IL-39 promotes chronic graft-versus-host disease by increasing T and B Cell pathogenicity

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

Abstract

Abstract 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.

Funder

National Natural Science Foundation of China

Science and Technology Program of Suzhou

Suzhou Science and Technology Development Project

China Postdoctoral Science Foundation

Jiangsu Planned Projects for Postdoctoral Research Funds

The Natural Science Foundation of the Jiangsu Higher Education Institutes of China

National Key Research and Development Program of China

National Science and Technology Major Project

Key R&D Program of Jiangsu Province

Priority Academic Program Development of Jiangsu Higher Education Institutions

Jiangsu Medical Outstanding Talents Project

Jiangsu Provincial Key Medical Center

Natural Science Foundation of Jiangsu Province

Translational Research Grant of NCRCH

Publisher

Springer Science and Business Media LLC

Subject

Cancer Research,Oncology,Hematology

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