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. 1994 Oct;94(4):1629–1636. doi: 10.1172/JCI117505

Activation and attenuation of transcription factor NF-kB in mouse glomerular mesangial cells in response to tumor necrosis factor-alpha, immunoglobulin G, and adenosine 3':5'-cyclic monophosphate. Evidence for involvement of reactive oxygen species.

J Satriano 1, D Schlondorff 1
PMCID: PMC295323  PMID: 7929839

Abstract

The transcription factor NF-kB may play an important role in the response to tissue injury and activation of cytokines. We therefore examined the regulation of NF-kB in mesangial cells. Treatment of mesangial cells with TNF-alpha increased nuclear proteins that bound to an NF-kB-specific DNA oligonucleotide. IgG aggregates also increased nuclear NF-kB demonstrating Fc-tau receptor-mediated activation of NF-kB. Treatment of a cytosolic preparation with the detergent deoxycholate also activated NF-kB. The binding characteristics were typical for NF-kB transcription factors as determined by competition experiments with NF-kB-binding wild type kB DNA oligonucleotides or mutated oligonucleotides. Furthermore, a monoclonal antibody against the p65 subunit of NF-kB prevented the binding of NF-kB to the kB oligonucleotide. To evaluate the potential role of reactive oxygen intermediates in the activation of NF-kB, we used PDTC as a scavenger and HMAP as an inhibitor of NADPH-dependent oxidase. Both PDTC and HMAP attenuated the increase in nuclear NF-kB in response to either TNF-alpha or IgG complexes. Finally, generation of superoxide anion by xanthine oxidase activated NF-kB, an effect also mitigated by PDTC. In contrast, exogenous H2O2 did not activate NF-kB. Preincubation of cells with 8 br-cAMP, forskolin, or PGE2 attenuated the increase in nuclear NF-kB in response to TNF-alpha, aggregated IgG, or superoxide anion. Our results provide support for a role of reactive oxygen intermediates as mediators for activation of NF-kB in MC after stimulation with TNF-alpha or IgG aggregates. As an unexpected novel finding we report that cAMP can inhibit activation of NF-kB in MC. These observations may help to explain effects of TNF-alpha, IgG aggregates and cAMP on generation of cytokines by mesangial cells and the resulting glomerular pathophysiology.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Baeuerle P. A., Baltimore D. Activation of DNA-binding activity in an apparently cytoplasmic precursor of the NF-kappa B transcription factor. Cell. 1988 Apr 22;53(2):211–217. doi: 10.1016/0092-8674(88)90382-0. [DOI] [PubMed] [Google Scholar]
  2. Baeuerle P. A. The inducible transcription activator NF-kappa B: regulation by distinct protein subunits. Biochim Biophys Acta. 1991 Apr 16;1072(1):63–80. doi: 10.1016/0304-419x(91)90007-8. [DOI] [PubMed] [Google Scholar]
  3. Bloom R. D., Florquin S., Singer G. G., Brennan D. C., Kelley V. R. Colony stimulating factor-1 in the induction of lupus nephritis. Kidney Int. 1993 May;43(5):1000–1009. doi: 10.1038/ki.1993.141. [DOI] [PubMed] [Google Scholar]
  4. Dressler K. A., Mathias S., Kolesnick R. N. Tumor necrosis factor-alpha activates the sphingomyelin signal transduction pathway in a cell-free system. Science. 1992 Mar 27;255(5052):1715–1718. doi: 10.1126/science.1313189. [DOI] [PubMed] [Google Scholar]
  5. Ernst T. J., Ritchie A. R., Demetri G. D., Griffin J. D. Regulation of granulocyte- and monocyte-colony stimulating factor mRNA levels in human blood monocytes is mediated primarily at a post-transcriptional level. J Biol Chem. 1989 Apr 5;264(10):5700–5703. [PubMed] [Google Scholar]
  6. Ghosh S., Baltimore D. Activation in vitro of NF-kappa B by phosphorylation of its inhibitor I kappa B. Nature. 1990 Apr 12;344(6267):678–682. doi: 10.1038/344678a0. [DOI] [PubMed] [Google Scholar]
