Iguratimod Represses B Cell Terminal Differentiation Linked With the Inhibition of PKC/EGR1 Axis

Yan Ye, Mei Liu, Longhai Tang, Fang Du, Yuanhua Liu, Pei Hao, Qiong Fu, Qiang Guo, Qingran Yan, Xiaoming Zhang, Chunde Bao

Arthritis Res Ther. 2019 Apr 11;21(1):92.

PMID: 30971291

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP123663490	Iguratimod		123663-49-0	Price