title: Oxidative stress modulates the cytokine response of differentiated Th17 and Th1 cells.
abstract: Reactive oxygen species (ROS) signaling is critical in T helper (Th) cell differentiation; however its role in differentiated Th cell functions is unclear. In this study, we investigated the role of oxidative stress on the effector functions of in vitro differentiated mouse Th17 and Th1 cells or CD4+T cells from patients with Rheumatoid Arthritis using pro-oxidants plumbagin (PB) and hydrogen peroxide. We found that in mouse Th cells, non-toxic concentration of pro-oxidants inhibited reactivation induced expression of IL-17A in Th17 and IFN-γ in Th1 cells by reducing the expression of their respective TFs, RORγt and T-bet. Interestingly, in both the subsets, PB increased the expression of IL-4 by enhancing reactivation induced ERK1/2 phosphorylation. We further investigated the cytokine modulatory effect of PB on CD4+T cells isolated from PBMCs of patients with Rheumatoid Arthritis, a well-known Th17 and or Th1 mediated disease. In human CD4+T cells from Rheumatoid Arthritis patients, PB reduced the frequencies of IL-17A+(Th17), IFN-γ+(Th1) and IL-17A+/IFN-γ+(Th17/1) cells and also inhibited the production of pro-inflammatory cytokines TNF-α and IL-6. N-Acetyl Cysteine (NAC) an antioxidant completely reversed PB mediated cytokine modulatory effects in both mouse and human cells indicating a direct role for ROS. Together our data suggest that oxidative microenvironment can alter cytokine response of terminally differentiated cells and thus altering intracellular ROS could be a potential way to target Th17 and Th1 cells in autoimmune disorders.
authors: Infectious Disease Biology, Institute of Life Sciences, Chandrashekarpur, Bhubaneswar 751023, Odisha, India.
authors: Thiruvaimozhi
authors: T
authors: Abimannan
authors: Infectious Disease Biology, Institute of Life Sciences, Chandrashekarpur, Bhubaneswar 751023, Odisha, India.
authors: Doureradjou
authors: D
authors: Peroumal
authors: Institute of Medical Sciences & SUM Hospital, Kalinga Nagar, Bhubaneswar 751003, Odisha, India.
authors: Jyoti R
authors: JR
authors: Parida
authors: Infectious Disease Biology, Institute of Life Sciences, Chandrashekarpur, Bhubaneswar 751023, Odisha, India.
authors: Prakash K
authors: PK
authors: Barik
authors: Kalinga Institute of Medical Sciences, Patia, Bhubaneswar 751024, Odisha, India.
authors: Prasanta
authors: P
authors: Padhan
authors: Infectious Disease Biology, Institute of Life Sciences, Chandrashekarpur, Bhubaneswar 751023, Odisha, India. Electronic address: satdevs@ils.res.in.
authors: Satish
authors: S
authors: Devadas
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D016022:Case-Control Studies; D002454:Cell Differentiation; D016207:Cytokines / Q000235:genetics / Q000276:immunology*; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology*; D006801:Humans; D006861:Hydrogen Peroxide / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000276:immunology; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000276:immunology; D009285:Naphthoquinones / Q000037:antagonists & inhibitors / Q000494:pharmacology; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000235:genetics / Q000276:immunology; D016877:Oxidants / Q000037:antagonists & inhibitors / Q000494:pharmacology; D018384:Oxidative Stress / Q000276:immunology*; D010766:Phosphorylation / Q000187:drug effects; D061251:Primary Cell Culture; D020825:T-Box Domain Proteins / Q000235:genetics / Q000276:immunology; D018417:Th1 Cells / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D058504:Th17 Cells / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D000098815:T-bet Transcription Factor
chemical_list: D016207:Cytokines; D009285:Naphthoquinones; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D016877:Oxidants; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D006861:Hydrogen Peroxide; C535148:Mapk1 protein, mouse; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D000111:Acetylcysteine; C014758:plumbagin
keywords: Autoimmunitys; Cytokines; Helper T cells; Oxidative stress; Transcription factors