Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1998 Mar 15;101(6):1462–1467. doi: 10.1172/JCI1031

Keratinocyte gene therapy for systemic diseases. Circulating interleukin 10 released from gene-transferred keratinocytes inhibits contact hypersensitivity at distant areas of the skin.

X Meng 1, D Sawamura 1, K Tamai 1, K Hanada 1, H Ishida 1, I Hashimoto 1
PMCID: PMC508702  PMID: 9502789

Abstract

This study has examined the systemic effects of a circulating gene product, human interleukin 10 (IL-10), released from transduced keratinocytes. IL-10 is an anti-inflammatory cytokine which has an inhibitory effect on contact hypersensitivity (CHS). An expression vector (phIL-10) was constructed for human IL-10 and was injected into the dorsal skin of hairless rats. Local expression of IL-10 mRNA and protein was detected by reverse-transcriptase polymerase chain reaction and immunohistochemical staining, respectively. Enzyme-linked immunosorbent assay showed that the amount of IL-10 in the local keratinocytes and in the circulation increased with the dose of phIL-10 transferred. To determine whether circulating IL-10 could inhibit the effector phase of CHS at a distant area of the skin, various doses of phIL-10 were injected into the dorsal skin of sensitized rats before challenge on the ears. Our results showed that the degree of swelling of the ears of phIL-10- treated rats was significantly lower than that in the negative control animals. These results suggest that IL-10 released from transduced keratinocytes can enter the bloodstream and cause biological effects at distant areas of the skin. This study demonstrates that it may be possible to treat systemic disease using keratinocyte gene therapy.

Full Text

The Full Text of this article is available as a PDF (234.9 KB).

