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. 1997 Mar 1;99(5):1057–1063. doi: 10.1172/JCI119233

Interferon gamma induces prostaglandin G/H synthase-2 through an autocrine loop via the epidermal growth factor receptor in human bronchial epithelial cells.

K Asano 1, H Nakamura 1, C M Lilly 1, M Klagsbrun 1, J M Drazen 1
PMCID: PMC507914  PMID: 9062364

Abstract

The induction of prostaglandin G/H synthase (PGHS; prostaglandin endoperoxide synthase, cyclooxygenase) by proinflammatory cytokines accounts, at least in part, for the altered eicosanoid biosynthesis in inflammatory diseases. In secondary cultures of normal human bronchial epithelial cells (NHBECs), interferon-gamma (IFN-gamma, 10 ng/ml for 24 h) increased the amount of prostaglandin E2 (PGE2) released in response to stimulation with exogenous arachidonic acid (5 microM). The enhanced production of PGE2 reflected the upregulation of PGHS-2 as indicated by enhanced expression of PGHS-2 RNA and increased recovery of PGHS-2 protein in NHBECs. IFN-gamma did not alter the production of PGE2 in A549 cells (a human lung adenocarcinoma cell line) or 6-keto-PGF1alpha in human umbilical vein endothelial cells (HUVECs), although prostaglandin release and/or the expression of PGHS-2 RNA in these cell lines was upregulated by other proinflammatory cytokines. Induction of PGHS-2 RNA in IFN-gamma-treated NHBECs, which peaked at 24 h, suggested the presence of an intermediary substance regulating the expression of PGHS-2. When the binding between the epidermal growth factor (EGF) receptor and its ligands was disrupted by a neutralizing antibody (LA-1), IFN-gamma failed to upregulate the release of PGE2 and the expression of PGHS-2 RNA in NHBECs. Furthermore, IFN-gamma induced the expression of RNAs for a number of ligands at the EGF receptor TGF-alpha; heparin-binding EGF-like growth factor (HB-EGF); and amphiregulin in NHBECs, and when administered exogenously, these ligands increased PGE2 release from NHBECs. Heparin at the concentration that neutralized the function of amphiregulin, or antibodies against TGFalpha or HB-EGF also reduced the release of PGE2 from IFN-gamma-stimulated NHBECs. These data are consistent with the presence of an autocrine growth factor/EGF receptor loop regulating PGHS-2 expression and PGE2 synthesis in bronchial epithelial cells.

