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. 1998 Feb 15;101(4):783–794. doi: 10.1172/JCI1476

IL-10 is a key cytokine in psoriasis. Proof of principle by IL-10 therapy: a new therapeutic approach.

K Asadullah 1, W Sterry 1, K Stephanek 1, D Jasulaitis 1, M Leupold 1, H Audring 1, H D Volk 1, W D Döcke 1
PMCID: PMC508626  PMID: 9466973

Abstract

Overexpression of proinflammatory, type 1 cytokines has been demonstrated in psoriasis and is believed to be of pathophysiological importance. IL-10 is a type 2 cytokine with major impact on immunoregulation, since it inhibits type 1/proinflammatory cytokine formation. Therefore, we investigated its role in psoriasis. We found a relative deficiency in cutaneous IL-10 mRNA expression compared with other inflammatory dermatoses. Interestingly, patients during established antipsoriatic therapy showed higher IL-10 mRNA expression of peripheral blood mononuclear cells than patients before therapy. This suggested that IL-10 may have antipsoriatic capacity. Therefore, we performed a phase 2 pilot trial with subcutaneous IL-10 administration (8 microg/kg/d) over 24 d in three patients. Clinical efficiency measured by objective and subjective parameters was found. Immunosuppressive effects (depressed monocytic HLA-DR expression, TNF-alpha and IL-12 secretion capacity, IL-12 plasma levels, and responsiveness to recall antigens) as well as a shift toward a type 2 cytokine pattern (increasing proportion of IL-4, IL-5, and IL-10 producing T cells, selective increase in IgE serum levels) were observed. Remarkably, IL-10 administration also enhanced the intracutaneous IL-10 mRNA expression. Our investigations demonstrate the major importance of IL-10 in psoriasis and show that IL-10 administration represents a new therapeutic approach. This is the first report on IL-10 therapy for cutaneous disorders.

