TNF-anti-TNF Immune Complexes Inhibit IL-12/IL-23 Secretion by Inflammatory Macrophages via an Fc-dependent Mechanism

TNF-anti-TNF Immune Complexes Inhibit IL-12/IL-23 Secretion by Inflammatory Macrophages via an... Abstract Background and Aims We have recently shown that the mode of action of IgG1 anti-TNF antibodies in inflammatory bowel disease (IBD) requires Fcγ-receptor (FcR) engagement on macrophages. Here we examine the effect of Fcγ-receptor signaling by anti-TNF on macrophage IL-12/IL-23 secretion. Methods Cytokine production by human inflammatory macrophages was assessed at the level of RNA and or protein. TNF-anti-TNF immune complex formation was determined by size-exclusion chromatography and signaling visualized by immunofluorescence. IL-12/IL-23p40 was measured in CD14+ lamina propria cells from IBD patients. Results Infliximab and adalimumab potently suppressed IL-12/IL-23 production by inflammatory macrophages, but Fab’ fragment certolizumab did not. IL-12/IL-23 suppression depended on Syk activity and was mediated at the level of IL-12/IL-23p40 mRNA. Etanercept, a soluble TNF receptor fused to an Fc-region, did not inhibit IL-12/L-23 secretion, suggesting that the presence of an Fc-region was not sufficient. Infliximab and adalimumab formed immune complexes with soluble TNF while etanercept did not, suggesting that FcR mediated suppression of IL-12/IL-23 required the formation of immune complexes. Indeed, non-specific IgG1 immune complexes but not uncomplexed IgG1 similarly suppressed IL-12/IL-23 secretion. Finally, infliximab significantly decreased IL-12/IL-23p40 production in myeloid cells isolated from the lamina propria of IBD patients. Conclusions TNF-anti-TNF antibody immune complexes potently inhibit IL-12/IL-23 expression by inflammatory macrophages. Our data suggest that anti-TNFs and antibodies against IL-12/IL-23 may therefore have partially overlapping modes of action in patients with IBD. anti-TNF, IL-12/IL-23 axis, Macrophage Copyright © 2018 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Crohn's and Colitis Oxford University Press

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Publisher
Elsevier Science
Copyright
Copyright © 2018 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com
ISSN
1873-9946
eISSN
1876-4479
D.O.I.
10.1093/ecco-jcc/jjy075
Publisher site
See Article on Publisher Site

Abstract

Abstract Background and Aims We have recently shown that the mode of action of IgG1 anti-TNF antibodies in inflammatory bowel disease (IBD) requires Fcγ-receptor (FcR) engagement on macrophages. Here we examine the effect of Fcγ-receptor signaling by anti-TNF on macrophage IL-12/IL-23 secretion. Methods Cytokine production by human inflammatory macrophages was assessed at the level of RNA and or protein. TNF-anti-TNF immune complex formation was determined by size-exclusion chromatography and signaling visualized by immunofluorescence. IL-12/IL-23p40 was measured in CD14+ lamina propria cells from IBD patients. Results Infliximab and adalimumab potently suppressed IL-12/IL-23 production by inflammatory macrophages, but Fab’ fragment certolizumab did not. IL-12/IL-23 suppression depended on Syk activity and was mediated at the level of IL-12/IL-23p40 mRNA. Etanercept, a soluble TNF receptor fused to an Fc-region, did not inhibit IL-12/L-23 secretion, suggesting that the presence of an Fc-region was not sufficient. Infliximab and adalimumab formed immune complexes with soluble TNF while etanercept did not, suggesting that FcR mediated suppression of IL-12/IL-23 required the formation of immune complexes. Indeed, non-specific IgG1 immune complexes but not uncomplexed IgG1 similarly suppressed IL-12/IL-23 secretion. Finally, infliximab significantly decreased IL-12/IL-23p40 production in myeloid cells isolated from the lamina propria of IBD patients. Conclusions TNF-anti-TNF antibody immune complexes potently inhibit IL-12/IL-23 expression by inflammatory macrophages. Our data suggest that anti-TNFs and antibodies against IL-12/IL-23 may therefore have partially overlapping modes of action in patients with IBD. anti-TNF, IL-12/IL-23 axis, Macrophage Copyright © 2018 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

Journal

Journal of Crohn's and ColitisOxford University Press

Published: May 30, 2018

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