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Selected References

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  1. Asano K., Chee C. B., Gaston B., Lilly C. M., Gerard C., Drazen J. M., Stamler J. S. Constitutive and inducible nitric oxide synthase gene expression, regulation, and activity in human lung epithelial cells. Proc Natl Acad Sci U S A. 1994 Oct 11;91(21):10089–10093. doi: 10.1073/pnas.91.21.10089. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Asano K., Lilly C. M., Drazen J. M. Prostaglandin G/H synthase-2 is the constitutive and dominant isoform in cultured human lung epithelial cells. Am J Physiol. 1996 Jul;271(1 Pt 1):L126–L131. doi: 10.1152/ajplung.1996.271.1.L126. [DOI] [PubMed] [Google Scholar]
  3. Bitterman P. B., Wewers M. D., Rennard S. I., Adelberg S., Crystal R. G. Modulation of alveolar macrophage-driven fibroblast proliferation by alternative macrophage mediators. J Clin Invest. 1986 Mar;77(3):700–708. doi: 10.1172/JCI112364. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Braunstein G., Labat C., Brunelleschi S., Benveniste J., Marsac J., Brink C. Evidence that the histamine sensitivity and responsiveness of guinea-pig isolated trachea are modulated by epithelial prostaglandin E2 production. Br J Pharmacol. 1988 Sep;95(1):300–308. doi: 10.1111/j.1476-5381.1988.tb16577.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Crofford L. J., Wilder R. L., Ristimäki A. P., Sano H., Remmers E. F., Epps H. R., Hla T. Cyclooxygenase-1 and -2 expression in rheumatoid synovial tissues. Effects of interleukin-1 beta, phorbol ester, and corticosteroids. J Clin Invest. 1994 Mar;93(3):1095–1101. doi: 10.1172/JCI117060. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. DuBois R. N., Awad J., Morrow J., Roberts L. J., 2nd, Bishop P. R. Regulation of eicosanoid production and mitogenesis in rat intestinal epithelial cells by transforming growth factor-alpha and phorbol ester. J Clin Invest. 1994 Feb;93(2):493–498. doi: 10.1172/JCI116998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Hamasaki Y., Kitzler J., Hardman R., Nettesheim P., Eling T. E. Phorbol ester and epidermal growth factor enhance the expression of two inducible prostaglandin H synthase genes in rat tracheal epithelial cells. Arch Biochem Biophys. 1993 Jul;304(1):226–234. doi: 10.1006/abbi.1993.1343. [DOI] [PubMed] [Google Scholar]
  8. Hamburger A. W., Pinnamaneni G. D. Increased epidermal growth factor receptor gene expression by gamma-interferon in a human breast carcinoma cell line. Br J Cancer. 1991 Jul;64(1):64–68. doi: 10.1038/bjc.1991.240. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Higashiyama S., Abraham J. A., Klagsbrun M. Heparin-binding EGF-like growth factor stimulation of smooth muscle cell migration: dependence on interactions with cell surface heparan sulfate. J Cell Biol. 1993 Aug;122(4):933–940. doi: 10.1083/jcb.122.4.933. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Hu Z. Q., Asano K., Seki H., Shimamura T. An essential role of prostaglandin E on mouse mast cell induction. J Immunol. 1995 Aug 15;155(4):2134–2142. [PubMed] [Google Scholar]
  11. Jackson B. A., Goldstein R. H., Roy R., Cozzani M., Taylor L., Polgar P. Effects of transforming growth factor beta and interleukin-1 beta on expression of cyclooxygenase 1 and 2 and phospholipase A2 mRNA in lung fibroblasts and endothelial cells in culture. Biochem Biophys Res Commun. 1993 Dec 30;197(3):1465–1474. doi: 10.1006/bbrc.1993.2642. [DOI] [PubMed] [Google Scholar]
  12. Jones D. A., Carlton D. P., McIntyre T. M., Zimmerman G. A., Prescott S. M. Molecular cloning of human prostaglandin endoperoxide synthase type II and demonstration of expression in response to cytokines. J Biol Chem. 1993 Apr 25;268(12):9049–9054. [PubMed] [Google Scholar]
  13. Look D. C., Pelletier M. R., Holtzman M. J. Selective interaction of a subset of interferon-gamma response element-binding proteins with the intercellular adhesion molecule-1 (ICAM-1) gene promoter controls the pattern of expression on epithelial cells. J Biol Chem. 1994 Mar 25;269(12):8952–8958. [PubMed] [Google Scholar]
