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IL-39 promotes chronic graft-versus-host disease by increasing T and B Cell pathogenicity
BACKGROUND: Chronic graft-versus-host disease (cGVHD) remains a major complication during the late phase of allogeneic hematopoietic stem cell transplantation (allo-HSCT). IL-39, a newly described pro-inflammatory cytokine belonging to the IL-12 family, plays a role in lupus development. Recently, I...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9161463/ https://www.ncbi.nlm.nih.gov/pubmed/35655245 http://dx.doi.org/10.1186/s40164-022-00286-x |
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author | Lv, Kangkang Hu, Bo Xu, Mingzhu Wan, Li Jin, Ziqi Xu, Mimi Du, Yuanyuan Ma, Kunpeng Lv, Quansheng Xu, Yang Lei, Lei Gong, Huanle Liu, Haiyan Wu, Depei Liu, Yuejun |
author_facet | Lv, Kangkang Hu, Bo Xu, Mingzhu Wan, Li Jin, Ziqi Xu, Mimi Du, Yuanyuan Ma, Kunpeng Lv, Quansheng Xu, Yang Lei, Lei Gong, Huanle Liu, Haiyan Wu, Depei Liu, Yuejun |
author_sort | Lv, Kangkang |
collection | PubMed |
description | BACKGROUND: Chronic graft-versus-host disease (cGVHD) remains a major complication during the late phase of allogeneic hematopoietic stem cell transplantation (allo-HSCT). IL-39, a newly described pro-inflammatory cytokine belonging to the IL-12 family, plays a role in lupus development. Recently, IL-39 has been identified as a pathogenic factor in acute GVHD (aGVHD). However, the role of IL-39 in the pathogenesis of cGVHD remains unclear. METHODS: We constructed a recombinant IL-39 plasmid and established scleroderma and lupus-like cGVHD models. Quantitative PCR and enzyme-linked immunosorbent assay (ELISA) were used to detect IL-39 expression in mice and patients post transplantation, respectively. Hydrodynamic gene transfer (HGT) was performed to achieve IL-39 overexpression in vivo. Multiparameter flow cytometry, western blotting, and assays in vitro were performed to investigate the effect of IL-39 on cGVHD. RESULTS: The relative expression of IL-23p19 and EBi3 was significantly increased in the intestine of cGVHD mice on day 40 post allo-HSCT, and IL-39 levels were significantly elevated in the serum of patients following allo-HSCT. Overexpression of IL-39 significantly aggravated the severity of cGVHD. Increased IL-39 levels promoted T-cell activation and germinal center responses, and may exacerbate thymic damage. Consistently, blocking IL-39 markedly ameliorated immune dysregulation in the cGVHD mice. Furthermore, we found that IL-39 was produced by B cells, CD11b(+) cells, and CD8(+)T cells after activation. Stimulation of IL-39 led to upregulation of the IL-39 receptor on CD4(+)T cells and further caused activation of the STAT1/STAT3 pathway, through which IL-39 may exert its pro-inflammatory effects. CONCLUSION: Our study reveals a critical role for IL-39 in cGVHD pathogenesis and indicates that IL-39 may serve as a potential therapeutic target for cGVHD prevention. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s40164-022-00286-x. |
format | Online Article Text |
id | pubmed-9161463 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-91614632022-06-03 IL-39 promotes chronic graft-versus-host disease by increasing T and B Cell pathogenicity Lv, Kangkang Hu, Bo Xu, Mingzhu Wan, Li Jin, Ziqi Xu, Mimi Du, Yuanyuan Ma, Kunpeng Lv, Quansheng Xu, Yang Lei, Lei Gong, Huanle Liu, Haiyan Wu, Depei Liu, Yuejun Exp Hematol Oncol Research BACKGROUND: Chronic graft-versus-host disease (cGVHD) remains a major complication during the late phase of allogeneic hematopoietic stem cell transplantation (allo-HSCT). IL-39, a newly described pro-inflammatory cytokine belonging to the IL-12 family, plays a role in lupus development. Recently, IL-39 has been identified as a pathogenic factor in acute GVHD (aGVHD). However, the role of IL-39 in the pathogenesis of cGVHD remains unclear. METHODS: We constructed a recombinant IL-39 plasmid and established scleroderma and lupus-like cGVHD models. Quantitative PCR and enzyme-linked immunosorbent assay (ELISA) were used to detect IL-39 expression in mice and patients post transplantation, respectively. Hydrodynamic gene transfer (HGT) was performed to achieve IL-39 overexpression in vivo. Multiparameter flow cytometry, western blotting, and assays in vitro were performed to investigate the effect of IL-39 on cGVHD. RESULTS: The relative expression of IL-23p19 and EBi3 was significantly increased in the intestine of cGVHD mice on day 40 post allo-HSCT, and IL-39 levels were significantly elevated in the serum of patients following allo-HSCT. Overexpression of IL-39 significantly aggravated the severity of cGVHD. Increased IL-39 levels promoted T-cell activation and germinal center responses, and may exacerbate thymic damage. Consistently, blocking IL-39 markedly ameliorated immune dysregulation in the cGVHD mice. Furthermore, we found that IL-39 was produced by B cells, CD11b(+) cells, and CD8(+)T cells after activation. Stimulation of IL-39 led to upregulation of the IL-39 receptor on CD4(+)T cells and further caused activation of the STAT1/STAT3 pathway, through which IL-39 may exert its pro-inflammatory effects. CONCLUSION: Our study reveals a critical role for IL-39 in cGVHD pathogenesis and indicates that IL-39 may serve as a potential therapeutic target for cGVHD prevention. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s40164-022-00286-x. BioMed Central 2022-06-02 /pmc/articles/PMC9161463/ /pubmed/35655245 http://dx.doi.org/10.1186/s40164-022-00286-x Text en © The Author(s) 2022 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 Lv, Kangkang Hu, Bo Xu, Mingzhu Wan, Li Jin, Ziqi Xu, Mimi Du, Yuanyuan Ma, Kunpeng Lv, Quansheng Xu, Yang Lei, Lei Gong, Huanle Liu, Haiyan Wu, Depei Liu, Yuejun IL-39 promotes chronic graft-versus-host disease by increasing T and B Cell pathogenicity |
title | IL-39 promotes chronic graft-versus-host disease by increasing T and B Cell pathogenicity |
title_full | IL-39 promotes chronic graft-versus-host disease by increasing T and B Cell pathogenicity |
title_fullStr | IL-39 promotes chronic graft-versus-host disease by increasing T and B Cell pathogenicity |
title_full_unstemmed | IL-39 promotes chronic graft-versus-host disease by increasing T and B Cell pathogenicity |
title_short | IL-39 promotes chronic graft-versus-host disease by increasing T and B Cell pathogenicity |
title_sort | il-39 promotes chronic graft-versus-host disease by increasing t and b cell pathogenicity |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9161463/ https://www.ncbi.nlm.nih.gov/pubmed/35655245 http://dx.doi.org/10.1186/s40164-022-00286-x |
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