Upregulation of FcγRIIB by resveratrol via NF-κB activation reduces B-cell numbers and ameliorates lupus.
- Author:
Jyun Pei JHOU
1
;
Se Jie CHEN
;
Ho Yin HUANG
;
Wan Wan LIN
;
Duen Yi HUANG
;
Shiang Jong TZENG
Author Information
- Publication Type:Original Article
- MeSH: Animals; Apoptosis; Autoantibodies; B-Lymphocytes*; Bone Marrow; Histone Deacetylases; Humans; Immunoglobulin G; Lupus Nephritis; Mice; Nephritis; Plasma Cells; Promoter Regions, Genetic; Spleen; Up-Regulation*
- From:Experimental & Molecular Medicine 2017;49(9):e381-
- CountryRepublic of Korea
- Language:English
- Abstract: Resveratrol, an anti-inflammatory agent, can inhibit pro-inflammatory mediators by activating Sirt1, which is a class III histone deacetylase. However, whether resveratrol can regulate inhibitory or anti-inflammatory molecules has been less studied. FcγRIIB, a receptor for IgG, is an essential inhibitory receptor of B cells for blocking B-cell receptor-mediated activation and for directly inducing apoptosis of B cells. Because mice deficient in either Sirt1 or FcγRIIB develop lupus-like diseases, we investigated whether resveratrol can alleviate lupus through FcγRIIB. We found that resveratrol enhanced the expression of FcγRIIB in B cells, resulting in a marked depletion of plasma cells in the spleen and notably in the bone marrow, thereby decreasing serum autoantibody titers in MRL/lpr mice. The upregulation of FcγRIIB by resveratrol involved an increase of Sirt1 protein and deacetylation of p65 NF-κB (K310). Moreover, increased binding of phosphor-p65 NF-κB (S536) but decreased association of acetylated p65 NF-κB (K310) and phosphor-p65 NF-κB (S468) to the −480 promoter region of Fcgr2b gene was responsible for the resveratrol-mediated enhancement of FcγRIIB gene transcription. Consequently, B cells, especially plasma cells, were considerably reduced in MRL/lpr mice, leading to improvement of nephritis and prolonged survival. Taken together, we provide evidence that pharmacological upregulation of FcγRIIB expression in B cells via resveratrol can selectively reduce B cells, decrease serum autoantibodies and ameliorate lupus nephritis. Our findings lead us to propose FcγRIIB as a new target for therapeutic exploitation, particularly for lupus patients whose FcγRIIB expression levels in B cells are downregulated.
