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Inflammation and inflammatory bowel disease
Treatment of Crohn's disease with recombinant human interleukin 10 induces the proinflammatory cytokine interferon γ
  1. H Tilg1,
  2. C van Montfrans2,
  3. A van den Ende2,
  4. A Kaser1,
  5. S J H van Deventer2,
  6. S Schreiber3,
  7. M Gregor4,
  8. O Ludwiczek1,
  9. P Rutgeerts5,
  10. C Gasche6,
  11. J C Koningsberger7,
  12. L Abreu8,
  13. I Kuhn9,
  14. M Cohard10,
  15. A LeBeaut10,
  16. P Grint10,
  17. G Weiss11
  1. 1Department of Medicine, Division of Gastroenterology and Hepatology, University Hospital Innsbruck, Austria
  2. 2Department of Experimental Internal Medicine, Academic Medical Centre, University of Amsterdam, the Netherlands
  3. 3Department of Medicine, Christian-Albrechts University, Kiel, Germany
  4. 4Department of Medicine, Eberhard-Karls University, Tübingen, Germany
  5. 5Department of Gastroenterology, U Z Gasthuisberg, Catholic University Leuven, Belgium
  6. 6Department of Gastroenterology, University of Vienna, Austria
  7. 7Department of Gastroenterology, University of Utrecht, the Netherlands
  8. 8Department of Medicine, University of Madrid, Spain
  9. 9AESCA GmbH, Traiskirchen, Austria
  10. 10Schering-Plough Research Institute, Kenilworth, NJ, USA
  11. 11Department of Medicine, Division of General Internal Medicine, University Hospital Innsbruck, Austria
  1. Correspondence to:
    Dr H Tilg, Department of Medicine, Division of Gastroenterology and Hepatology, University Hospital Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria;
    Herbert.Tilg{at}uibk.ac.at

Abstract

Background: Interleukin 10 (IL-10) exerts anti-inflammatory actions by counteracting many biological effects of interferon γ (IFN-γ).

Aims: To investigate this in humans, we studied the effects of human recombinant IL-10 administration on IFN-γ production by patient leucocytes. Furthermore, we assessed the IFN-γ inducible molecule neopterin and nitrite/nitrate serum levels, which are indicative of endogenous nitric oxide formation.

Methods: As part of two placebo controlled double blind studies, we analysed patients with chronic active Crohn's disease (CACD) who received either subcutaneous recombinant human IL-10 (n=44) or placebo (n=10) daily for 28 days, and patients with mild to moderate Crohn's disease (MCD) treated with either subcutaneous IL-10 (n=52) or placebo (n=16) daily for 28 days. Neopterin and nitrite/nitrate concentrations were measured in serum, and ex vivo IFN-γ formation by lipopolysaccharide or phytohaemagglutinin (PHA) stimulated whole blood cells were investigated before, during, and after IL-10 therapy.

Results: In patients with CACD, the highest dose of 20 μg/kg IL-10 caused a significant increase in serum neopterin on days +15 and +29 of therapy compared with pretreatment levels. No changes were observed for nitrite/nitrate levels under either condition. In MCD, treatment with 20 μg/kg IL-10 resulted in a significant increase in PHA induced IFN-γ production.

Conclusions: High doses of IL-10 upregulate the production of IFN-γ and neopterin. This phenomenon may be responsible for the lack of efficacy of high doses of IL-10 in the treatment of CACD and MCD.

  • inflammatory bowel disease
  • inflammation
  • interleukin 10
  • neopterin
  • interferon γ
  • CACD, chronic active Crohn's disease
  • CD, Crohn's disease
  • CDAI, Crohn's disease activity index
  • GVHD, graft versus host disease
  • IFN-γ, interferon γ
  • IL, interleukin
  • rHuIL-10, recombinant human IL-10
  • iNOS, inducible nitric oxide synthase
  • LPS, lipopolysaccharide
  • MCD, mild to moderately active CD
  • NO, nitric oxide
  • PHA, phytohaemagglutinin
  • Th, T helper cells
  • TNF-α, tumour necrosis factor α

https://doi.org/10.1136/gut.50.2.191

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