Multidimensional Single Cell Based STAT Phosphorylation Profiling Identifies a Novel Biosignature for Evaluation of Systemic Lupus Erythematosus Activity

Huang, Xinfang; Guo, Yanzhi; Bao, Chunde; Shen, Nan

doi:10.1371/journal.pone.0021671

Cited by 42 publications

(28 citation statements)

References 32 publications

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“…The differences in the cytokine-stimulated pSTAT responses between pSS patients and controls were observed mainly in STAT1, whereas the cytokine-induced STAT5 phosphorylation in T cells from pSS patients was found to be comparable to controls. Similar findings have previously been reported in SLE patients with elevated constitutive activation of STAT5 in B cells and T cells, but reduced responses of STAT5 to IFN-α in T cells, B cells and monocytes from SLE patients [18].…”

Section: Discussionsupporting

confidence: 90%

Cytokine-induced STAT1 activation is increased in patients with primary Sjögren's syndrome

Pertovaara

Silvennoinen

Isomäki

2016

Clinical Immunology

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Section: Discussionsupporting

confidence: 90%

Cytokine-induced STAT1 activation is increased in patients with primary Sjögren's syndrome

Pertovaara

Silvennoinen

Isomäki

2016

Clinical Immunology

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“…This effect might be related with the inhibitory effect on lymphocyte proliferation induced by this agent. 40,41 Infiltration of T cells into the kidney is a typical feature of human and experimental lupus nephritis that contributes to renal tissue injury. 42,43 Thus, reducing Th17 cells by hydroxychloroquine treatment might be the main mechanism involved in the protective effects of hydroxychloroquine in lupus nephritis.…”

Section: Discussionmentioning

confidence: 99%

Chronic Hydroxychloroquine Improves Endothelial Dysfunction and Protects Kidney in a Mouse Model of Systemic Lupus Erythematosus

et al. 2014

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S ystemic lupus erythematosus (SLE) is a multisystemic chronic autoimmune inflammatory disorder that is associated with a high risk for the development of renal and cardiovascular disease, 1,2 which are major causes of mortality in these patients. 3 It predominantly affects young women of child-bearing age, the same population that is at lowest relative risk of atherosclerotic heart disease. In fact, women with lupus (age, 35-44 years) are >50 times as likely as healthy women without lupus to have a myocardial infarction. 4 Indeed, SLE is characterized by a high incidence of hypertension, 5-7 a wellestablished risk factor for the development and acceleration of atherosclerosis and ischemic heart disease. Oxidative stress and the inactivation of nitric oxide (NO) by vascular superoxide anion (O 2 ·− ) play a critical role in the pathogenesis of endothelial dysfunction, an early event in most cardiovascular diseases, including hypertension. 8,9 Reactive oxygen species (ROS) have been considered as risk and enhancer factors for autoimmune diseases, 10 and oxidation is one of the major factors responsible for atheroma development in this context. Indeed, SLE is a disease characterized by an increased oxidative damage.11-14 Free radical-mediated reactions are implicated in endothelial dysfunction in SLE, 15 and renal oxidative stress plays an important mechanistic role in the development of autoimmune-mediated hypertension. 16Abstract-Hydroxychloroquine has been shown to be efficacious in the treatment of autoimmune diseases, including systemic lupus erythematosus. Hydroxychloroquine-treated lupus patients showed a lower incidence of thromboembolic disease. Endothelial dysfunction, the earliest indicator of the development of cardiovascular disease, is present in lupus.Whether hydroxychloroquine improves endothelial function in lupus is not clear. The aim of this study was to analyze the effects of hydroxychloroquine on hypertension, endothelial dysfunction, and renal injury in a female mouse model of lupus. NZBWF1 (lupus) and NZW/LacJ (control) mice were treated with hydroxychloroquine 10 mg/kg per day by oral gavage, or with tempol and apocynin in the drinking water, for 5 weeks. Hydroxychloroquine treatment did not alter lupus disease activity (assessed by plasma double-stranded DNA autoantibodies) but prevented hypertension, cardiac and renal hypertrophy, proteinuria, and renal injury in lupus mice. Aortae from lupus mice showed reduced endotheliumdependent vasodilator responses to acetylcholine and enhanced contraction to phenylephrine, which were normalized by hydroxychloroquine or antioxidant treatments. No differences among all experimental groups were found in both the relaxant responses to acetylcholine and the contractile responses to phenylephrine in rings incubated with the nitric oxide synthase inhibitor N G -nitro-l-arginine methyl ester. Vascular reactive oxygen species content and mRNA levels of nicotinamide adenine dinucleotide phosphate oxidase subunits NOX-1 and p47 phox were increased in lupus...

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“…Conflicting data exist regarding Stat5 in SLE (21,22). Although attenuated IL-2 expression in SLE T cells suggests reduced Stat5 activation (23)(24)(25), one study demonstrated increased Stat5 phosphorylation in SLE (22). In T cells from SLE patients and lupus-prone MRL/lpr mice, pStat3 is increased (19,26).…”

Section: Discussionmentioning

confidence: 99%

Stat3 promotes IL-10 expression in lupus T cells through trans- activation and chromatin remodeling

Hedrich

Rauen

Apostolidis

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

151

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The immune-regulatory cytokine IL-10 plays a central role during innate and adaptive immune responses. IL-10 is elevated in the serum and tissues of patients with systemic lupus erythematosus (SLE), an autoimmune disorder characterized by autoantibody production, immune-complex formation, and altered cytokine expression. Because of its B cell-promoting effects, IL-10 may contribute to autoantibody production and tissue damage in SLE. We aimed to determine molecular events governing T cell-derived IL-10 expression in health and disease. We link reduced DNA methylation of the IL10 gene with increased recruitment of Stat family transcription factors. Stat3 and Stat5 recruitment to the IL10 promoter and an intronic enhancer regulate gene expression. Both Stat3 and Stat5 mediate trans-activation and epigenetic remodeling of IL10 through their interaction with the histone acetyltransferase p300. In T cells from SLE patients, activation of Stat3 is increased, resulting in enhanced recruitment to regulatory regions and competitive replacement of Stat5, subsequently promoting IL-10 expression. A complete understanding of the molecular events governing cytokine expression will provide new treatment options in autoimmune disorders, including SLE. The observation that altered activation of Stat3 influences IL-10 expression in T cells from SLE patients offers molecular targets in the search for novel target-directed treatment options.

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Multidimensional Single Cell Based STAT Phosphorylation Profiling Identifies a Novel Biosignature for Evaluation of Systemic Lupus Erythematosus Activity

Cited by 42 publications

References 32 publications

Cytokine-induced STAT1 activation is increased in patients with primary Sjögren's syndrome

Cytokine-induced STAT1 activation is increased in patients with primary Sjögren's syndrome

Chronic Hydroxychloroquine Improves Endothelial Dysfunction and Protects Kidney in a Mouse Model of Systemic Lupus Erythematosus

Stat3 promotes IL-10 expression in lupus T cells through trans- activation and chromatin remodeling

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