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. 1995 Feb;84(2):265–271.

TGF-beta and IL-1 beta act in synergy to enhance IL-6 and IL-8 mRNA levels and IL-6 production by human retinal pigment epithelial cells.

M C Kuppner 1, S McKillop-Smith 1, J V Forrester 1
PMCID: PMC1415109  PMID: 7751003

Abstract

Cytokines produced by human retinal pigment epithelial (RPE) cells may function as important regulators of intraocular inflammation. We investigated the effect of transforming growth factor-beta (TGF-beta) on interleukin-1 beta (IL-1 beta) induction of IL-6 and IL-8 mRNA levels and protein production by human RPE cells. Both TGF-beta and IL-1 beta alone induce IL-6 mRNA and IL-6 production in human RPE cells and synergize to enhance IL-6 mRNA levels and IL-6 production over a range of TGF-beta (0.1-10 ng/ml) and IL-1 beta concentrations (5-500 U/ml). TGF-beta was also found to enhance IL-1 beta induction of IL-8 mRNA levels at lower IL-1 beta concentrations (50 U/ml) but had no effect at higher IL-1 beta concentrations (500 U/ml). However, TGF-beta had no synergistic effect on IL-1 beta induction of IL-8 secretion. These results suggest that expression of IL-6 and IL-8 in human RPE cells is regulated by different transcriptional and translational mechanisms, and that RPE cells are important regulators of cytokine production within the ocular microenvironment.

