Interleukin-10 promotes activation-induced cell death of SLE lymphocytes mediated by Fas ligand.

Georgescu, Liviu; Vakkalanka, Radhakrishna; Elkon, Keith B.; Crow, Mary K.

doi:10.1172/jci119806

Cited by 166 publications

(116 citation statements)

References 67 publications

(52 reference statements)

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“…Spontaneous T cell apoptosis was not statistically different between EPEPϩ/ϩ, EPEPϩ/Ϫ, and EPEPϪ/Ϫ individuals among either SLE patients or healthy controls. Several investigators have reported the analysis of spontaneous T cell apoptosis in patients with SLE (36)(37)(38). Spontaneous apoptosis immediately after isolation of T cells from SLE patients (regardless of their level of disease activity) was not significantly increased compared with that of T cells from healthy controls (37).…”

Section: Discussionmentioning

confidence: 99%

“…Several investigators have reported the analysis of spontaneous T cell apoptosis in patients with SLE (36)(37)(38). Spontaneous apoptosis immediately after isolation of T cells from SLE patients (regardless of their level of disease activity) was not significantly increased compared with that of T cells from healthy controls (37). When cultured for several days, T cells from SLE patients showed significantly increased apoptosis compared with those obtained from controls.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Association of a four–amino acid residue insertion polymorphism of the HS1 gene with systemic lupus erythematosus: Molecular and functional analysis

Otsuka

Horiuchi

Yoshizawa

et al. 2004

Arthritis & Rheumatism

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Objective. To investigate whether polymorphism(s) or mutation(s) in the hematopoietic cellspecific Lyn substrate 1 (HS1) gene are involved in the pathogenesis of systemic lupus erythematosus (SLE).Methods. The entire coding region of the HS1 gene was analyzed by reverse transcriptase-polymerase chain reaction/single-strand conformational polymorphism analysis. HS1-transfected WEHI-231 cells or B lymphocytes from patients with SLE were studied for apoptosis, activation, and proliferation by flow cytometric analysis and MTT assay.Results. We identified a glutamic acid-prolineglutamic acid-proline insertion between codons 366 and 367 (EPEP366-367ins) and 2 amino acid substitutions (A235T and E361K). The genotype frequency among individuals homozygous for the EPEP؉ allele was 0.184 in 201 patients with SLE but only 0.098 in 184 healthy individuals (P ‫؍‬ 0.016). The allele frequency of EPEP366-367ins was 0.408 in patients with SLE; this frequency was significantly higher than that in healthy controls (0.312) (P ‫؍‬ 0.006). WEHI-231 cells transfected with EPEP؉ HS1 were 100-fold more sensitive to B cell receptor (BCR)-mediated apoptosis than were those transfected with HS1 without EPEP. B lymphocytes from SLE patients with the EPEP؉ allele were significantly more apoptotic without BCR stimulation and less activated after BCR stimulation than were those from SLE patients without the EPEP allele. Conclusion. These results suggest that HS1 with the EPEP insertion polymorphism transmits accelerated signals from BCR and is involved in the pathogenesis of SLE.Systemic lupus erythematosus (SLE) is a prototypic systemic autoimmune disease characterized by the presence of a variety of autoantibodies. Various genetic and environmental factors, including B cell hyperactivity, T cell dysfunction, and cytokine dysregulation, initiate immune activation in SLE that culminates in organ inflammation and damage (1-9). It has been considered that B cells are innocent bystanders that are activated secondarily by autoreactive T lymphocytes. However, recent evidence from the study of human SLE and its murine models suggests that B lymphocytes are intrinsically defective and are primarily essential for the maintenance of activated/memory T cells by presenting antigens to T cells.B cells from mice deficient in Lyn (10-12), CD22 (13-16), SHP-1 (17,18) exhibit a hyperreactive phenotype and produce autoantibodies. Indeed, Lyn-deficient mice demonstrate activation of autoreactive B cells and subsequent SLE-like symptoms, such as the production of anti-double-stranded DNA (anti-dsDNA)

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Association of a four–amino acid residue insertion polymorphism of the HS1 gene with systemic lupus erythematosus: Molecular and functional analysis

Otsuka

Horiuchi

Yoshizawa

et al. 2004

Arthritis & