Skip to main content
Mediators of Inflammation logoLink to Mediators of Inflammation
. 2003 Oct;12(5):277–283. doi: 10.1080/09629350310001619681

Regulation of nuclear factor-kappaB in intestinal epithelial cells in a cell model of inflammation.

Fadia R Homaidan 1, Iman Chakroun 1, Marwan E El-Sabban 1
PMCID: PMC1781626  PMID: 14760934

Abstract

BACKGROUND: Interleukin-1 (IL-1), an inflammatory cytokine whose levels are elevated in inflamed mucosa, causes part of its effect on intestinal epithelial cells (IEC) through inducing ceramide production. AIM: To study the role of nuclear factor-kappaB (NF-kappaB), a pro-inflammatory and anti-apoptotic factor, in IL-1-treated IEC. METHODS: NF-kappaB activity and levels of apoptotic proteins were assessed by electrophoretic mobility shift assay and RNA-protection assay, respectively. RESULTS: IL-1 and ceramide, which have been shown to partially mediate IL-1 effects on IEC, activated NF-kappaB levels significantly. This activation was due to a decrease in IkappaB-alpha and IkappaB-beta protein levels. Moreover, the ratio of mRNA levels of anti-apoptotic to pro-apoptotic proteins was significantly increased in IL-1-treated IEC. CONCLUSION: NF-kappaB may play a key role in the regulation of the expression of pro-inflammatory and/or apoptotic genes in inflammatory bowel disease, making this protein an attractive target for therapeutic intervention.

Full Text

The Full Text of this article is available as a PDF (167.7 KB).

