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Iguratimod represses B cell terminal differentiation linked with the inhibition of PKC/EGR1 axis

Authors :
Yan Ye
Mei Liu
Longhai Tang
Fang Du
Yuanhua Liu
Pei Hao
Qiong Fu
Qiang Guo
Qingran Yan
Xiaoming Zhang
Chunde Bao
Source :
Arthritis Research & Therapy, Vol 21, Iss 1, Pp 1-13 (2019)
Publication Year :
2019
Publisher :
BMC, 2019.

Abstract

Abstract Background This study aimed to explore the molecular mechanism and clinical relevance of iguratimod in the regulation of human B cell terminal differentiation. Methods An in vitro human antibody-secreting cell (ASC) differentiation system was established to test the effect of iguratimod. B cell phenotype and key transcription factors (TFs) relevant to ASC differentiation were analyzed through flow cytometry and qPCR. The COX-2 activity was measured by enzyme immunoassay (EIA). RNA sequencing was used to identify potential targets of iguratimod. We enrolled six treatment-naive rheumatoid arthritis (RA) patients whose blood samples were collected for phenotypic and molecular studies along with 12-week iguratimod monotherapy. Results Iguratimod inhibited human ASC generation without affecting B cell activation and proliferation. Iguratimod showed only weak COX-2 activity. Gene set enrichment analysis (GSEA) identified that protein kinase C (PKC) pathway was targeted by iguratimod which was confirmed by PKC activity detection. Furthermore, early growth response 1 (EGR1), a target of PKC and a non-redundant TF for ASC differentiation, was found to be the most downregulated gene in iguratimod-treated B cells. Lastly, iguratimod monotherapy decreased peripheral ASCs and was associated with improved disease activity. The expression of major ASC-related TFs, including EGR1, was similarly downregulated in patient blood samples. Conclusions Iguratimod inhibits ASC differentiation both in vitro and in RA patients. Our study suggests that PKC/EGR1 axis, rather than COX-2, is critically involved in the inhibitory effect by iguratimod on human ASC differentiation. Iguratimod could have a broader application to treat B cell-related autoimmune diseases in clinics.

Details

Language :
English
ISSN :
14786362
Volume :
21
Issue :
1
Database :
Directory of Open Access Journals
Journal :
Arthritis Research & Therapy
Publication Type :
Academic Journal
Accession number :
edsdoj.495c723bc07a429a97b2b4178b4f42be
Document Type :
article
Full Text :
https://doi.org/10.1186/s13075-019-1874-2