Selected References

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

  1. Berg D. J., Leach M. W., Kühn R., Rajewsky K., Müller W., Davidson N. J., Rennick D. Interleukin 10 but not interleukin 4 is a natural suppressant of cutaneous inflammatory responses. J Exp Med. 1995 Jul 1;182(1):99–108. doi: 10.1084/jem.182.1.99. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Cheng L., Ziegelhoffer P. R., Yang N. S. In vivo promoter activity and transgene expression in mammalian somatic tissues evaluated by using particle bombardment. Proc Natl Acad Sci U S A. 1993 May 15;90(10):4455–4459. doi: 10.1073/pnas.90.10.4455. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Enk A. H., Katz S. I. Identification and induction of keratinocyte-derived IL-10. J Immunol. 1992 Jul 1;149(1):92–95. [PubMed] [Google Scholar]
  4. Fenjves E. S. Approaches to gene transfer in keratinocytes. J Invest Dermatol. 1994 Nov;103(5 Suppl):70S–75S. doi: 10.1111/1523-1747.ep12399089. [DOI] [PubMed] [Google Scholar]
  5. Fenjves E. S., Gordon D. A., Pershing L. K., Williams D. L., Taichman L. B. Systemic distribution of apolipoprotein E secreted by grafts of epidermal keratinocytes: implications for epidermal function and gene therapy. Proc Natl Acad Sci U S A. 1989 Nov;86(22):8803–8807. doi: 10.1073/pnas.86.22.8803. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Ferguson T. A., Dube P., Griffith T. S. Regulation of contact hypersensitivity by interleukin 10. J Exp Med. 1994 May 1;179(5):1597–1604. doi: 10.1084/jem.179.5.1597. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Gerrard A. J., Hudson D. L., Brownlee G. G., Watt F. M. Towards gene therapy for haemophilia B using primary human keratinocytes. Nat Genet. 1993 Feb;3(2):180–183. doi: 10.1038/ng0293-180. [DOI] [PubMed] [Google Scholar]
  8. Greenhalgh D. A., Rothnagel J. A., Roop D. R. Epidermis: an attractive target tissue for gene therapy. J Invest Dermatol. 1994 Nov;103(5 Suppl):63S–69S. doi: 10.1111/1523-1747.ep12399070. [DOI] [PubMed] [Google Scholar]
  9. Grewe M., Gyufko K., Krutmann J. Interleukin-10 production by cultured human keratinocytes: regulation by ultraviolet B and ultraviolet A1 radiation. J Invest Dermatol. 1995 Jan;104(1):3–6. doi: 10.1111/1523-1747.ep12613446. [DOI] [PubMed] [Google Scholar]
  10. Hanada K., Chiyoya S., Suzuki K., Hashimoto I., Hatayama I. Study of the skin of a new hairless rat mutant. J Dermatol. 1988 Jun;15(3):257–262. doi: 10.1111/j.1346-8138.1988.tb03687.x. [DOI] [PubMed] [Google Scholar]
  11. Hengge U. R., Chan E. F., Foster R. A., Walker P. S., Vogel J. C. Cytokine gene expression in epidermis with biological effects following injection of naked DNA. Nat Genet. 1995 Jun;10(2):161–166. doi: 10.1038/ng0695-161. [DOI] [PubMed] [Google Scholar]
  12. Hengge U. R., Walker P. S., Vogel J. C. Expression of naked DNA in human, pig, and mouse skin. J Clin Invest. 1996 Jun 15;97(12):2911–2916. doi: 10.1172/JCI118750. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Kitabayashi A., Hirokawa M., Miura A. B. The role of interleukin-10 (IL-10) in chronic B-lymphocytic leukemia: IL-10 prevents leukemic cells from apoptotic cell death. Int J Hematol. 1995 Aug;62(2):99–106. doi: 10.1016/0925-5710(95)00395-9. [DOI] [PubMed] [Google Scholar]
  14. Kondo S., McKenzie R. C., Sauder D. N. Interleukin-10 inhibits the elicitation phase of allergic contact hypersensitivity. J Invest Dermatol. 1994 Dec;103(6):811–814. doi: 10.1111/1523-1747.ep12413470. [DOI] [PubMed] [Google Scholar]
  15. Li L., Elliott J. F., Mosmann T. R. IL-10 inhibits cytokine production, vascular leakage, and swelling during T helper 1 cell-induced delayed-type hypersensitivity. J Immunol. 1994 Nov 1;153(9):3967–3978. [PubMed] [Google Scholar]
  16. Moritani M., Yoshimoto K., Ii S., Kondo M., Iwahana H., Yamaoka T., Sano T., Nakano N., Kikutani H., Itakura M. Prevention of adoptively transferred diabetes in nonobese diabetic mice with IL-10-transduced islet-specific Th1 lymphocytes. A gene therapy model for autoimmune diabetes. J Clin Invest. 1996 Oct 15;98(8):1851–1859. doi: 10.1172/JCI118986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Nonoyama S., Farrington M., Ishida H., Howard M., Ochs H. D. Activated B cells from patients with common variable immunodeficiency proliferate and synthesize immunoglobulin. J Clin Invest. 1993 Sep;92(3):1282–1287. doi: 10.1172/JCI116701. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Sawamura D., Meng X., Ina S., Ishikawa H., Tamai K., Nomura K., Hanada K., Hashimoto I., Kaneda Y. In vivo transfer of a foreign gene to keratinocytes using the hemagglutinating virus of Japan-liposome method. J Invest Dermatol. 1997 Feb;108(2):195–199. doi: 10.1111/1523-1747.ep12334229. [DOI] [PubMed] [Google Scholar]
  19. Schwarz A., Grabbe S., Riemann H., Aragane Y., Simon M., Manon S., Andrade S., Luger T. A., Zlotnik A., Schwarz T. In vivo effects of interleukin-10 on contact hypersensitivity and delayed-type hypersensitivity reactions. J Invest Dermatol. 1994 Aug;103(2):211–216. doi: 10.1111/1523-1747.ep12393073. [DOI] [PubMed] [Google Scholar]
  20. Setoguchi Y., Jaffe H. A., Danel C., Crystal R. G. Ex vivo and in vivo gene transfer to the skin using replication-deficient recombinant adenovirus vectors. J Invest Dermatol. 1994 Apr;102(4):415–421. doi: 10.1111/1523-1747.ep12372181. [DOI] [PubMed] [Google Scholar]
  21. Sun W. H., Burkholder J. K., Sun J., Culp J., Turner J., Lu X. G., Pugh T. D., Ershler W. B., Yang N. S. In vivo cytokine gene transfer by gene gun reduces tumor growth in mice. Proc Natl Acad Sci U S A. 1995 Mar 28;92(7):2889–2893. doi: 10.1073/pnas.92.7.2889. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Teumer J., Lindahl A., Green H. Human growth hormone in the blood of athymic mice grafted with cultures of hormone-secreting human keratinocytes. FASEB J. 1990 Nov;4(14):3245–3250. doi: 10.1096/fasebj.4.14.2227214. [DOI] [PubMed] [Google Scholar]
  23. Tripathy S. K., Goldwasser E., Lu M. M., Barr E., Leiden J. M. Stable delivery of physiologic levels of recombinant erythropoietin to the systemic circulation by intramuscular injection of replication-defective adenovirus. Proc Natl Acad Sci U S A. 1994 Nov 22;91(24):11557–11561. doi: 10.1073/pnas.91.24.11557. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Tripathy S. K., Svensson E. C., Black H. B., Goldwasser E., Margalith M., Hobart P. M., Leiden J. M. Long-term expression of erythropoietin in the systemic circulation of mice after intramuscular injection of a plasmid DNA vector. Proc Natl Acad Sci U S A. 1996 Oct 1;93(20):10876–10880. doi: 10.1073/pnas.93.20.10876. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Vieira P., de Waal-Malefyt R., Dang M. N., Johnson K. E., Kastelein R., Fiorentino D. F., deVries J. E., Roncarolo M. G., Mosmann T. R., Moore K. W. Isolation and expression of human cytokine synthesis inhibitory factor cDNA clones: homology to Epstein-Barr virus open reading frame BCRFI. Proc Natl Acad Sci U S A. 1991 Feb 15;88(4):1172–1176. doi: 10.1073/pnas.88.4.1172. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Vogel J. C. Keratinocyte gene therapy. Arch Dermatol. 1993 Nov;129(11):1478–1483. [PubMed] [Google Scholar]
  27. Wanidworanun C., Strober W. Predominant role of tumor necrosis factor-alpha in human monocyte IL-10 synthesis. J Immunol. 1993 Dec 15;151(12):6853–6861. [PubMed] [Google Scholar]
  28. Wolff J. A., Ludtke J. J., Acsadi G., Williams P., Jani A. Long-term persistence of plasmid DNA and foreign gene expression in mouse muscle. Hum Mol Genet. 1992 Sep;1(6):363–369. doi: 10.1093/hmg/1.6.363. [DOI] [PubMed] [Google Scholar]
  29. Wolff J. A., Malone R. W., Williams P., Chong W., Acsadi G., Jani A., Felgner P. L. Direct gene transfer into mouse muscle in vivo. Science. 1990 Mar 23;247(4949 Pt 1):1465–1468. doi: 10.1126/science.1690918. [DOI] [PubMed] [Google Scholar]
  30. Zheng L. M., Ojcius D. M., Garaud F., Roth C., Maxwell E., Li Z., Rong H., Chen J., Wang X. Y., Catino J. J. Interleukin-10 inhibits tumor metastasis through an NK cell-dependent mechanism. J Exp Med. 1996 Aug 1;184(2):579–584. doi: 10.1084/jem.184.2.579. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES