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. 1992 Aug;90(2):571–583. doi: 10.1172/JCI115896

Interleukin-1 receptor antagonist in normal and psoriatic epidermis.

C Hammerberg 1, W P Arend 1, G J Fisher 1, L S Chan 1, A E Berger 1, J S Haskill 1, J J Voorhees 1, K D Cooper 1
PMCID: PMC443136  PMID: 1386612

Abstract

The objective of these studies was to characterize the IL-1 inhibitory activity present in normal and psoriatic epidermis from clinically stable lesions. Fractionation of normal epidermal cytosol on a molecular sizing column failed to reveal the presence of IL-1 inhibitory bioactivity. However, specific ELISAs indicated that both the IL-1 receptor antagonist (IL-1ra) and IL-1 alpha were present in overlapping peaks. Further fractionation of the normal epidermal cytosol by anion exchange chromatography separated these two molecules, revealing the IL-1 inhibitory bioactivity of the IL-1ra molecule. Similar studies on psoriatic epidermal cytosol indicated the presence of IL-1 inhibitory bioactivity and IL-1ra protein. The IL-1 inhibitory bioactivity of both normal and psoriatic cytosol was neutralized by a mAb specific for IL-1ra. The ratio of IL-1ra to IL-1 alpha proteins was significantly increased in involved psoriatic skin compared with normal skin. By Western blot analysis this IL-1ra was approximately 20 kD, slightly larger than monocyte-derived IL-1ra and equivalent to an intracellular variant of IL-1ra expressed by keratinocytes. Polymerase chain reaction indicated the presence of mRNA for both forms of IL-1ra in normal epidermis, with both forms increased in psoriatic-involved skin. Immunofluorescence studies revealed the IL-1ra protein to be concentrated in the stratum granulosum of normal skin and in the basal-midbasal layers of psoriatic epidermis. These results suggest that the balance between intracellular IL-1ra and IL-1 alpha may be an important influence on keratinocyte growth and/or differentiation, as well as on the inflammatory potential of IL-1 in injured skin.

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Selected References

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  1. Ansel J. C., Luger T. A., Green I. The effect of in vitro and in vivo UV irradiation on the production of ETAF activity by human and murine keratinocytes. J Invest Dermatol. 1983 Dec;81(6):519–523. doi: 10.1111/1523-1747.ep12522862. [DOI] [PubMed] [Google Scholar]
  2. Anttila H. S., Reitamo S., Erkko P., Miettinen A., Didierjean L., Saurat J. H. Membrane and cytosolic interleukin-1 alpha and beta in normal human epidermal cells: variability of epitope exposure in immunohistochemistry. J Invest Dermatol. 1990 Jul;95(1):31–38. doi: 10.1111/1523-1747.ep12873278. [DOI] [PubMed] [Google Scholar]
  3. Araneo B. A., Dowell T., Moon H. B., Daynes R. A. Regulation of murine lymphokine production in vivo. Ultraviolet radiation exposure depresses IL-2 and enhances IL-4 production by T cells through an IL-1-dependent mechanism. J Immunol. 1989 Sep 15;143(6):1737–1744. [PubMed] [Google Scholar]
  4. Arend W. P., Welgus H. G., Thompson R. C., Eisenberg S. P. Biological properties of recombinant human monocyte-derived interleukin 1 receptor antagonist. J Clin Invest. 1990 May;85(5):1694–1697. doi: 10.1172/JCI114622. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Baadsgaard O., Gupta A. K., Taylor R. S., Ellis C. N., Voorhees J. J., Cooper K. D. Psoriatic epidermal cells demonstrate increased numbers and function of non-Langerhans antigen-presenting cells. J Invest Dermatol. 1989 Feb;92(2):190–195. doi: 10.1111/1523-1747.ep12276718. [DOI] [PubMed] [Google Scholar]
  6. Baadsgaard O., Tong P., Elder J. T., Hansen E. R., Ho V., Hammerberg C., Lange-Vejlsgaard G., Fox D. A., Fisher G., Chan L. S. UM4D4+ (CDw60) T cells are compartmentalized into psoriatic skin and release lymphokines that induce a keratinocyte phenotype expressed in psoriatic lesions. J Invest Dermatol. 1990 Sep;95(3):275–282. doi: 10.1111/1523-1747.ep12484908. [DOI] [PubMed] [Google Scholar]
  7. Baker B. S., Swain A. F., Fry L., Valdimarsson H. Epidermal T lymphocytes and HLA-DR expression in psoriasis. Br J Dermatol. 1984 May;110(5):555–564. doi: 10.1111/j.1365-2133.1984.tb04678.x. [DOI] [PubMed] [Google Scholar]
  8. Bernard B. A., Asselineau D., Schaffar-Deshayes L., Darmon M. Y. Abnormal sequence of expression of differentiation markers in psoriatic epidermis: inversion of two steps in the differentiation program? J Invest Dermatol. 1988 Jun;90(6):801–805. doi: 10.1111/1523-1747.ep12462014. [DOI] [PubMed] [Google Scholar]
  9. Bernard B. A., Reano A., Darmon Y. M., Thivolet J. Precocious appearance of involucrin and epidermal transglutaminase during differentiation of psoriatic skin. Br J Dermatol. 1986 Mar;114(3):279–283. doi: 10.1111/j.1365-2133.1986.tb02818.x. [DOI] [PubMed] [Google Scholar]
  10. Bernard B. A., Robinson S. M., Vandaele S., Mansbridge J. N., Darmon M. Abnormal maturation pathway of keratinocytes in psoriatic skin. Br J Dermatol. 1985 Jun;112(6):647–653. doi: 10.1111/j.1365-2133.1985.tb02332.x. [DOI] [PubMed] [Google Scholar]
  11. Bigler C. F., Norris D. A., Weston W. L., Arend W. P. Interleukin-1 receptor antagonist production by human keratinocytes. J Invest Dermatol. 1992 Jan;98(1):38–44. doi: 10.1111/1523-1747.ep12494196. [DOI] [PubMed] [Google Scholar]
  12. Braverman I. M., Sibley J. Role of the microcirculation in the treatment and pathogenesis of psoriasis. J Invest Dermatol. 1982 Jan;78(1):12–17. doi: 10.1111/1523-1747.ep12497850. [DOI] [PubMed] [Google Scholar]
  13. 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]
  14. Chan L. S., Hammerberg C., Cooper K. D. Cicatricial pemphigoid. Identification of two distinct sets of epidermal antigens by IgA and IgG class circulating autoantibodies. Arch Dermatol. 1990 Nov;126(11):1466–1468. doi: 10.1001/archderm.126.11.1466. [DOI] [PubMed] [Google Scholar]
  15. Cooper K. D., Baadsgaard O., Ellis C. N., Duell E., Voorhees J. J. Mechanisms of cyclosporine A inhibition of antigen-presenting activity in uninvolved and lesional psoriatic epidermis. J Invest Dermatol. 1990 May;94(5):649–656. doi: 10.1111/1523-1747.ep12876222. [DOI] [PubMed] [Google Scholar]
  16. Cooper K. D., Hammerberg C., Baadsgaard O., Elder J. T., Chan L. S., Sauder D. N., Voorhees J. J., Fisher G. IL-1 activity is reduced in psoriatic skin. Decreased IL-1 alpha and increased nonfunctional IL-1 beta. J Immunol. 1990 Jun 15;144(12):4593–4603. [PubMed] [Google Scholar]
  17. Dasch J. R., Pace D. R., Waegell W., Inenaga D., Ellingsworth L. Monoclonal antibodies recognizing transforming growth factor-beta. Bioactivity neutralization and transforming growth factor beta 2 affinity purification. J Immunol. 1989 Mar 1;142(5):1536–1541. [PubMed] [Google Scholar]
  18. Dayer J. M., de Rochemonteix B., Burrus B., Demczuk S., Dinarello C. A. Human recombinant interleukin 1 stimulates collagenase and prostaglandin E2 production by human synovial cells. J Clin Invest. 1986 Feb;77(2):645–648. doi: 10.1172/JCI112350. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Didierjean L., Salomon D., Mérot Y., Siegenthaler G., Shaw A., Dayer J. M., Saurat J. H. Localization and characterization of the interleukin 1 immunoreactive pool (IL-1 alpha and beta forms) in normal human epidermis. J Invest Dermatol. 1989 Jun;92(6):809–816. doi: 10.1111/1523-1747.ep12696825. [DOI] [PubMed] [Google Scholar]
  20. Dinarello C. A. Interleukin-1 and its biologically related cytokines. Adv Immunol. 1989;44:153–205. doi: 10.1016/s0065-2776(08)60642-2. [DOI] [PubMed] [Google Scholar]
  21. Dover R., Watt F. M. Measurement of the rate of epidermal terminal differentiation: expression of involucrin by S-phase keratinocytes in culture and in psoriatic plaques. J Invest Dermatol. 1987 Oct;89(4):349–352. doi: 10.1111/1523-1747.ep12471751. [DOI] [PubMed] [Google Scholar]
  22. Dowd P. M., Camp R. D., Greaves M. W. Human recombinant interleukin-1 alpha is proinflammatory in normal human skin. Skin Pharmacol. 1988;1(1):30–37. doi: 10.1159/000210749. [DOI] [PubMed] [Google Scholar]
  23. Dripps D. J., Verderber E., Ng R. K., Thompson R. C., Eisenberg S. P. Interleukin-1 receptor antagonist binds to the type II interleukin-1 receptor on B cells and neutrophils. J Biol Chem. 1991 Oct 25;266(30):20311–20315. [PubMed] [Google Scholar]
  24. Eisenberg S. P., Evans R. J., Arend W. P., Verderber E., Brewer M. T., Hannum C. H., Thompson R. C. Primary structure and functional expression from complementary DNA of a human interleukin-1 receptor antagonist. Nature. 1990 Jan 25;343(6256):341–346. doi: 10.1038/343341a0. [DOI] [PubMed] [Google Scholar]
  25. Elder J. T., Fisher G. J., Lindquist P. B., Bennett G. L., Pittelkow M. R., Coffey R. J., Jr, Ellingsworth L., Derynck R., Voorhees J. J. Overexpression of transforming growth factor alpha in psoriatic epidermis. Science. 1989 Feb 10;243(4892):811–814. doi: 10.1126/science.2916128. [DOI] [PubMed] [Google Scholar]
  26. Ellis C. N., Fradin M. S., Messana J. M., Brown M. D., Siegel M. T., Hartley A. H., Rocher L. L., Wheeler S., Hamilton T. A., Parish T. G. Cyclosporine for plaque-type psoriasis. Results of a multidose, double-blind trial. N Engl J Med. 1991 Jan 31;324(5):277–284. doi: 10.1056/NEJM199101313240501. [DOI] [PubMed] [Google Scholar]
  27. Ellis C. N., Gorsulowsky D. C., Hamilton T. A., Billings J. K., Brown M. D., Headington J. T., Cooper K. D., Baadsgaard O., Duell E. A., Annesley T. M. Cyclosporine improves psoriasis in a double-blind study. JAMA. 1986 Dec 12;256(22):3110–3116. [PubMed] [Google Scholar]
