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. 1997 May 15;99(10):2423–2428. doi: 10.1172/JCI119425

Stress response decreases NF-kappaB nuclear translocation and increases I-kappaBalpha expression in A549 cells.

H R Wong 1, M Ryan 1, J R Wispé 1
PMCID: PMC508082  PMID: 9153285

Abstract

The stress response and stress proteins confer protection against diverse forms of cellular and tissue injury, including acute lung injury. The stress response can inhibit nonstress protein gene expression, therefore transcriptional inhibition of proinflammatory responses could be a mechanism of protection against acute lung injury. To explore this possibility, we determined the effects of the stress response on nuclear translocation of the transcription factor NF-kappaB, an important regulator of proinflammatory gene expression. In A549 cells induction of the stress response decreased tumor necrosis factor-alpha (TNF-alpha)-mediated NF-kappaB nuclear translocation. TNF-alpha initiates NF-kappaB nuclear translocation by causing dissociation of the inhibitory protein I-kappaBalpha from NF-kappaB and rapid degradation of I-kappaBalpha. Prior induction of the stress response inhibited TNF-alpha-mediated dissociation of I-kappaBalpha from NF-kappaB and subsequent degradation of I-kappaBalpha. Induction of the stress response also increased expression of I-kappaBalpha. We conclude that the stress response affects NFkappaB-mediated gene regulation by two independent mechanisms. The stress response stabilizes I-kappaBalpha and induces expression of I-kappaBalpha. The composite result of these two effects is to decrease NF-kappaB nuclear translocation. We speculate that the protective effect of the stress response against acute lung injury involves a similar effect on the I-kappaB/NF-kappaB pathway.

