IL4-10 fusion protein: a novel immunoregulatory drug combining activities of interleukin 4 and interleukin 10
Steen-Louws, C.; Hartgring, S. A.Y.; Popov-Celeketic, J.; Lopes, A. P.; de Smet, M. B.M.; Eijkelkamp, N.; Lafeber, F. P.J.G.; Hack, C. E.; van Roon, J. A.G.
(2019) Clinical and Experimental Immunology, volume 195, issue 1, pp. 1 - 9
(Article)
Abstract
The objective of this study was to test the capacity of a newly developed fusion protein of interleukin 4 (IL-4) and IL-10 [IL4-10 fusion protein (FP)] to shift multiple pro-inflammatory pathways towards immune regulation, and to inhibit pro-inflammatory activity in arthritis models. The effects of IL4-10 FP in comparison with
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IL-4, IL-10 and IL-4 plus IL-10 on pro- and anti-inflammatory mediators, T cells and immunoglobulin (Ig) receptors in favour of immunoregulatory activity were studied. In addition, the capacity of IL4-10 FP to inhibit pro-inflammatory activity in ex-vivo and in-vivo arthritis models was investigated. IL4-10 FP robustly inhibited pro-inflammatory cytokine [IL-1β, tumour necrosis factor (TNF)-α, IL-6 and IL-8] production in whole blood cultures, mediated by both the IL-10 and the IL-4 moiety. IL4-10 fusion protein induced IL-1 receptor antagonist (IL-1RA) production and preserved soluble TNF receptor (sTNFR) levels, strongly increasing IL-1RA/IL-1β and sTNFR/TNF-α ratios. In addition, IL4-10 FP strongly inhibited T helper (Th) type 1 and 17 cytokine secretion, while maintaining FoxP3 expression and up-regulating Th2 activity. In addition, while largely leaving expression of activating Fc gamma receptor (FcγR)I, III and Fc epsilon receptor (FcεR) unaffected, it significantly shifted the FcγRIIa/FcγRIIb ratio in favour of the inhibitory FcγRIIb. Moreover, IL4–10 FP robustly inhibited secretion of pro-inflammatory cytokines by rheumatoid arthritis synovial tissue and suppressed experimental arthritis in mice, without inducing B cell hyperactivity. IL4-10 fusion protein is a novel drug, signalling cells to induce immunoregulatory activity that overcomes limitations of IL-4 and IL-10 stand-alone therapy, and therefore has therapeutic potential for inflammatory diseases such as rheumatoid arthritis.
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Keywords: arthritis, autoinflammatory diseases, cytokines, inflammation, Th1/Th2 cells, Cell Proliferation, Immunotherapy/methods, Humans, Interleukin-4/genetics, Inflammation/immunology, Flow Cytometry, Interleukin-10/immunology, Female, Synovial Membrane/metabolism, Arthritis, Rheumatoid/chemically induced, Disease Models, Animal, Recombinant Fusion Proteins/genetics, Proteoglycans, Immunomodulation, Cells, Cultured, Lipopolysaccharides/immunology, Animals, Leukocytes, Mononuclear/immunology, Mice, Mice, Inbred BALB C, Immunology and Allergy, Immunology, Research Support, Non-U.S. Gov't, Journal Article
ISSN: 0009-9104
Publisher: Wiley-Blackwell
Note: Funding Information: The authors would like to thank Dr C. P. J. Bekker for performing qPCR. This project was mainly financed by internal funding. Publisher Copyright: © 2018 The Authors. Clinical & Experimental Immunology published by John Wiley & Sons Ltd on behalf of British Society for Immunology Copyright: Copyright 2019 Elsevier B.V., All rights reserved.
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