Selected References

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

  1. Abbadie C., Kabrun N., Bouali F., Smardova J., Stéhelin D., Vandenbunder B., Enrietto P. J. High levels of c-rel expression are associated with programmed cell death in the developing avian embryo and in bone marrow cells in vitro. Cell. 1993 Dec 3;75(5):899–912. doi: 10.1016/0092-8674(93)90534-w. [DOI] [PubMed] [Google Scholar]
  2. Aghajanian Carol, Soignet Steven, Dizon Don S., Pien Christine S., Adams Julian, Elliott Peter J., Sabbatini Paul, Miller Vincent, Hensley Martee L., Pezzulli Sandra. A phase I trial of the novel proteasome inhibitor PS341 in advanced solid tumor malignancies. Clin Cancer Res. 2002 Aug;8(8):2505–2511. [PubMed] [Google Scholar]
  3. Baeuerle P. A., Baltimore D. NF-kappa B: ten years after. Cell. 1996 Oct 4;87(1):13–20. doi: 10.1016/s0092-8674(00)81318-5. [DOI] [PubMed] [Google Scholar]
  4. Baeuerle P. A., Henkel T. Function and activation of NF-kappa B in the immune system. Annu Rev Immunol. 1994;12:141–179. doi: 10.1146/annurev.iy.12.040194.001041. [DOI] [PubMed] [Google Scholar]
  5. Baldwin A. S., Jr The NF-kappa B and I kappa B proteins: new discoveries and insights. Annu Rev Immunol. 1996;14:649–683. doi: 10.1146/annurev.immunol.14.1.649. [DOI] [PubMed] [Google Scholar]
  6. Barnes P. J., Karin M. Nuclear factor-kappaB: a pivotal transcription factor in chronic inflammatory diseases. N Engl J Med. 1997 Apr 10;336(15):1066–1071. doi: 10.1056/NEJM199704103361506. [DOI] [PubMed] [Google Scholar]
  7. Beg A. A., Sha W. C., Bronson R. T., Ghosh S., Baltimore D. Embryonic lethality and liver degeneration in mice lacking the RelA component of NF-kappa B. Nature. 1995 Jul 13;376(6536):167–170. doi: 10.1038/376167a0. [DOI] [PubMed] [Google Scholar]
  8. Brown K., Gerstberger S., Carlson L., Franzoso G., Siebenlist U. Control of I kappa B-alpha proteolysis by site-specific, signal-induced phosphorylation. Science. 1995 Mar 10;267(5203):1485–1488. doi: 10.1126/science.7878466. [DOI] [PubMed] [Google Scholar]
  9. Chen C. C., Sun Y. T., Chen J. J., Chang Y. J. Tumor necrosis factor-alpha-induced cyclooxygenase-2 expression via sequential activation of ceramide-dependent mitogen-activated protein kinases, and IkappaB kinase 1/2 in human alveolar epithelial cells. Mol Pharmacol. 2001 Mar;59(3):493–500. doi: 10.1124/mol.59.3.493. [DOI] [PubMed] [Google Scholar]
  10. DiDonato J. A., Hayakawa M., Rothwarf D. M., Zandi E., Karin M. A cytokine-responsive IkappaB kinase that activates the transcription factor NF-kappaB. Nature. 1997 Aug 7;388(6642):548–554. doi: 10.1038/41493. [DOI] [PubMed] [Google Scholar]
  11. Finco T. S., Baldwin A. S. Mechanistic aspects of NF-kappa B regulation: the emerging role of phosphorylation and proteolysis. Immunity. 1995 Sep;3(3):263–272. doi: 10.1016/1074-7613(95)90112-4. [DOI] [PubMed] [Google Scholar]
  12. Gilmore T. D., Morin P. J. The I kappa B proteins: members of a multifunctional family. Trends Genet. 1993 Dec;9(12):427–433. doi: 10.1016/0168-9525(93)90106-r. [DOI] [PubMed] [Google Scholar]
  13. Gukovsky I., Gukovskaya A. S., Blinman T. A., Zaninovic V., Pandol S. J. Early NF-kappaB activation is associated with hormone-induced pancreatitis. Am J Physiol. 1998 Dec;275(6 Pt 1):G1402–G1414. doi: 10.1152/ajpgi.1998.275.6.G1402. [DOI] [PubMed] [Google Scholar]
  14. Hideshima Teru, Mitsiades Constantine, Akiyama Masaharu, Hayashi Toshiaki, Chauhan Dharminder, Richardson Paul, Schlossman Robert, Podar Klaus, Munshi Nikhil C., Mitsiades Nicholas. Molecular mechanisms mediating antimyeloma activity of proteasome inhibitor PS-341. Blood. 2002 Sep 26;101(4):1530–1534. doi: 10.1182/blood-2002-08-2543. [DOI] [PubMed] [Google Scholar]
  15. Homaidan F. R., Chakroun, Dbaibo G. S., El-Assaad W., El-Sabban M. E. IL-1 activates two phospholipid signaling pathways in intestinal epithelial cells. Inflamm Res. 2001 Jul;50(7):375–381. doi: 10.1007/PL00000259. [DOI] [PubMed] [Google Scholar]
  16. Homaidan Fadia R., El-Sabban Marwan E., Chakroun Iman, El-Sibai Mirvat, Dbaibo Ghassan S. IL-1 stimulates ceramide accumulation without inducing apoptosis in intestinal epithelial cells. Mediators Inflamm. 2002 Feb;11(1):39–45. doi: 10.1080/09629350210313. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Jobin C., Sartor R. B. The I kappa B/NF-kappa B system: a key determinant of mucosalinflammation and protection. Am J Physiol Cell Physiol. 2000 Mar;278(3):C451–C462. doi: 10.1152/ajpcell.2000.278.3.C451. [DOI] [PubMed] [Google Scholar]
