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Original research
Anti-TNF therapy in IBD exerts its therapeutic effect through macrophage IL-10 signalling
  1. Pim J Koelink1,
  2. Felicia M Bloemendaal1,2,
  3. Bofeng Li3,
  4. Liset Westera1,
  5. Esther W M Vogels1,
  6. Manon van Roest1,
  7. Anouk K Gloudemans4,
  8. Angelique B van 't Wout4,
  9. Hannelie Korf5,
  10. Séverine Vermeire5,
  11. Anje A te Velde1,
  12. Cyriel Y Ponsioen6,
  13. Geert RAM D'Haens6,
  14. J Sjef Verbeek7,
  15. Terrence L Geiger3,
  16. Manon E Wildenberg1,6,
  17. Gijs R van den Brink1,6,8
  1. 1 Tytgat Insitute for Liver & Intestinal Research, Amsterdam UMC, Amsterdam, The Netherlands
  2. 2 Department of Gastroenterology and hepatology, Amsterdam UMC, Amsterdam, The Netherlands
  3. 3 Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
  4. 4 Janssen Prevention Center of Janssen Vaccines & Prevention BV, Janssen Pharmaceutical Companies of Johnson & Johnson, Leiden, The Netherlands
  5. 5 Translational Research Center for Gastrointestinal Disorders (TARGID), Department of Clinical and Experimental Medicine, KU Leuven, Leuven, Belgium
  6. 6 Gastroenterology & Hepatology, Amsterdam UMC, Amsterdam, The Netherlands
  7. 7 Human Genetics, Leids Universitair Medisch Centrum, Leiden, The Netherlands
  8. 8 Roche Innovation Center Basel, F Hoffmann-La Roche AG, Basel, Switzerland
  1. Correspondence to Dr Pim J Koelink, Tytgat Insitute for Liver & Intestinal Research, Amsterdam UMC, Amsterdam 1105 BK, The Netherlands; p.j.koelink{at}


Objective Macrophage interleukin (IL)-10 signalling plays a critical role in the maintenance of a regulatory phenotype that prevents the development of IBD. We have previously found that anti-tumour necrosis factor (TNF) monoclonal antibodies act through Fcγ-receptor (FcγR) signalling to promote repolarisation of proinflammatory intestinal macrophages to a CD206+ regulatory phenotype. The role of IL-10 in anti-TNF-induced macrophage repolarisation has not been examined.

Design We used human peripheral blood monocytes and mouse bone marrow-derived macrophages to study IL-10 production and CD206+ regulatory macrophage differentiation. To determine whether the efficacy of anti-TNF was dependent on IL-10 signalling in vivo and in which cell type, we used the CD4+CD45Rbhigh T-cell transfer model in combination with several genetic mouse models.

Results Anti-TNF therapy increased macrophage IL-10 production in an FcγR-dependent manner, which caused differentiation of macrophages to a more regulatory CD206+ phenotype in vitro. Pharmacological blockade of IL-10 signalling prevented the induction of these CD206+ regulatory macrophages and diminished the therapeutic efficacy of anti-TNF therapy in the CD4+CD45Rbhigh T-cell transfer model of IBD. Using cell type-specific IL-10 receptor mutant mice, we found that IL-10 signalling in macrophages but not T cells was critical for the induction of CD206+ regulatory macrophages and therapeutic response to anti-TNF.

Conclusion The therapeutic efficacy of anti-TNF in resolving intestinal inflammation is critically dependent on IL-10 signalling in macrophages.

  • IBD basic research
  • TNF
  • antibody targeted therapy
  • infliximab
  • interleukins

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  • PJK and FMB contributed equally.

  • Correction notice This article has been corrected since it published Online First. Affiliation 8 has been added.

  • Contributors PJK, FMB, LW, MEW, EWMV and MvR performed experiments and analysed and discussed the data. AKG, ABvtW, GRAMD’H and GRvdB discussed the data. TLG and BL provided the LysMcreIl10rafl/flRag1KO mice and discussed the data. JSV provided FcgRKO/Rag1KO mice and discussed the data. HK, SV, AAtV and CYP provided patient samples and discussed the data. GRvdB and PJK supervised the study. PJK, FMB and GRvdB wrote the manuscript with input of all the authors.

  • Funding This work was supported by a unrestricted research grant from the Janssen Prevention Center of Janssen Vaccines & Prevention BV, Leiden, the Netherlands, part of the Janssen Pharmaceutical Companies of Johnson & Johnson, and by Health Holland, Top Sector Life Sciences and Health.

  • Competing interests AKG and ABvtW are employees of Janssen Vaccines and Prevention B.V. GRvdB is currently an employee of Roche. CYP received research support from Takeda, speaker’s fees from Takeda, Abbvie and Dr. Falk Pharma, and consultancy fee from Takeda outside this work. Other authors declare no conflict of interest related to this work.

  • Patient consent for publication Not required.

  • Ethics approval The Medical Ethical Committee of the Amsterdam UMC(METC 2009_113) and the Institutional Review Board of the Hospital in Leuven (B322201213950/S53684) approved this study.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information.

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