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Open Access 01-12-2019 | Celecoxib | Research article

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

Published in: Arthritis Research & Therapy | Issue 1/2019

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.

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Title: 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
Publication date: 01-12-2019
Publisher: BioMed Central
Keywords: Celecoxib
Rheumatoid Arthritis
Published in: Arthritis Research & Therapy / Issue 1/2019
Electronic ISSN: 1478-6362
DOI: https://doi.org/10.1186/s13075-019-1874-2

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