  7. Harrington M. A., Edenberg H. J., Saxman S., Pedigo L. M., Daub R., Broxmeyer H. E. Cloning and characterization of the murine promoter for the colony-stimulating factor-1-encoding gene. Gene. 1991 Jun 30;102(2):165–170. doi: 10.1016/0378-1119(91)90074-l. [DOI] [PubMed] [Google Scholar]
  8. Hora K., Satriano J. A., Santiago A., Mori T., Stanley E. R., Shan Z., Schlondorff D. Receptors for IgG complexes activate synthesis of monocyte chemoattractant peptide 1 and colony-stimulating factor 1. Proc Natl Acad Sci U S A. 1992 Mar 1;89(5):1745–1749. doi: 10.1073/pnas.89.5.1745. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Horiguchi J., Sariban E., Kufe D. Transcriptional and posttranscriptional regulation of CSF-1 gene expression in human monocytes. Mol Cell Biol. 1988 Sep;8(9):3951–3954. doi: 10.1128/mcb.8.9.3951. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Introna M., Bast R. C., Jr, Tannenbaum C. S., Hamilton T. A., Adams D. O. The effect of LPS on expression of the early "competence" genes JE and KC in murine peritoneal macrophages. J Immunol. 1987 Jun 1;138(11):3891–3896. [PubMed] [Google Scholar]
  11. Johnson P. F., McKnight S. L. Eukaryotic transcriptional regulatory proteins. Annu Rev Biochem. 1989;58:799–839. doi: 10.1146/annurev.bi.58.070189.004055. [DOI] [PubMed] [Google Scholar]
  12. Kawahara R. S., Deuel T. F. Platelet-derived growth factor-inducible gene JE is a member of a family of small inducible genes related to platelet factor 4. J Biol Chem. 1989 Jan 15;264(2):679–682. [PubMed] [Google Scholar]
  13. Krieger-Brauer H. I., Kather H. Human fat cells possess a plasma membrane-bound H2O2-generating system that is activated by insulin via a mechanism bypassing the receptor kinase. J Clin Invest. 1992 Mar;89(3):1006–1013. doi: 10.1172/JCI115641. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Lenardo M. J., Baltimore D. NF-kappa B: a pleiotropic mediator of inducible and tissue-specific gene control. Cell. 1989 Jul 28;58(2):227–229. doi: 10.1016/0092-8674(89)90833-7. [DOI] [PubMed] [Google Scholar]
  15. Leonard E. J., Yoshimura T. Human monocyte chemoattractant protein-1 (MCP-1). Immunol Today. 1990 Mar;11(3):97–101. doi: 10.1016/0167-5699(90)90035-8. [DOI] [PubMed] [Google Scholar]
  16. Liu J. L., Chiles T. C., Sen R. J., Rothstein T. L. Inducible nuclear expression of NF-kappa B in primary B cells stimulated through the surface Ig receptor. J Immunol. 1991 Mar 1;146(5):1685–1691. [PubMed] [Google Scholar]
  17. Mathias S., Dressler K. A., Kolesnick R. N. Characterization of a ceramide-activated protein kinase: stimulation by tumor necrosis factor alpha. Proc Natl Acad Sci U S A. 1991 Nov 15;88(22):10009–10013. doi: 10.1073/pnas.88.22.10009. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. McKnight S., Tjian R. Transcriptional selectivity of viral genes in mammalian cells. Cell. 1986 Sep 12;46(6):795–805. doi: 10.1016/0092-8674(86)90061-9. [DOI] [PubMed] [Google Scholar]
  19. Meichle A., Schütze S., Hensel G., Brunsing D., Krönke M. Protein kinase C-independent activation of nuclear factor kappa B by tumor necrosis factor. J Biol Chem. 1990 May 15;265(14):8339–8343. [PubMed] [Google Scholar]
  20. Meyer M., Schreck R., Baeuerle P. A. H2O2 and antioxidants have opposite effects on activation of NF-kappa B and AP-1 in intact cells: AP-1 as secondary antioxidant-responsive factor. EMBO J. 1993 May;12(5):2005–2015. doi: 10.1002/j.1460-2075.1993.tb05850.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Novak U., Cocks B. G., Hamilton J. A. A labile repressor acts through the NFkB-like binding sites of the human urokinase gene. Nucleic Acids Res. 1991 Jun 25;19(12):3389–3393. doi: 10.1093/nar/19.12.3389. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Oppenheim J. J., Zachariae C. O., Mukaida N., Matsushima K. Properties of the novel proinflammatory supergene "intercrine" cytokine family. Annu Rev Immunol. 1991;9:617–648. doi: 10.1146/annurev.iy.09.040191.003153. [DOI] [PubMed] [Google Scholar]