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Selected References

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  1. Akira S., Hirano T., Taga T., Kishimoto T. Biology of multifunctional cytokines: IL 6 and related molecules (IL 1 and TNF). FASEB J. 1990 Aug;4(11):2860–2867. [PubMed] [Google Scholar]
  2. Carter D. B., Deibel M. R., Jr, Dunn C. J., Tomich C. S., Laborde A. L., Slightom J. L., Berger A. E., Bienkowski M. J., Sun F. F., McEwan R. N. Purification, cloning, expression and biological characterization of an interleukin-1 receptor antagonist protein. Nature. 1990 Apr 12;344(6267):633–638. doi: 10.1038/344633a0. [DOI] [PubMed] [Google Scholar]
  3. Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
  4. Cousins S. W., McCabe M. M., Danielpour D., Streilein J. W. Identification of transforming growth factor-beta as an immunosuppressive factor in aqueous humor. Invest Ophthalmol Vis Sci. 1991 Jul;32(8):2201–2211. [PubMed] [Google Scholar]
  5. De Vos A. F., Hoekzema R., Kijlstra A. Cytokines and uveitis, a review. Curr Eye Res. 1992 Jun;11(6):581–597. doi: 10.3109/02713689209001814. [DOI] [PubMed] [Google Scholar]
  6. Elias J. A., Lentz V., Cummings P. J. Transforming growth factor-beta regulation of IL-6 production by unstimulated and IL-1-stimulated human fibroblasts. J Immunol. 1991 May 15;146(10):3437–3443. [PubMed] [Google Scholar]
  7. Elner V. M., Strieter R. M., Elner S. G., Baggiolini M., Lindley I., Kunkel S. L. Neutrophil chemotactic factor (IL-8) gene expression by cytokine-treated retinal pigment epithelial cells. Am J Pathol. 1990 Apr;136(4):745–750. [PMC free article] [PubMed] [Google Scholar]
  8. Ferrick M. R., Thurau S. R., Oppenheim M. H., Herbort C. P., Ni M., Zachariae C. O., Matsushima K., Chan C. C. Ocular inflammation stimulated by intravitreal interleukin-8 and interleukin-1. Invest Ophthalmol Vis Sci. 1991 Apr;32(5):1534–1539. [PubMed] [Google Scholar]
  9. Flood M. T., Gouras P., Kjeldbye H. Growth characteristics and ultrastructure of human retinal pigment epithelium in vitro. Invest Ophthalmol Vis Sci. 1980 Nov;19(11):1309–1320. [PubMed] [Google Scholar]
  10. Hoekzema R., Murray P. I., Kijlstra A. Cytokines and intraocular inflammation. Curr Eye Res. 1990;9 (Suppl):207–211. doi: 10.3109/02713689008999443. [DOI] [PubMed] [Google Scholar]
  11. Hoekzema R., Murray P. I., van Haren M. A., Helle M., Kijlstra A. Analysis of interleukin-6 in endotoxin-induced uveitis. Invest Ophthalmol Vis Sci. 1991 Jan;32(1):88–95. [PubMed] [Google Scholar]
  12. Jaffe G. J., Van Le L., Valea F., Haskill S., Roberts W., Arend W. P., Stuart A., Peters W. P. Expression of interleukin-1 alpha, interleukin-1 beta, and an interleukin-1 receptor antagonist in human retinal pigment epithelial cells. Exp Eye Res. 1992 Aug;55(2):325–335. doi: 10.1016/0014-4835(92)90197-z. [DOI] [PubMed] [Google Scholar]
  13. Kopf M., Baumann H., Freer G., Freudenberg M., Lamers M., Kishimoto T., Zinkernagel R., Bluethmann H., Köhler G. Impaired immune and acute-phase responses in interleukin-6-deficient mice. Nature. 1994 Mar 24;368(6469):339–342. doi: 10.1038/368339a0. [DOI] [PubMed] [Google Scholar]
  14. Larsen C. G., Anderson A. O., Appella E., Oppenheim J. J., Matsushima K. The neutrophil-activating protein (NAP-1) is also chemotactic for T lymphocytes. Science. 1989 Mar 17;243(4897):1464–1466. doi: 10.1126/science.2648569. [DOI] [PubMed] [Google Scholar]
  15. McGee D. W., Beagley K. W., Aicher W. K., McGhee J. R. Transforming growth factor-beta and IL-1 beta act in synergy to enhance IL-6 secretion by the intestinal epithelial cell line, IEC-6. J Immunol. 1993 Jul 15;151(2):970–978. [PubMed] [Google Scholar]
  16. Musso T., Espinoza-Delgado I., Pulkki K., Gusella G. L., Longo D. L., Varesio L. Transforming growth factor beta downregulates interleukin-1 (IL-1)-induced IL-6 production by human monocytes. Blood. 1990 Dec 15;76(12):2466–2469. [PubMed] [Google Scholar]
  17. Planck S. R., Dang T. T., Graves D., Tara D., Ansel J. C., Rosenbaum J. T. Retinal pigment epithelial cells secrete interleukin-6 in response to interleukin-1. Invest Ophthalmol Vis Sci. 1992 Jan;33(1):78–82. [PubMed] [Google Scholar]
  18. Roberge F. G., Caspi R. R., Nussenblatt R. B. Glial retinal Müller cells produce IL-1 activity and have a dual effect on autoimmune T helper lymphocytes. Antigen presentation manifested after removal of suppressive activity. J Immunol. 1988 Apr 1;140(7):2193–2196. [PubMed] [Google Scholar]
  19. Rosenbaum J. T., Boney R. S. Activity of an interleukin 1 receptor antagonist in rabbit models of uveitis. Arch Ophthalmol. 1992 Apr;110(4):547–549. doi: 10.1001/archopht.1992.01080160125049. [DOI] [PubMed] [Google Scholar]
  20. Sutherland G. R., Baker E., Callen D. F., Hyland V. J., Wong G., Clark S., Jones S. S., Eglinton L. K., Shannon M. F., Lopez A. F. Interleukin 4 is at 5q31 and interleukin 6 is at 7p15. Hum Genet. 1988 Aug;79(4):335–337. doi: 10.1007/BF00282171. [DOI] [PubMed] [Google Scholar]
  21. Wahl S. M., Costa G. L., Corcoran M., Wahl L. M., Berger A. E. Transforming growth factor-beta mediates IL-1-dependent induction of IL-1 receptor antagonist. J Immunol. 1993 Apr 15;150(8 Pt 1):3553–3560. [PubMed] [Google Scholar]
  22. Wahl S. M., McCartney-Francis N., Mergenhagen S. E. Inflammatory and immunomodulatory roles of TGF-beta. Immunol Today. 1989 Aug;10(8):258–261. doi: 10.1016/0167-5699(89)90136-9. [DOI] [PubMed] [Google Scholar]
  23. Yasumoto K., Okamoto S., Mukaida N., Murakami S., Mai M., Matsushima K. Tumor necrosis factor alpha and interferon gamma synergistically induce interleukin 8 production in a human gastric cancer cell line through acting concurrently on AP-1 and NF-kB-like binding sites of the interleukin 8 gene. J Biol Chem. 1992 Nov 5;267(31):22506–22511. [PubMed] [Google Scholar]
  24. Zhou D., Munster A., Winchurch R. A. Pathologic concentrations of interleukin 6 inhibit T cell responses via induction of activation of TGF-beta. FASEB J. 1991 Aug;5(11):2582–2585. doi: 10.1096/fasebj.5.11.1868982. [DOI] [PubMed] [Google Scholar]
  25. 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]
  26. de Boer J. H., van Haren M. A., de Vries-Knoppert W. A., Baarsma G. S., de Jong P. V., Postema F. J., Rademakers A. J., Kijlstra A. Analysis of IL-6 levels in human vitreous fluid obtained from uveitis patients, patients with proliferative intraocular disorders and eye bank eyes. Curr Eye Res. 1992;11 (Suppl):181–186. doi: 10.3109/02713689208999530. [DOI] [PubMed] [Google Scholar]

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