title: Curcumin induces apoptotic cell death of activated human CD4+ T cells via increasing endoplasmic reticulum stress and mitochondrial dysfunction.
abstract: Curcumin, a natural polyphenolic antioxidant compound, exerts well-known anti-inflammatory and immunomodulatory effects, the latter which can influence the activation of immune cells including T cells. Furthermore, curcumin can inhibit the expression of pro-inflammatory cytokines and chemokines, through suppression of the NF-κB signaling pathway. The beneficial effects of curcumin in diseases such as arthritis, allergy, asthma, atherosclerosis, diabetes and cancer may be due to its immunomodulatory properties. We studied the potential of curcumin to modulate CD4+ T cells-mediated autoimmune disease, by examining the effects of this compound on human CD4+ lymphocyte activation. Stimulation of human T cells with PHA or CD3/CD28 induced IL-2 mRNA expression and activated the endoplasmic reticulum (ER) stress response. The treatment of T cells with curcumin induced the unfolded protein response (UPR) signaling pathway, initiated by the phosphorylation of PERK and IRE1. Furthermore, curcumin increased the expression of the ER stress associated transcriptional factors XBP-1, cleaved p50ATF6α and C/EBP homologous protein (CHOP) in human CD4+ and Jurkat T cells. In PHA-activated T cells, curcumin further enhanced PHA-induced CHOP expression and reduced the expression of the anti-apoptotic protein Bcl-2. Finally, curcumin treatment induced apoptotic cell death in activated T cells via eliciting an excessive ER stress response, which was reversed by the ER-stress inhibitor 4-phenylbutyric acid or transfection with CHOP-specific siRNA. These results suggest that curcumin can impact both ER stress and mitochondria functional pathways, and thereby could be used as a promising therapy in the context of Th1-mediated autoimmune diseases.
authors: Department of Medical Science, University of Ulsan, Republic of Korea.
authors: Min
authors: M
authors: Zheng
authors: Qinggao
authors: Q
authors: Zhang
authors: Yeonsoo
authors: Y
authors: Joe
authors: Bong Hee
authors: BH
authors: Lee
authors: Do Gon
authors: DG
authors: Ryu
authors: Kang Beom
authors: KB
authors: Kwon
authors: Stefan W
authors: SW
authors: Ryter
authors: Hun Taeg
authors: HT
authors: Chung
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001327:Autoimmune Diseases / Q000188:drug therapy / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D003474:Curcumin / Q000494:pharmacology* / Q000627:therapeutic use; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D004722:Endoribonucleases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000187:drug effects / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D010654:Phenylbutyrates / Q000494:pharmacology; D010835:Phytohemagglutinins / Q000276:immunology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D000071701:Regulatory Factor X Transcription Factors; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D056811:Unfolded Protein Response / Q000187:drug effects / Q000235:genetics; D000071717:X-Box Binding Protein 1; D019892:eIF-2 Kinase / Q000235:genetics / Q000378:metabolism
chemical_list: D003474:Curcumin; D004268:DNA-Binding Proteins; D004722:Endoribonucleases; D008565:Membrane Proteins; D010654:Phenylbutyrates; D010835:Phytohemagglutinins; D017346:Protein Serine-Threonine Kinases; D034741:RNA, Small Interfering; D000071701:Regulatory Factor X Transcription Factors; D051742:Transcription Factor CHOP; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; D019892:eIF-2 Kinase; C497249:DDIT3 protein, human; C000605543:XBP1 protein, human; C075773:4-phenylbutyric acid; C403982:ERN2 protein, human