Journal article
Inhibiting ex-vivo Th17 responses in Ankylosing Spondylitis by targeting Janus kinases
- Abstract:
- Treatment options for Ankylosing Spondylitis (AS) are still limited. The T helper cell 17 (Th17) pathway has emerged as a major driver of disease pathogenesis and a good treatment target. Janus kinases (JAK) are key transducers of cytokine signals in Th17 cells and therefore promising targets for the treatment of AS. Here we investigate the therapeutic potential of four different JAK inhibitors on cells derived from AS patients and healthy controls, cultured in-vitro under Th17-promoting conditions. Levels of IL-17A, IL-17F, IL-22, GM-CSF and IFNγ were assessed by ELISA and inhibitory effects were investigated with Phosphoflow. JAK1/2/3 and TYK2 were silenced in CD4+ T cells with siRNA and effects analyzed by ELISA (IL-17A, IL-17F and IL-22), Western Blot, qPCR and Phosphoflow. In-vitro inhibition of CD4+ T lymphocyte production of multiple Th17 cytokines (IL-17A, IL-17F and IL-22) was achieved with JAK inhibitors of differing specificity, as well as by silencing of JAK1-3 and Tyk2, without impacting on cell viability or proliferation. Our preclinical data suggest JAK inhibitors as promising candidates for therapeutic trials in AS, since they can inhibit multiple Th17 cytokines simultaneously. Improved targeting of TYK2 or other JAK isoforms may confer tailored effects on Th17 responses in AS.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
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(Preview, pdf, 2.3MB, Terms of use)
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- Publisher copy:
- 10.1038/s41598-018-34026-1
Authors
+ National Institute for Health Research
More from this funder
- Funding agency for:
- Ridley, A
- Bowness, P
- Grant:
- Oxford Biomedical Research Centre
+ Deutsche Forschungsgemeinschaft
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- Funding agency for:
- Hammitzsch, A
- Grant:
- HA-7021/1-1
- Publisher:
- Springer Nature
- Journal:
- Scientific Reports More from this journal
- Publication date:
- 2018-10-23
- Acceptance date:
- 2018-09-07
- DOI:
- EISSN:
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2045-2322
- ISSN:
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2045-2322
- Pubs id:
-
pubs:927481
- UUID:
-
uuid:2420862b-2a77-4e50-8603-f95b8f56b757
- Local pid:
-
pubs:927481
- Deposit date:
-
2018-10-15
Terms of use
- Copyright holder:
- Hammitzsch et al
- Copyright date:
- 2018
- Notes:
- © The Authors 2018. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. Te images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
- Licence:
- CC Attribution (CC BY)
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