  28. Esmann J., Voorhees J. J., Fisher G. J. Increased membrane-associated transglutaminase activity in psoriasis. Biochem Biophys Res Commun. 1989 Oct 16;164(1):219–224. doi: 10.1016/0006-291x(89)91705-1. [DOI] [PubMed] [Google Scholar]
  29. Gahring L. C., Buckley A., Daynes R. A. Presence of epidermal-derived thymocyte activating factor/interleukin 1 in normal human stratum corneum. J Clin Invest. 1985 Oct;76(4):1585–1591. doi: 10.1172/JCI112141. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Gottlieb A. B., Luster A. D., Posnett D. N., Carter D. M. Detection of a gamma interferon-induced protein IP-10 in psoriatic plaques. J Exp Med. 1988 Sep 1;168(3):941–948. doi: 10.1084/jem.168.3.941. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Granowitz E. V., Clark B. D., Mancilla J., Dinarello C. A. Interleukin-1 receptor antagonist competitively inhibits the binding of interleukin-1 to the type II interleukin-1 receptor. J Biol Chem. 1991 Aug 5;266(22):14147–14150. [PubMed] [Google Scholar]
  32. Granstein R. D., Sauder D. N. Whole-body exposure to ultraviolet radiation results in increased serum interleukin-1 activity in humans. Lymphokine Res. 1987 Summer;6(3):187–193. [PubMed] [Google Scholar]
  33. Grenfell S., Smithers N., Miller K., Solari R. Receptor-mediated endocytosis and nuclear transport of human interleukin 1 alpha. Biochem J. 1989 Dec 15;264(3):813–822. doi: 10.1042/bj2640813. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Grossman R. M., Krueger J., Yourish D., Granelli-Piperno A., Murphy D. P., May L. T., Kupper T. S., Sehgal P. B., Gottlieb A. B. Interleukin 6 is expressed in high levels in psoriatic skin and stimulates proliferation of cultured human keratinocytes. Proc Natl Acad Sci U S A. 1989 Aug;86(16):6367–6371. doi: 10.1073/pnas.86.16.6367. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Gupta A. K., Baadsgaard O., Ellis C. N., Voorhees J. J., Cooper K. D. Lymphocytes and macrophages of the epidermis and dermis in lesional psoriatic skin, but not epidermal Langerhans cells, are depleted by treatment with cyclosporin A. Arch Dermatol Res. 1989;281(4):219–226. doi: 10.1007/BF00431054. [DOI] [PubMed] [Google Scholar]
  36. Hammarström S., Hamberg M., Samuelsson B., Duell E. A., Stawiski M., Voorhees J. J. Increased concentrations of nonesterified arachidonic acid, 12L-hydroxy-5,8,10,14-eicosatetraenoic acid, prostaglandin E2, and prostaglandin F2alpha in epidermis of psoriasis. Proc Natl Acad Sci U S A. 1975 Dec;72(12):5130–5134. doi: 10.1073/pnas.72.12.5130. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Hannum C. H., Wilcox C. J., Arend W. P., Joslin F. G., Dripps D. J., Heimdal P. L., Armes L. G., Sommer A., Eisenberg S. P., Thompson R. C. Interleukin-1 receptor antagonist activity of a human interleukin-1 inhibitor. Nature. 1990 Jan 25;343(6256):336–340. doi: 10.1038/343336a0. [DOI] [PubMed] [Google Scholar]
  38. Haskill S., Martin G., Van Le L., Morris J., Peace A., Bigler C. F., Jaffe G. J., Hammerberg C., Sporn S. A., Fong S. cDNA cloning of an intracellular form of the human interleukin 1 receptor antagonist associated with epithelium. Proc Natl Acad Sci U S A. 1991 May 1;88(9):3681–3685. doi: 10.1073/pnas.88.9.3681. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Hauser C., Saurat J. H., Schmitt A., Jaunin F., Dayer J. M. Interleukin 1 is present in normal human epidermis. J Immunol. 1986 May 1;136(9):3317–3323. [PubMed] [Google Scholar]