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Selected References

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  1. Amin J., Ananthan J., Voellmy R. Key features of heat shock regulatory elements. Mol Cell Biol. 1988 Sep;8(9):3761–3769. doi: 10.1128/mcb.8.9.3761. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. 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]
  3. Bellmann K., Wenz A., Radons J., Burkart V., Kleemann R., Kolb H. Heat shock induces resistance in rat pancreatic islet cells against nitric oxide, oxygen radicals and streptozotocin toxicity in vitro. J Clin Invest. 1995 Jun;95(6):2840–2845. doi: 10.1172/JCI117989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Hauser G. J., Dayao E. K., Wasserloos K., Pitt B. R., Wong H. R. HSP induction inhibits iNOS mRNA expression and attenuates hypotension in endotoxin-challenged rats. Am J Physiol. 1996 Dec;271(6 Pt 2):H2529–H2535. doi: 10.1152/ajpheart.1996.271.6.H2529. [DOI] [PubMed] [Google Scholar]
  5. Ito C. Y., Kazantsev A. G., Baldwin A. S., Jr Three NF-kappa B sites in the I kappa B-alpha promoter are required for induction of gene expression by TNF alpha. Nucleic Acids Res. 1994 Sep 11;22(18):3787–3792. doi: 10.1093/nar/22.18.3787. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Jättelä M., Wissing D., Bauer P. A., Li G. C. Major heat shock protein hsp70 protects tumor cells from tumor necrosis factor cytotoxicity. EMBO J. 1992 Oct;11(10):3507–3512. doi: 10.1002/j.1460-2075.1992.tb05433.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Kollef M. H., Schuster D. P. The acute respiratory distress syndrome. N Engl J Med. 1995 Jan 5;332(1):27–37. doi: 10.1056/NEJM199501053320106. [DOI] [PubMed] [Google Scholar]
  8. Li G. C., Werb Z. Correlation between synthesis of heat shock proteins and development of thermotolerance in Chinese hamster fibroblasts. Proc Natl Acad Sci U S A. 1982 May;79(10):3218–3222. doi: 10.1073/pnas.79.10.3218. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Minowada G., Welch W. J. Clinical implications of the stress response. J Clin Invest. 1995 Jan;95(1):3–12. doi: 10.1172/JCI117655. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Schmidt J. A., Abdulla E. Down-regulation of IL-1 beta biosynthesis by inducers of the heat-shock response. J Immunol. 1988 Sep 15;141(6):2027–2034. [PubMed] [Google Scholar]
  11. Schwartz M. D., Moore E. E., Moore F. A., Shenkar R., Moine P., Haenel J. B., Abraham E. Nuclear factor-kappa B is activated in alveolar macrophages from patients with acute respiratory distress syndrome. Crit Care Med. 1996 Aug;24(8):1285–1292. doi: 10.1097/00003246-199608000-00004. [DOI] [PubMed] [Google Scholar]
  12. Snyder Y. M., Guthrie L., Evans G. F., Zuckerman S. H. Transcriptional inhibition of endotoxin-induced monokine synthesis following heat shock in murine peritoneal macrophages. J Leukoc Biol. 1992 Feb;51(2):181–187. doi: 10.1002/jlb.51.2.181. [DOI] [PubMed] [Google Scholar]
  13. Villar J., Edelson J. D., Post M., Mullen J. B., Slutsky A. S. Induction of heat stress proteins is associated with decreased mortality in an animal model of acute lung injury. Am Rev Respir Dis. 1993 Jan;147(1):177–181. doi: 10.1164/ajrccm/147.1.177. [DOI] [PubMed] [Google Scholar]
  14. Villar J., Ribeiro S. P., Mullen J. B., Kuliszewski M., Post M., Slutsky A. S. Induction of the heat shock response reduces mortality rate and organ damage in a sepsis-induced acute lung injury model. Crit Care Med. 1994 Jun;22(6):914–921. [PubMed] [Google Scholar]
  15. Welch W. J. Mammalian stress response: cell physiology, structure/function of stress proteins, and implications for medicine and disease. Physiol Rev. 1992 Oct;72(4):1063–1081. doi: 10.1152/physrev.1992.72.4.1063. [DOI] [PubMed] [Google Scholar]
  16. Wong H. R., Finder J. D., Wasserloos K., Pitt B. R. Expression of iNOS in cultured rat pulmonary artery smooth muscle cells is inhibited by the heat shock response. Am J Physiol. 1995 Dec;269(6 Pt 1):L843–L848. doi: 10.1152/ajplung.1995.269.6.L843. [DOI] [PubMed] [Google Scholar]
  17. Wong H. R., Mannix R. J., Rusnak J. M., Boota A., Zar H., Watkins S. C., Lazo J. S., Pitt B. R. The heat-shock response attenuates lipopolysaccharide-mediated apoptosis in cultured sheep pulmonary artery endothelial cells. Am J Respir Cell Mol Biol. 1996 Dec;15(6):745–751. doi: 10.1165/ajrcmb.15.6.8969269. [DOI] [PubMed] [Google Scholar]
  18. Wong H. R., Ryan M., Gebb S., Wispé J. R. Selective and transient in vitro effects of heat shock on alveolar type II cell gene expression. Am J Physiol. 1997 Jan;272(1 Pt 1):L132–L138. doi: 10.1152/ajplung.1997.272.1.L132. [DOI] [PubMed] [Google Scholar]
  19. Wong H. R., Ryan M., Wispé J. R. The heat shock response inhibits inducible nitric oxide synthase gene expression by blocking I kappa-B degradation and NF-kappa B nuclear translocation. Biochem Biophys Res Commun. 1997 Feb 13;231(2):257–263. doi: 10.1006/bbrc.1997.6076. [DOI] [PubMed] [Google Scholar]
  20. de Martin R., Vanhove B., Cheng Q., Hofer E., Csizmadia V., Winkler H., Bach F. H. Cytokine-inducible expression in endothelial cells of an I kappa B alpha-like gene is regulated by NF kappa B. EMBO J. 1993 Jul;12(7):2773–2779. doi: 10.1002/j.1460-2075.1993.tb05938.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. de Vera M. E., Kim Y. M., Wong H. R., Wang Q., Billiar T. R., Geller D. A. Heat shock response inhibits cytokine-inducible nitric oxide synthase expression in rat hepatocytes. Hepatology. 1996 Nov;24(5):1238–1245. doi: 10.1002/hep.510240542. [DOI] [PubMed] [Google Scholar]
  22. de Vera M. E., Wong J. M., Zhou J. Y., Tzeng E., Wong H. R., Billiar T. R., Geller D. A. Cytokine-induced nitric oxide synthase gene transcription is blocked by the heat shock response in human liver cells. Surgery. 1996 Aug;120(2):144–149. doi: 10.1016/s0039-6060(96)80281-9. [DOI] [PubMed] [Google Scholar]

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