  23. Radeke H. H., Cross A. R., Hancock J. T., Jones O. T., Nakamura M., Kaever V., Resch K. Functional expression of NADPH oxidase components (alpha- and beta-subunits of cytochrome b558 and 45-kDa flavoprotein) by intrinsic human glomerular mesangial cells. J Biol Chem. 1991 Nov 5;266(31):21025–21029. [PubMed] [Google Scholar]
  24. Radeke H. H., Meier B., Topley N., Flöge J., Habermehl G. G., Resch K. Interleukin 1-alpha and tumor necrosis factor-alpha induce oxygen radical production in mesangial cells. Kidney Int. 1990 Feb;37(2):767–775. doi: 10.1038/ki.1990.44. [DOI] [PubMed] [Google Scholar]
  25. Rollins B. J., Yoshimura T., Leonard E. J., Pober J. S. Cytokine-activated human endothelial cells synthesize and secrete a monocyte chemoattractant, MCP-1/JE. Am J Pathol. 1990 Jun;136(6):1229–1233. [PMC free article] [PubMed] [Google Scholar]
  26. Rovin B. H., Yoshiumura T., Tan L. Cytokine-induced production of monocyte chemoattractant protein-1 by cultured human mesangial cells. J Immunol. 1992 Apr 1;148(7):2148–2153. [PubMed] [Google Scholar]
  27. Saran M., Bors W. Oxygen radicals acting as chemical messengers: a hypothesis. Free Radic Res Commun. 1989;7(3-6):213–220. doi: 10.3109/10715768909087944. [DOI] [PubMed] [Google Scholar]
  28. Satriano J. A., Hora K., Shan Z., Stanley E. R., Mori T., Schlondorff D. Regulation of monocyte chemoattractant protein-1 and macrophage colony-stimulating factor-1 by IFN-gamma, tumor necrosis factor-alpha, IgG aggregates, and cAMP in mouse mesangial cells. J Immunol. 1993 Mar 1;150(5):1971–1978. [PubMed] [Google Scholar]
  29. Satriano J. A., Shuldiner M., Hora K., Xing Y., Shan Z., Schlondorff D. Oxygen radicals as second messengers for expression of the monocyte chemoattractant protein, JE/MCP-1, and the monocyte colony-stimulating factor, CSF-1, in response to tumor necrosis factor-alpha and immunoglobulin G. Evidence for involvement of reduced nicotinamide adenine dinucleotide phosphate (NADPH)-dependent oxidase. J Clin Invest. 1993 Sep;92(3):1564–1571. doi: 10.1172/JCI116737. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Schlondorff D. The glomerular mesangial cell: an expanding role for a specialized pericyte. FASEB J. 1987 Oct;1(4):272–281. doi: 10.1096/fasebj.1.4.3308611. [DOI] [PubMed] [Google Scholar]
  31. Schreck R., Baeuerle P. A. A role for oxygen radicals as second messengers. Trends Cell Biol. 1991 Aug;1(2-3):39–42. doi: 10.1016/0962-8924(91)90072-h. [DOI] [PubMed] [Google Scholar]
  32. Schreck R., Rieber P., Baeuerle P. A. Reactive oxygen intermediates as apparently widely used messengers in the activation of the NF-kappa B transcription factor and HIV-1. EMBO J. 1991 Aug;10(8):2247–2258. doi: 10.1002/j.1460-2075.1991.tb07761.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Schreiber E., Matthias P., Müller M. M., Schaffner W. Rapid detection of octamer binding proteins with 'mini-extracts', prepared from a small number of cells. Nucleic Acids Res. 1989 Aug 11;17(15):6419–6419. doi: 10.1093/nar/17.15.6419. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Schütze S., Potthoff K., Machleidt T., Berkovic D., Wiegmann K., Krönke M. TNF activates NF-kappa B by phosphatidylcholine-specific phospholipase C-induced "acidic" sphingomyelin breakdown. Cell. 1992 Nov 27;71(5):765–776. doi: 10.1016/0092-8674(92)90553-o. [DOI] [PubMed] [Google Scholar]
  35. Sedor J. R., Carey S. W., Emancipator S. N. Immune complexes bind to cultured rat glomerular mesangial cells to stimulate superoxide release. Evidence for an Fc receptor. J Immunol. 1987 Jun 1;138(11):3751–3757. [PubMed] [Google Scholar]
  36. Sen R., Baltimore D. Multiple nuclear factors interact with the immunoglobulin enhancer sequences. Cell. 1986 Aug 29;46(5):705–716. doi: 10.1016/0092-8674(86)90346-6. [DOI] [PubMed] [Google Scholar]
  37. Sherman M. L., Weber B. L., Datta R., Kufe D. W. Transcriptional and posttranscriptional regulation of macrophage-specific colony stimulating factor gene expression by tumor necrosis factor. Involvement of arachidonic acid metabolites. J Clin Invest. 1990 Feb;85(2):442–447. doi: 10.1172/JCI114457. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Shirakawa F., Mizel S. B. In vitro activation and nuclear translocation of NF-kappa B catalyzed by cyclic AMP-dependent protein kinase and protein kinase C. Mol Cell Biol. 1989 Jun;9(6):2424–2430. doi: 10.1128/mcb.9.6.2424. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Shyy Y. J., Li Y. S., Kolattukudy P. E. Structure of human monocyte chemotactic protein gene and its regulation by TPA. Biochem Biophys Res Commun. 1990 Jun 15;169(2):346–351. doi: 10.1016/0006-291x(90)90338-n. [DOI] [PubMed] [Google Scholar]
  40. Staal F. J., Roederer M., Herzenberg L. A., Herzenberg L. A. Intracellular thiols regulate activation of nuclear factor kappa B and transcription of human immunodeficiency virus. Proc Natl Acad Sci U S A. 1990 Dec;87(24):9943–9947. doi: 10.1073/pnas.87.24.9943. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Standiford T. J., Kunkel S. L., Phan S. H., Rollins B. J., Strieter R. M. Alveolar macrophage-derived cytokines induce monocyte chemoattractant protein-1 expression from human pulmonary type II-like epithelial cells. J Biol Chem. 1991 May 25;266(15):9912–9918. [PubMed] [Google Scholar]
  42. Strieter R. M., Wiggins R., Phan S. H., Wharram B. L., Showell H. J., Remick D. G., Chensue S. W., Kunkel S. L. Monocyte chemotactic protein gene expression by cytokine-treated human fibroblasts and endothelial cells. Biochem Biophys Res Commun. 1989 Jul 31;162(2):694–700. doi: 10.1016/0006-291x(89)92366-8. [DOI] [PubMed] [Google Scholar]
  43. Suzuki Y., Wang W., Vu T. H., Raffin T. A. Effect of NADPH oxidase inhibition on endothelial cell ELAM-1 mRNA expression. Biochem Biophys Res Commun. 1992 May 15;184(3):1339–1343. doi: 10.1016/s0006-291x(05)80029-4. [DOI] [PubMed] [Google Scholar]
  44. Toledano M. B., Leonard W. J. Modulation of transcription factor NF-kappa B binding activity by oxidation-reduction in vitro. Proc Natl Acad Sci U S A. 1991 May 15;88(10):4328–4332. doi: 10.1073/pnas.88.10.4328. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Wolf G., Haberstroh U., Neilson E. G. Angiotensin II stimulates the proliferation and biosynthesis of type I collagen in cultured murine mesangial cells. Am J Pathol. 1992 Jan;140(1):95–107. [PMC free article] [PubMed] [Google Scholar]
  46. Yoshimura T., Yuhki N., Moore S. K., Appella E., Lerman M. I., Leonard E. J. Human monocyte chemoattractant protein-1 (MCP-1). Full-length cDNA cloning, expression in mitogen-stimulated blood mononuclear leukocytes, and sequence similarity to mouse competence gene JE. FEBS Lett. 1989 Feb 27;244(2):487–493. doi: 10.1016/0014-5793(89)80590-3. [DOI] [PubMed] [Google Scholar]
  47. Zabel U., Schreck R., Baeuerle P. A. DNA binding of purified transcription factor NF-kappa B. Affinity, specificity, Zn2+ dependence, and differential half-site recognition. J Biol Chem. 1991 Jan 5;266(1):252–260. [PubMed] [Google Scholar]
  48. Zoja C., Wang J. M., Bettoni S., Sironi M., Renzi D., Chiaffarino F., Abboud H. E., Van Damme J., Mantovani A., Remuzzi G. Interleukin-1 beta and tumor necrosis factor-alpha induce gene expression and production of leukocyte chemotactic factors, colony-stimulating factors, and interleukin-6 in human mesangial cells. Am J Pathol. 1991 Apr;138(4):991–1003. [PMC free article] [PubMed] [Google Scholar]

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