  40. Kim N. I., Cooper K. D., Fisher G. J., Baadsgaard O., Voorhees J. J., Hammerberg C. Psoriatic skin reveals the in vivo presence of an epidermal IL-1 inhibitor. Arch Dermatol Res. 1992;284(2):71–76. doi: 10.1007/BF00373372. [DOI] [PubMed] [Google Scholar]
  41. Krueger J. G., Krane J. F., Carter D. M., Gottlieb A. B. Role of growth factors, cytokines, and their receptors in the pathogenesis of psoriasis. J Invest Dermatol. 1990 Jun;94(6 Suppl):135S–140S. doi: 10.1111/1523-1747.ep12876121. [DOI] [PubMed] [Google Scholar]
  42. Kupper T. S., Chua A. O., Flood P., McGuire J., Gubler U. Interleukin 1 gene expression in cultured human keratinocytes is augmented by ultraviolet irradiation. J Clin Invest. 1987 Aug;80(2):430–436. doi: 10.1172/JCI113090. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Kupper T. S., McGuire J. Hydrocortisone reduces both constitutive and UV-elicited release of epidermal thymocyte activating factor (ETAF) by cultured keratinocytes. J Invest Dermatol. 1986 Nov;87(5):570–573. doi: 10.1111/1523-1747.ep12455811. [DOI] [PubMed] [Google Scholar]
  44. Leeuwenberg J. F., von Asmuth E. J., Jeunhomme T. M., Buurman W. A. IFN-gamma regulates the expression of the adhesion molecule ELAM-1 and IL-6 production by human endothelial cells in vitro. J Immunol. 1990 Oct 1;145(7):2110–2114. [PubMed] [Google Scholar]
  45. Luger T. A., Stadler B. M., Katz S. I., Oppenheim J. J. Epidermal cell (keratinocyte)-derived thymocyte-activating factor (ETAF). J Immunol. 1981 Oct;127(4):1493–1498. [PubMed] [Google Scholar]
  46. Malyak M., Joslin F. G., Verderber E. L., Eisenberg S. P., Arend W. P. IL-1ra ELISA: reduction and alkylation of synovial fluid eliminates interference by IgM rheumatoid factors. J Immunol Methods. 1991 Jul 5;140(2):281–288. doi: 10.1016/0022-1759(91)90381-o. [DOI] [PubMed] [Google Scholar]
  47. Mizutani H., Black R., Kupper T. S. Human keratinocytes produce but do not process pro-interleukin-1 (IL-1) beta. Different strategies of IL-1 production and processing in monocytes and keratinocytes. J Clin Invest. 1991 Mar;87(3):1066–1071. doi: 10.1172/JCI115067. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Morganroth G. S., Chan L. S., Weinstein G. D., Voorhees J. J., Cooper K. D. Proliferating cells in psoriatic dermis are comprised primarily of T cells, endothelial cells, and factor XIIIa+ perivascular dendritic cells. J Invest Dermatol. 1991 Mar;96(3):333–340. doi: 10.1111/1523-1747.ep12465237. [DOI] [PubMed] [Google Scholar]
  49. Morhenn V. B., Wastek G. J., Cua A. B., Mansbridge J. N. Effects of recombinant interleukin 1 and interleukin 2 on human keratinocytes. J Invest Dermatol. 1989 Jul;93(1):121–126. doi: 10.1111/1523-1747.ep12277378. [DOI] [PubMed] [Google Scholar]
  50. Murphy G. M., Dowd P. M., Hudspith B. N., Brostoff J., Greaves M. W. Local increase in interleukin-1-like activity following UVB irradiation of human skin in vivo. Photodermatol. 1989 Dec;6(6):268–274. [PubMed] [Google Scholar]
