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Tofacitinib downregulates antiviral immune defence in keratinocytes and reduces T cell activation

BACKGROUND: Tofacitinib is a novel Janus kinase (JAK) inhibitor approved for the treatment of rheumatoid arthritis, psoriatic arthritis, and ulcerative colitis. In clinical trials, the most common adverse events observed were nasopharyngitis, upper respiratory tract infections, and zoster. JAKs are...

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Autores principales: Hawerkamp, Heike C., Domdey, Alina, Radau, Lisa, Sewerin, Philipp, Oláh, Péter, Homey, Bernhard, Meller, Stephan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8138978/
https://www.ncbi.nlm.nih.gov/pubmed/34020693
http://dx.doi.org/10.1186/s13075-021-02509-8
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author Hawerkamp, Heike C.
Domdey, Alina
Radau, Lisa
Sewerin, Philipp
Oláh, Péter
Homey, Bernhard
Meller, Stephan
author_facet Hawerkamp, Heike C.
Domdey, Alina
Radau, Lisa
Sewerin, Philipp
Oláh, Péter
Homey, Bernhard
Meller, Stephan
author_sort Hawerkamp, Heike C.
collection PubMed
description BACKGROUND: Tofacitinib is a novel Janus kinase (JAK) inhibitor approved for the treatment of rheumatoid arthritis, psoriatic arthritis, and ulcerative colitis. In clinical trials, the most common adverse events observed were nasopharyngitis, upper respiratory tract infections, and zoster. JAKs are found downstream of the type II cytokine receptor family used by a number of T(H)17 cell-associated cytokines for signal transduction. These cytokines lead to the secretion of antiviral and antimicrobial peptides (AMPs) by keratinocytes or synoviocytes. Blocking the JAK pathway might result in a diminished secretion of antimicrobial and antiviral peptides causing higher susceptibility to infections in patients treated with JAK inhibitors. METHODS: We treated primary human keratinocytes and synoviocytes with tofacitinib and subsequently added various cytokines and bacterial surface proteins before evaluation of the response via RT-qPCR. CD69 expression on tofacitinib-treated PBMCs was investigated via flow cytometry. RESULTS: We found a markedly reduced gene expression of all tested antiviral peptides such as MX1 or ISG15 in keratinocytes and synoviocytes in the presence of tofacitinib in vitro. Additionally, we found that JAK inhibition reduced activation of T cells after stimulation with bacterial LPS or viral VZV gE. CONCLUSIONS: The antiviral immunity is strongly inhibited in the presence of tofacitinib in vitro, while the antimicrobial immunity does not seem to be affected. In T cells, the overall activation process seems to be influenced by tofacitinib. These findings suggest that tofacitinib has an impact on antiviral immunity such as patients treated with tofacitinib often show adverse events like herpes zoster. GRAPHICAL ABSTRACT: [Image: see text]
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spelling pubmed-81389782021-05-21 Tofacitinib downregulates antiviral immune defence in keratinocytes and reduces T cell activation Hawerkamp, Heike C. Domdey, Alina Radau, Lisa Sewerin, Philipp Oláh, Péter Homey, Bernhard Meller, Stephan Arthritis Res Ther Research Article BACKGROUND: Tofacitinib is a novel Janus kinase (JAK) inhibitor approved for the treatment of rheumatoid arthritis, psoriatic arthritis, and ulcerative colitis. In clinical trials, the most common adverse events observed were nasopharyngitis, upper respiratory tract infections, and zoster. JAKs are found downstream of the type II cytokine receptor family used by a number of T(H)17 cell-associated cytokines for signal transduction. These cytokines lead to the secretion of antiviral and antimicrobial peptides (AMPs) by keratinocytes or synoviocytes. Blocking the JAK pathway might result in a diminished secretion of antimicrobial and antiviral peptides causing higher susceptibility to infections in patients treated with JAK inhibitors. METHODS: We treated primary human keratinocytes and synoviocytes with tofacitinib and subsequently added various cytokines and bacterial surface proteins before evaluation of the response via RT-qPCR. CD69 expression on tofacitinib-treated PBMCs was investigated via flow cytometry. RESULTS: We found a markedly reduced gene expression of all tested antiviral peptides such as MX1 or ISG15 in keratinocytes and synoviocytes in the presence of tofacitinib in vitro. Additionally, we found that JAK inhibition reduced activation of T cells after stimulation with bacterial LPS or viral VZV gE. CONCLUSIONS: The antiviral immunity is strongly inhibited in the presence of tofacitinib in vitro, while the antimicrobial immunity does not seem to be affected. In T cells, the overall activation process seems to be influenced by tofacitinib. These findings suggest that tofacitinib has an impact on antiviral immunity such as patients treated with tofacitinib often show adverse events like herpes zoster. GRAPHICAL ABSTRACT: [Image: see text] BioMed Central 2021-05-21 2021 /pmc/articles/PMC8138978/ /pubmed/34020693 http://dx.doi.org/10.1186/s13075-021-02509-8 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open AccessThis 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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence 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 licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research Article
Hawerkamp, Heike C.
Domdey, Alina
Radau, Lisa
Sewerin, Philipp
Oláh, Péter
Homey, Bernhard
Meller, Stephan
Tofacitinib downregulates antiviral immune defence in keratinocytes and reduces T cell activation
title Tofacitinib downregulates antiviral immune defence in keratinocytes and reduces T cell activation
title_full Tofacitinib downregulates antiviral immune defence in keratinocytes and reduces T cell activation
title_fullStr Tofacitinib downregulates antiviral immune defence in keratinocytes and reduces T cell activation
title_full_unstemmed Tofacitinib downregulates antiviral immune defence in keratinocytes and reduces T cell activation
title_short Tofacitinib downregulates antiviral immune defence in keratinocytes and reduces T cell activation
title_sort tofacitinib downregulates antiviral immune defence in keratinocytes and reduces t cell activation
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8138978/
https://www.ncbi.nlm.nih.gov/pubmed/34020693
http://dx.doi.org/10.1186/s13075-021-02509-8
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