TNFAIP3 downregulation mediated by histone modification contributes to T-cell dysfunction in systemic lupus erythematosus.
TNF-α-induced protein 3 ( TNFAIP3 ) is one of the major SLE susceptibility genes involved in the regulation of inflammatory responses through modulation of the nuclear factor-κB (NF-κB) pathway. We aim to assess TNFAIP3 expression in CD4 + T cells and the molecular mechanism underlying TNFAIP3 regulation in the pathogenesis of SLE.



The expression and epigenetic regulation of TNFAIP3 in CD4 + T cells from SLE patients and normal controls (NCs) were investigated by RT-quantitative PCR, western blot and chromatin immunoprecipitation. The functional effect of TNFAIP3 was further evaluated by knockdown or overproduction of TNFAIP3 in CD4 + T cells from SLE patients and NCs.



TNFAIP3 mRNA was significantly downregulated in the CD4 + T cells of SLE patients compared with NCs. The reduced expression of TNFAIP3 was associated with the reduction of H3K4me3 in the gene promoter region. Functional blockage of TNFAIP3 in normal CD4 + T cells using small interfering RNA increased the expression of IFN-γ and IL-17, but not IL-2, IL-4 and IL-5. Nevertheless, overexpression of TNFAIP3 in CD4 + T cells from SLE patients resulted in the suppression of IFN-γ and IL-17 production.



The downregulation of TNFAIP3 in CD4 + T cells of SLE was potentially regulated by demethylation of histone H3K4, which led to a decreased amount of H3K4me3 in the promoter of the TNFAIP3 gene. The dysregulation of TNFAIP3 in CD4 + T cells may contribute to the pathogenesis of SLE by overproduction of inflammatory cytokine IFN-γ and IL-17. TNFAIP3 may serve as a promising target for the treatment of SLE in clinical practice.
Department of Rheumatology and Clinical Immunology, Xiangya Hospital, Central South University, Changsha, Hunan Province, People's Republic of China.|Department of Immunology and Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Hongjun
H
Zhao
Department of Rheumatology and Clinical Immunology, Xiangya Hospital, Central South University, Changsha, Hunan Province, People's Republic of China.|Department of Immunology and Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Lijing
L
Wang
Department of Rheumatology and Clinical Immunology, Xiangya Hospital, Central South University, Changsha, Hunan Province, People's Republic of China.
Hui
H
Luo
Department of Rheumatology and Clinical Immunology, Xiangya Hospital, Central South University, Changsha, Hunan Province, People's Republic of China.|Department of Immunology and Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Quan-Zhen
QZ
Li
Department of Rheumatology and Clinical Immunology, Xiangya Hospital, Central South University, Changsha, Hunan Province, People's Republic of China.
Xiaoxia
X
Zuo
D000293:Adolescent; D000328:Adult; D001168:Arthritis / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D016022:Case-Control Studies; D019175:DNA Methylation / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics; D044127:Epigenesis, Genetic; D005260:Female; D055785:Gene Knockdown Techniques; D020868:Gene Silencing / Q000502:physiology; D006657:Histones / Q000378:metabolism*; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D008180:Lupus Erythematosus, Systemic / Q000235:genetics*; D009393:Nephritis / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D011506:Proteins / Q000235:genetics* / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000494:pharmacology; D018417:Th1 Cells / Q000378:metabolism; D058504:Th17 Cells / Q000378:metabolism; D014158:Transcription, Genetic / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics; D055815:Young Adult
D006657:Histones; D020381:Interleukin-17; D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C426747:TNIP3 protein, human; D007371:Interferon-gamma
CD4+ T cell; TNFAIP3; histone modification; inflammatory cytokines; systemic lupus erythematosus