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Selected References

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  1. Abel E. A., DiCicco L. M., Orenberg E. K., Fraki J. E., Farber E. M. Drugs in exacerbation of psoriasis. J Am Acad Dermatol. 1986 Nov;15(5 Pt 1):1007–1022. doi: 10.1016/s0190-9622(86)70265-x. [DOI] [PubMed] [Google Scholar]
  2. Altmeyer P. J., Matthes U., Pawlak F., Hoffmann K., Frosch P. J., Ruppert P., Wassilew S. W., Horn T., Kreysel H. W., Lutz G. Antipsoriatic effect of fumaric acid derivatives. Results of a multicenter double-blind study in 100 patients. J Am Acad Dermatol. 1994 Jun;30(6):977–981. doi: 10.1016/s0190-9622(94)70121-0. [DOI] [PubMed] [Google Scholar]
  3. Asadullah K., Döcke W. D., Haeussler A., Sterry W., Volk H. D. Progression of mycosis fungoides is associated with increasing cutaneous expression of interleukin-10 mRNA. J Invest Dermatol. 1996 Dec;107(6):833–837. doi: 10.1111/1523-1747.ep12330869. [DOI] [PubMed] [Google Scholar]
  4. Asadullah K., Schmid H., Friedrich M., Randow F., Volk H. D., Sterry W., Döcke W. D. Influence of monomethylfumarate on monocytic cytokine formation--explanation for adverse and therapeutic effects in psoriasis? Arch Dermatol Res. 1997 Oct;289(11):623–630. doi: 10.1007/s004030050251. [DOI] [PubMed] [Google Scholar]
  5. Boehncke W. H., Dressel D., Manfras B., Zollner T. M., Wettstein A., Böhm B. O., Sterry W. T-cell-receptor repertoire in chronic plaque-stage psoriasis is restricted and lacks enrichment of superantigen-associated V beta regions. J Invest Dermatol. 1995 May;104(5):725–728. doi: 10.1111/1523-1747.ep12606966. [DOI] [PubMed] [Google Scholar]
  6. Boyd A. S., Morris L. F., Phillips C. M., Menter M. A. Psoriasis and pregnancy: hormone and immune system interaction. Int J Dermatol. 1996 Mar;35(3):169–172. doi: 10.1111/j.1365-4362.1996.tb01632.x. [DOI] [PubMed] [Google Scholar]
  7. Bécherel P. A., Le Goff L., Ktorza S., Ouaaz F., Mencia-Huerta J. M., Dugas B., Debré P., Mossalayi M. D., Arock M. Interleukin-10 inhibits IgE-mediated nitric oxide synthase induction and cytokine synthesis in normal human keratinocytes. Eur J Immunol. 1995 Oct;25(10):2992–2995. doi: 10.1002/eji.1830251042. [DOI] [PubMed] [Google Scholar]
  8. Chernoff A. E., Granowitz E. V., Shapiro L., Vannier E., Lonnemann G., Angel J. B., Kennedy J. S., Rabson A. R., Wolff S. M., Dinarello C. A. A randomized, controlled trial of IL-10 in humans. Inhibition of inflammatory cytokine production and immune responses. J Immunol. 1995 May 15;154(10):5492–5499. [PubMed] [Google Scholar]
  9. D'Andrea A., Aste-Amezaga M., Valiante N. M., Ma X., Kubin M., Trinchieri G. Interleukin 10 (IL-10) inhibits human lymphocyte interferon gamma-production by suppressing natural killer cell stimulatory factor/IL-12 synthesis in accessory cells. J Exp Med. 1993 Sep 1;178(3):1041–1048. doi: 10.1084/jem.178.3.1041. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Das N. S., Chowdary T. N., Sobhanadri C., Rao K. V. The effect of topical isoprenaline on psoriatic skin. Br J Dermatol. 1978 Aug;99(2):197–200. doi: 10.1111/j.1365-2133.1978.tb01982.x. [DOI] [PubMed] [Google Scholar]
  11. Döcke W. D., Randow F., Syrbe U., Krausch D., Asadullah K., Reinke P., Volk H. D., Kox W. Monocyte deactivation in septic patients: restoration by IFN-gamma treatment. Nat Med. 1997 Jun;3(6):678–681. doi: 10.1038/nm0697-678. [DOI] [PubMed] [Google Scholar]
  12. Enk C. D., Sredni D., Blauvelt A., Katz S. I. Induction of IL-10 gene expression in human keratinocytes by UVB exposure in vivo and in vitro. J Immunol. 1995 May 1;154(9):4851–4856. [PubMed] [Google Scholar]
  13. Enk C. D., Sredni D., Blauvelt A., Katz S. I. Induction of IL-10 gene expression in human keratinocytes by UVB exposure in vivo and in vitro. J Immunol. 1995 May 1;154(9):4851–4856. [PubMed] [Google Scholar]
  14. Ettehadi P., Greaves M. W., Wallach D., Aderka D., Camp R. D. Elevated tumour necrosis factor-alpha (TNF-alpha) biological activity in psoriatic skin lesions. Clin Exp Immunol. 1994 Apr;96(1):146–151. doi: 10.1111/j.1365-2249.1994.tb06244.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Fiorentino D. F., Zlotnik A., Mosmann T. R., Howard M., O'Garra A. IL-10 inhibits cytokine production by activated macrophages. J Immunol. 1991 Dec 1;147(11):3815–3822. [PubMed] [Google Scholar]
  16. Fredriksson T., Pettersson U. Severe psoriasis--oral therapy with a new retinoid. Dermatologica. 1978;157(4):238–244. doi: 10.1159/000250839. [DOI] [PubMed] [Google Scholar]
  17. Germann T., Rüde E. Interleukin-12. Int Arch Allergy Immunol. 1995 Oct;108(2):103–112. doi: 10.1159/000237126. [DOI] [PubMed] [Google Scholar]
  18. Gilhar A., Grossman N., Kahanovicz S., Reuveni H., Cohen S., Eitan A. Antiproliferative effect of pentoxifylline on psoriatic and normal epidermis. In vitro and in vivo studies. Acta Derm Venereol. 1996 Nov;76(6):437–441. doi: 10.2340/0001555576437441. [DOI] [PubMed] [Google Scholar]
  19. Hoffmann K., Dirschka T., Schwarze H., el-Gammal S., Matthes U., Hoffmann A., Altmeyer P. 20 MHz sonography, colorimetry and image analysis in the evaluation of psoriasis vulgaris. J Dermatol Sci. 1995 Mar;9(2):103–110. doi: 10.1016/0923-1811(94)00358-l. [DOI] [PubMed] [Google Scholar]
  20. Jeffes E. W., 3rd, Lee G. C., Said S., Sabahi M., McCullough J. L., Herrod R., Alzona C. P., Linden K. G., Soundararajan D., Edwards S. Elevated numbers of proliferating mononuclear cells in the peripheral blood of psoriatic patients correlate with disease severity. J Invest Dermatol. 1995 Dec;105(6):733–738. doi: 10.1111/1523-1747.ep12325496. [DOI] [PubMed] [Google Scholar]
  21. Jegasothy B. V., Ackerman C. D., Todo S., Fung J. J., Abu-Elmagd K., Starzl T. E. Tacrolimus (FK 506)--a new therapeutic agent for severe recalcitrant psoriasis. Arch Dermatol. 1992 Jun;128(6):781–785. [PMC free article] [PubMed] [Google Scholar]
  22. Jenkins J. K., Malyak M., Arend W. P. The effects of interleukin-10 on interleukin-1 receptor antagonist and interleukin-1 beta production in human monocytes and neutrophils. Lymphokine Cytokine Res. 1994 Feb;13(1):47–54. [PubMed] [Google Scholar]
  23. Kang K., Hammerberg C., Meunier L., Cooper K. D. CD11b+ macrophages that infiltrate human epidermis after in vivo ultraviolet exposure potently produce IL-10 and represent the major secretory source of epidermal IL-10 protein. J Immunol. 1994 Dec 1;153(11):5256–5264. [PubMed] [Google Scholar]
  24. Kristensen M., Deleuran B., Eedy D. J., Feldmann M., Breathnach S. M., Brennan F. M. Distribution of interleukin 1 receptor antagonist protein (IRAP), interleukin 1 receptor, and interleukin 1 alpha in normal and psoriatic skin. Decreased expression of IRAP in psoriatic lesional epidermis. Br J Dermatol. 1992 Oct;127(4):305–311. doi: 10.1111/j.1365-2133.1992.tb00446.x. [DOI] [PubMed] [Google Scholar]
  25. 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]
  26. Lemster B. H., Carroll P. B., Rilo H. R., Johnson N., Nikaein A., Thomson A. W. IL-8/IL-8 receptor expression in psoriasis and the response to systemic tacrolimus (FK506) therapy. Clin Exp Immunol. 1995 Feb;99(2):148–154. doi: 10.1111/j.1365-2249.1995.tb05525.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Mitra R. S., Judge T. A., Nestle F. O., Turka L. A., Nickoloff B. J. Psoriatic skin-derived dendritic cell function is inhibited by exogenous IL-10. Differential modulation of B7-1 (CD80) and B7-2 (CD86) expression. J Immunol. 1995 Mar 15;154(6):2668–2677. [PubMed] [Google Scholar]
  28. Mussi A., Bonifati C., Carducci M., Viola M., Tomaselli R., Sacerdoti G., Fazio M., Ameglio F. IL-10 levels are decreased in psoriatic lesional skin as compared to the psoriatic lesion-free and normal skin suction blister fluids. J Biol Regul Homeost Agents. 1994 Oct-Dec;8(4):117–120. [PubMed] [Google Scholar]
  29. Nickoloff B. J., Fivenson D. P., Kunkel S. L., Strieter R. M., Turka L. A. Keratinocyte interleukin-10 expression is upregulated in tape-stripped skin, poison ivy dermatitis, and Sezary syndrome, but not in psoriatic plaques. Clin Immunol Immunopathol. 1994 Oct;73(1):63–68. doi: 10.1006/clin.1994.1170. [DOI] [PubMed] [Google Scholar]
  30. Nickoloff B. J. The cytokine network in psoriasis. Arch Dermatol. 1991 Jun;127(6):871–884. [PubMed] [Google Scholar]
  31. Norris D. A., Travers J. B., Leung D. Y. Lymphocyte activation in the pathogenesis of psoriasis. J Invest Dermatol. 1997 Jul;109(1):1–4. doi: 10.1111/1523-1747.ep12276285. [DOI] [PubMed] [Google Scholar]
  32. Ockenfels H. M., Wagner S. N., Keim-Maas C., Funk R., Nussbaum G., Goos M. Lithium and psoriasis: cytokine modulation of cultured lymphocytes and psoriatic keratinocytes by lithium. Arch Dermatol Res. 1996 Apr;288(4):173–178. doi: 10.1007/BF02505220. [DOI] [PubMed] [Google Scholar]
  33. Ohmen J. D., Hanifin J. M., Nickoloff B. J., Rea T. H., Wyzykowski R., Kim J., Jullien D., McHugh T., Nassif A. S., Chan S. C. Overexpression of IL-10 in atopic dermatitis. Contrasting cytokine patterns with delayed-type hypersensitivity reactions. J Immunol. 1995 Feb 15;154(4):1956–1963. [PubMed] [Google Scholar]
  34. Ohta Y., Katayama I., Funato T., Yokozeki H., Nishiyama S., Hirano T., Kishimoto T., Nishioka K. In situ expression of messenger RNA of interleukin-1 and interleukin-6 in psoriasis: interleukin-6 involved in formation of psoriatic lesions. Arch Dermatol Res. 1991;283(6):351–356. doi: 10.1007/BF00371814. [DOI] [PubMed] [Google Scholar]
  35. Olaniran A. K., Baker B. S., Paige D. G., Garioch J. J., Powles A. V., Fry L. Cytokine expression in psoriatic skin lesions during PUVA therapy. Arch Dermatol Res. 1996 Jul;288(8):421–425. doi: 10.1007/BF02505228. [DOI] [PubMed] [Google Scholar]
  36. Platzer C., Meisel C., Vogt K., Platzer M., Volk H. D. Up-regulation of monocytic IL-10 by tumor necrosis factor-alpha and cAMP elevating drugs. Int Immunol. 1995 Apr;7(4):517–523. doi: 10.1093/intimm/7.4.517. [DOI] [PubMed] [Google Scholar]
  37. Platzer C., Ode-Hakim S., Reinke P., Döcke W. D., Ewert R., Volk H. D. Quantitative PCR analysis of cytokine transcription patterns in peripheral mononuclear cells after anti-CD3 rejection therapy using two novel multispecific competitor fragments. Transplantation. 1994 Jul 27;58(2):264–268. [PubMed] [Google Scholar]
  38. Rivas J. M., Ullrich S. E. Systemic suppression of delayed-type hypersensitivity by supernatants from UV-irradiated keratinocytes. An essential role for keratinocyte-derived IL-10. J Immunol. 1992 Dec 15;149(12):3865–3871. [PubMed] [Google Scholar]
  39. Romagnani S. Biology of human TH1 and TH2 cells. J Clin Immunol. 1995 May;15(3):121–129. doi: 10.1007/BF01543103. [DOI] [PubMed] [Google Scholar]
  40. Schlaak J. F., Buslau M., Jochum W., Hermann E., Girndt M., Gallati H., Meyer zum Büschenfelde K. H., Fleischer B. T cells involved in psoriasis vulgaris belong to the Th1 subset. J Invest Dermatol. 1994 Feb;102(2):145–149. doi: 10.1111/1523-1747.ep12371752. [DOI] [PubMed] [Google Scholar]
  41. Takashima A., Morita A. Genomic, phenotypic, and functional analyses of T cells in patients with psoriasis undergoing systemic cyclosporin A treatment. J Invest Dermatol. 1991 Mar;96(3):376–382. doi: 10.1111/1523-1747.ep12466215. [DOI] [PubMed] [Google Scholar]
  42. Teunissen M. B., Koomen C. W., Jansen J., de Waal Malefyt R., Schmitt E., Van den Wijngaard R. M., Das P. K., Bos J. D. In contrast to their murine counterparts, normal human keratinocytes and human epidermoid cell lines A431 and HaCaT fail to express IL-10 mRNA and protein. Clin Exp Immunol. 1997 Jan;107(1):213–223. doi: 10.1046/j.1365-2249.1997.d01-900.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Uyemura K., Yamamura M., Fivenson D. F., Modlin R. L., Nickoloff B. J. The cytokine network in lesional and lesion-free psoriatic skin is characterized by a T-helper type 1 cell-mediated response. J Invest Dermatol. 1993 Nov;101(5):701–705. doi: 10.1111/1523-1747.ep12371679. [DOI] [PubMed] [Google Scholar]
  44. Volk H. D., Reinke P., Krausch D., Zuckermann H., Asadullah K., Müller J. M., Döcke W. D., Kox W. J. Monocyte deactivation--rationale for a new therapeutic strategy in sepsis. Intensive Care Med. 1996 Oct;22 (Suppl 4):S474–S481. doi: 10.1007/BF01743727. [DOI] [PubMed] [Google Scholar]
  45. Wegmann T. G., Lin H., Guilbert L., Mosmann T. R. Bidirectional cytokine interactions in the maternal-fetal relationship: is successful pregnancy a TH2 phenomenon? Immunol Today. 1993 Jul;14(7):353–356. doi: 10.1016/0167-5699(93)90235-D. [DOI] [PubMed] [Google Scholar]
  46. Weinstein G. D. Can immunomodulatory molecules work topically for psoriasis? J Invest Dermatol. 1996 Apr;106(4):589–589. doi: 10.1111/1523-1747.ep12345035. [DOI] [PubMed] [Google Scholar]
  47. Wrone-Smith T., Nickoloff B. J. Dermal injection of immunocytes induces psoriasis. J Clin Invest. 1996 Oct 15;98(8):1878–1887. doi: 10.1172/JCI118989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Wölfer L. U., Goerdt S., Schröder K., Zouboulis C. C., Orfanos C. E. Interferon-alpha-induzierte Psoriasis vulgaris. Hautarzt. 1996 Feb;47(2):124–128. doi: 10.1007/s001050050388. [DOI] [PubMed] [Google Scholar]
  49. de Waal Malefyt R., Abrams J., Bennett B., Figdor C. G., de Vries J. E. Interleukin 10(IL-10) inhibits cytokine synthesis by human monocytes: an autoregulatory role of IL-10 produced by monocytes. J Exp Med. 1991 Nov 1;174(5):1209–1220. doi: 10.1084/jem.174.5.1209. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. van Deventer S. J., Elson C. O., Fedorak R. N. Multiple doses of intravenous interleukin 10 in steroid-refractory Crohn's disease. Crohn's Disease Study Group. Gastroenterology. 1997 Aug;113(2):383–389. doi: 10.1053/gast.1997.v113.pm9247454. [DOI] [PubMed] [Google Scholar]

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