  18. Keates S., Hitti Y. S., Upton M., Kelly C. P. Helicobacter pylori infection activates NF-kappa B in gastric epithelial cells. Gastroenterology. 1997 Oct;113(4):1099–1109. doi: 10.1053/gast.1997.v113.pm9322504. [DOI] [PubMed] [Google Scholar]
  19. Mustapha S., Kirshner A., De Moissac D., Kirshenbaum L. A. A direct requirement of nuclear factor-kappa B for suppression of apoptosis in ventricular myocytes. Am J Physiol Heart Circ Physiol. 2000 Sep;279(3):H939–H945. doi: 10.1152/ajpheart.2000.279.3.H939. [DOI] [PubMed] [Google Scholar]
  20. Orlowski Robert Z., Stinchcombe Thomas E., Mitchell Beverly S., Shea Thomas C., Baldwin Albert S., Stahl Stephanie, Adams Julian, Esseltine Dixie-Lee, Elliott Peter J., Pien Christine S. Phase I trial of the proteasome inhibitor PS-341 in patients with refractory hematologic malignancies. J Clin Oncol. 2002 Nov 15;20(22):4420–4427. doi: 10.1200/JCO.2002.01.133. [DOI] [PubMed] [Google Scholar]
  21. Pausawasdi Nonthalee, Ramamoorthy Saravanan, Crofford Leslie J., Askari Frederick K., Todisco Andrea. Regulation and function of COX-2 gene expression in isolated gastric parietal cells. Am J Physiol Gastrointest Liver Physiol. 2002 Jun;282(6):G1069–G1078. doi: 10.1152/ajpgi.00164.2001. [DOI] [PubMed] [Google Scholar]
  22. Reddy S. A., Chaturvedi M. M., Darnay B. G., Chan H., Higuchi M., Aggarwal B. B. Reconstitution of nuclear factor kappa B activation induced by tumor necrosis factor requires membrane-associated components. Comparison with pathway activated by ceramide. J Biol Chem. 1994 Oct 14;269(41):25369–25372. [PubMed] [Google Scholar]
  23. Reed J. C. Bcl-2 family proteins: regulators of apoptosis and chemoresistance in hematologic malignancies. Semin Hematol. 1997 Oct;34(4 Suppl 5):9–19. [PubMed] [Google Scholar]
  24. 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]
  25. Thanos D., Maniatis T. Identification of the rel family members required for virus induction of the human beta interferon gene. Mol Cell Biol. 1995 Jan;15(1):152–164. doi: 10.1128/mcb.15.1.152. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Thanos D., Maniatis T. NF-kappa B: a lesson in family values. Cell. 1995 Feb 24;80(4):529–532. doi: 10.1016/0092-8674(95)90506-5. [DOI] [PubMed] [Google Scholar]
  27. Traenckner E. B., Pahl H. L., Henkel T., Schmidt K. N., Wilk S., Baeuerle P. A. Phosphorylation of human I kappa B-alpha on serines 32 and 36 controls I kappa B-alpha proteolysis and NF-kappa B activation in response to diverse stimuli. EMBO J. 1995 Jun 15;14(12):2876–2883. doi: 10.1002/j.1460-2075.1995.tb07287.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Van Antwerp D. J., Martin S. J., Kafri T., Green D. R., Verma I. M. Suppression of TNF-alpha-induced apoptosis by NF-kappaB. Science. 1996 Nov 1;274(5288):787–789. doi: 10.1126/science.274.5288.787. [DOI] [PubMed] [Google Scholar]
  29. Vidal K., Grosjean I., evillard J. P., Gespach C., Kaiserlian D. Immortalization of mouse intestinal epithelial cells by the SV40-large T gene. Phenotypic and immune characterization of the MODE-K cell line. J Immunol Methods. 1993 Nov 5;166(1):63–73. doi: 10.1016/0022-1759(93)90329-6. [DOI] [PubMed] [Google Scholar]
  30. Wahl C., Liptay S., Adler G., Schmid R. M. Sulfasalazine: a potent and specific inhibitor of nuclear factor kappa B. J Clin Invest. 1998 Mar 1;101(5):1163–1174. doi: 10.1172/JCI992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Wang C. Y., Mayo M. W., Baldwin A. S., Jr TNF- and cancer therapy-induced apoptosis: potentiation by inhibition of NF-kappaB. Science. 1996 Nov 1;274(5288):784–787. doi: 10.1126/science.274.5288.784. [DOI] [PubMed] [Google Scholar]
  32. Yamamoto K., Arakawa T., Ueda N., Yamamoto S. Transcriptional roles of nuclear factor kappa B and nuclear factor-interleukin-6 in the tumor necrosis factor alpha-dependent induction of cyclooxygenase-2 in MC3T3-E1 cells. J Biol Chem. 1995 Dec 29;270(52):31315–31320. doi: 10.1074/jbc.270.52.31315. [DOI] [PubMed] [Google Scholar]
  33. Zandi E., Chen Y., Karin M. Direct phosphorylation of IkappaB by IKKalpha and IKKbeta: discrimination between free and NF-kappaB-bound substrate. Science. 1998 Aug 28;281(5381):1360–1363. doi: 10.1126/science.281.5381.1360. [DOI] [PubMed] [Google Scholar]
  34. Zumbansen M., Stoffel W. Tumor necrosis factor alpha activates NF-kappaB in acid sphingomyelinase-deficient mouse embryonic fibroblasts. J Biol Chem. 1997 Apr 18;272(16):10904–10909. doi: 10.1074/jbc.272.16.10904. [DOI] [PubMed] [Google Scholar]

Articles from Mediators of Inflammation are provided here courtesy of Wiley

RESOURCES