface proteoglycan receptors is required for Neisseria gonorrhoeae entry into human mucosal cells. EMBO J.14, 2144–2154.10.1002/j.1460-2075.1995.tb07208.xSearch in Google Scholar
Virji, M., Makepeace, K.D.J., and Watt, S.M. (1996). Carcinoembryonic antigens (CD66) on epithelial cells and neutrophils are receptors for Opa proteins of pathogenic Neisseriae. Mol. Microbiol.22, 941–950.10.1046/j.1365-2958.1996.01551.xSearch in Google Scholar
Virji, M., Evans, D., Hadfield, A., Grunert, F., Teixeira, A.M., and Watt, S.M. (1999). Critical determinants of host receptor targeting by Neisseria meningitidis and Neisseria gonorrhoeae: identification of Opa adhesiotopes on the N-domain of CD66 molecules. Mol. Microbiol.34, 538–551.10.1046/j.1365-2958.1999.01620.xSearch in Google Scholar
Wang, J., Gray-Owen, S.D., Knorre, A., Meyer, T.F., and Dehio, C. (1998). Opa binding to cellular CD66 receptors mediates the transcellular traversal of Neisseria gonorrhoeae across polarized T84 epithelial cell monolayers. Mol. Microbiol.30, 657–671.10.1046/j.1365-2958.1998.01102.xSearch in Google Scholar
Yamaoka, S., Courtois, G., Bessia, C., Whiteside, S.T., Weil, R., Agou, F., Kirk, H.E., Kay, R.J., and Israel, A. (1998). Complementation cloning of NEMO, a component of the IκB kinase complex essential for NF-κB activation. Cell93, 1231–1240.10.1016/S0092-8674(00)81466-XSearch in Google Scholar
Zandi, E. and Karin, M. (1999). Bridging the gap: composition, regulation, and physiological function of the IκB kinase complex. Mol. Cell. Biol.19, 4547–4551.10.1128/MCB.19.7.4547Search in Google Scholar PubMed PubMed Central
Zenilman, J.M. (1993). Gonorrhea: clinical and public health issues. Hosp. Pract.28, 29–35.10.1080/21548331.1993.11442893Search in Google Scholar PubMed
© Walter de Gruyter Berlin New York
Articles in the same Issue
- Saccharomyces cerevisiae translational activator Cbs1p is associated with translationally active mitochondrial ribosomes
- Evolution of vitamin B2 biosynthesis: riboflavin synthase of Arabidopsis thaliana and its inhibition by riboflavin
- Molecular basis of the complex formation between the two calcium-binding proteins S100A8 (MRP8) and S100A9 (MRP14)
- An extracellular carboxylesterase from the basidiomycete Pleurotus sapidus hydrolyses xanthophyll esters
- The composition, structural properties and binding of very-low-density and low-density lipoproteins to the LDL receptor in normo- and hypertriglyceridemia: relation to the apolipoprotein E phenotype
- Adrenodoxin (Adx) and CYP11A1 (P450scc) induce apoptosis by the generation of reactive oxygen species in mitochondria
- Ultraspiracle promotes the nuclear localization of ecdysteroid receptor in mammalian cells
- Polyadenylate polymerase modulations in human epithelioid cervix and breast cancer cell lines, treated with etoposide or cordycepin, follow cell cycle rather than apoptosis induction
- The anti-inflammatory compound curcumin inhibits Neisseria gonorrhoeae-induced NF-κB signaling, release of pro-inflammatory cytokines/chemokines and attenuates adhesion in late infection
- Susceptibility of the interchain peptide of a bromelain inhibitor precursor to the target proteases bromelain, chymotrypsin, and trypsin
- Blocking effect of a biotinylated protease inhibitor on the egress of Plasmodium falciparum merozoites from infected red blood cells
Articles in the same Issue
- Saccharomyces cerevisiae translational activator Cbs1p is associated with translationally active mitochondrial ribosomes
- Evolution of vitamin B2 biosynthesis: riboflavin synthase of Arabidopsis thaliana and its inhibition by riboflavin
- Molecular basis of the complex formation between the two calcium-binding proteins S100A8 (MRP8) and S100A9 (MRP14)
- An extracellular carboxylesterase from the basidiomycete Pleurotus sapidus hydrolyses xanthophyll esters
- The composition, structural properties and binding of very-low-density and low-density lipoproteins to the LDL receptor in normo- and hypertriglyceridemia: relation to the apolipoprotein E phenotype
- Adrenodoxin (Adx) and CYP11A1 (P450scc) induce apoptosis by the generation of reactive oxygen species in mitochondria
- Ultraspiracle promotes the nuclear localization of ecdysteroid receptor in mammalian cells
- Polyadenylate polymerase modulations in human epithelioid cervix and breast cancer cell lines, treated with etoposide or cordycepin, follow cell cycle rather than apoptosis induction
- The anti-inflammatory compound curcumin inhibits Neisseria gonorrhoeae-induced NF-κB signaling, release of pro-inflammatory cytokines/chemokines and attenuates adhesion in late infection
- Susceptibility of the interchain peptide of a bromelain inhibitor precursor to the target proteases bromelain, chymotrypsin, and trypsin
- Blocking effect of a biotinylated protease inhibitor on the egress of Plasmodium falciparum merozoites from infected red blood cells