  51. Pober J. S., Bevilacqua M. P., Mendrick D. L., Lapierre L. A., Fiers W., Gimbrone M. A., Jr Two distinct monokines, interleukin 1 and tumor necrosis factor, each independently induce biosynthesis and transient expression of the same antigen on the surface of cultured human vascular endothelial cells. J Immunol. 1986 Mar 1;136(5):1680–1687. [PubMed] [Google Scholar]
  52. Reitamo S., Anttila H. S., Didierjean L., Saurat J. H. Immunohistochemical identification of interleukin I alpha and beta in human eccrine sweat-gland apparatus. Br J Dermatol. 1990 Mar;122(3):315–323. doi: 10.1111/j.1365-2133.1990.tb08279.x. [DOI] [PubMed] [Google Scholar]
  53. Ristow H. J. A major factor contributing to epidermal proliferation in inflammatory skin diseases appears to be interleukin 1 or a related protein. Proc Natl Acad Sci U S A. 1987 Apr;84(7):1940–1944. doi: 10.1073/pnas.84.7.1940. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Ristow H. J. Interleukin-1 does not stimulate DNA synthesis of cultured human keratinocytes growth-arrested in growth-factor-depleted medium. J Invest Dermatol. 1990 Dec;95(6):688–692. doi: 10.1111/1523-1747.ep12514351. [DOI] [PubMed] [Google Scholar]
  55. Sackstein R., Falanga V., Streilein J. W., Chin Y. H. Lymphocyte adhesion to psoriatic dermal endothelium is mediated by a tissue-specific receptor/ligand interaction. J Invest Dermatol. 1988 Nov;91(5):423–428. doi: 10.1111/1523-1747.ep12476441. [DOI] [PubMed] [Google Scholar]
  56. Sauder D. N., Carter C. S., Katz S. I., Oppenheim J. J. Epidermal cell production of thymocyte activating factor (ETAF). J Invest Dermatol. 1982 Jul;79(1):34–39. doi: 10.1111/1523-1747.ep12510569. [DOI] [PubMed] [Google Scholar]
  57. Sauder D. N., Stanulis-Praeger B. M., Gilchrest B. A. Autocrine growth stimulation of human keratinocytes by epidermal cell-derived thymocyte-activating factor: implications for skin aging. Arch Dermatol Res. 1988;280(2):71–76. doi: 10.1007/BF00417707. [DOI] [PubMed] [Google Scholar]
  58. Schmidt J. A., Mizel S. B., Cohen D., Green I. Interleukin 1, a potential regulator of fibroblast proliferation. J Immunol. 1982 May;128(5):2177–2182. [PubMed] [Google Scholar]
  59. Schwarz T., Urbanska A., Gschnait F., Luger T. A. UV-irradiated epidermal cells produce a specific inhibitor of interleukin 1 activity. J Immunol. 1987 Mar 1;138(5):1457–1463. [PubMed] [Google Scholar]
  60. Sticherling M., Bornscheuer E., Schröder J. M., Christophers E. Localization of neutrophil-activating peptide-1/interleukin-8-immunoreactivity in normal and psoriatic skin. J Invest Dermatol. 1991 Jan;96(1):26–30. doi: 10.1111/1523-1747.ep12514689. [DOI] [PubMed] [Google Scholar]
  61. Stingl G., Wolff K., Diem E., Baumgartner G., Knapp W. In situ identification of lymphoreticular cells in benign and malignant infiltrates by membrane receptor sites. J Invest Dermatol. 1977 Aug;69(2):231–235. doi: 10.1111/1523-1747.ep12506348. [DOI] [PubMed] [Google Scholar]
  62. Wang A. M., Doyle M. V., Mark D. F. Quantitation of mRNA by the polymerase chain reaction. Proc Natl Acad Sci U S A. 1989 Dec;86(24):9717–9721. doi: 10.1073/pnas.86.24.9717. [DOI] [PMC free article] [PubMed] [Google Scholar]
  63. Weinstein G. D., Frost P. Abnormal cell proliferation in psoriasis. J Invest Dermatol. 1968 Mar;50(3):254–259. [PubMed] [Google Scholar]

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