  14. Look D. C., Rapp S. R., Keller B. T., Holtzman M. J. Selective induction of intercellular adhesion molecule-1 by interferon-gamma in human airway epithelial cells. Am J Physiol. 1992 Jul;263(1 Pt 1):L79–L87. doi: 10.1152/ajplung.1992.263.1.L79. [DOI] [PubMed] [Google Scholar]
  15. Madtes D. K., Busby H. K., Strandjord T. P., Clark J. G. Expression of transforming growth factor-alpha and epidermal growth factor receptor is increased following bleomycin-induced lung injury in rats. Am J Respir Cell Mol Biol. 1994 Nov;11(5):540–551. doi: 10.1165/ajrcmb.11.5.7524566. [DOI] [PubMed] [Google Scholar]
  16. Mitchell J. A., Akarasereenont P., Thiemermann C., Flower R. J., Vane J. R. Selectivity of nonsteroidal antiinflammatory drugs as inhibitors of constitutive and inducible cyclooxygenase. Proc Natl Acad Sci U S A. 1993 Dec 15;90(24):11693–11697. doi: 10.1073/pnas.90.24.11693. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Mitchell J. A., Belvisi M. G., Akarasereenont P., Robbins R. A., Kwon O. J., Croxtall J., Barnes P. J., Vane J. R. Induction of cyclo-oxygenase-2 by cytokines in human pulmonary epithelial cells: regulation by dexamethasone. Br J Pharmacol. 1994 Nov;113(3):1008–1014. doi: 10.1111/j.1476-5381.1994.tb17093.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. O'Banion M. K., Winn V. D., Young D. A. cDNA cloning and functional activity of a glucocorticoid-regulated inflammatory cyclooxygenase. Proc Natl Acad Sci U S A. 1992 Jun 1;89(11):4888–4892. doi: 10.1073/pnas.89.11.4888. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Phipps R. P., Stein S. H., Roper R. L. A new view of prostaglandin E regulation of the immune response. Immunol Today. 1991 Oct;12(10):349–352. doi: 10.1016/0167-5699(91)90064-Z. [DOI] [PubMed] [Google Scholar]
  20. Ristimäki A., Garfinkel S., Wessendorf J., Maciag T., Hla T. Induction of cyclooxygenase-2 by interleukin-1 alpha. Evidence for post-transcriptional regulation. J Biol Chem. 1994 Apr 22;269(16):11769–11775. [PubMed] [Google Scholar]
  21. Sirois J., Richards J. S. Transcriptional regulation of the rat prostaglandin endoperoxide synthase 2 gene in granulosa cells. Evidence for the role of a cis-acting C/EBP beta promoter element. J Biol Chem. 1993 Oct 15;268(29):21931–21938. [PubMed] [Google Scholar]
  22. Strassmann G., Patil-Koota V., Finkelman F., Fong M., Kambayashi T. Evidence for the involvement of interleukin 10 in the differential deactivation of murine peritoneal macrophages by prostaglandin E2. J Exp Med. 1994 Dec 1;180(6):2365–2370. doi: 10.1084/jem.180.6.2365. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Tazawa R., Xu X. M., Wu K. K., Wang L. H. Characterization of the genomic structure, chromosomal location and promoter of human prostaglandin H synthase-2 gene. Biochem Biophys Res Commun. 1994 Aug 30;203(1):190–199. doi: 10.1006/bbrc.1994.2167. [DOI] [PubMed] [Google Scholar]
  24. Valyi-Nagy I., Jensen P. J., Albelda S. M., Rodeck U. Cytokine-induced expression of transforming growth factor-alpha and the epidermal growth factor receptor in neonatal skin explants. J Invest Dermatol. 1992 Sep;99(3):350–356. doi: 10.1111/1523-1747.ep12616672. [DOI] [PubMed] [Google Scholar]
  25. Vane J. R., Mitchell J. A., Appleton I., Tomlinson A., Bishop-Bailey D., Croxtall J., Willoughby D. A. Inducible isoforms of cyclooxygenase and nitric-oxide synthase in inflammation. Proc Natl Acad Sci U S A. 1994 Mar 15;91(6):2046–2050. doi: 10.1073/pnas.91.6.2046. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Xie W., Herschman H. R. v-src induces prostaglandin synthase 2 gene expression by activation of the c-Jun N-terminal kinase and the c-Jun transcription factor. J Biol Chem. 1995 Nov 17;270(46):27622–27628. doi: 10.1074/jbc.270.46.27622. [DOI] [PubMed] [Google Scholar]
  27. de Brum-Fernandes A. J., Laporte S., Heroux M., Lora M., Patry C., Ménard H. A., Dumais R., Leduc R. Expression of prostaglandin endoperoxide synthase-1 and prostaglandin endoperoxide synthase-2 in human osteoblasts. Biochem Biophys Res Commun. 1994 Feb 15;198(3):955–960. doi: 10.1006/bbrc.1994.1136. [DOI] [PubMed] [Google Scholar]

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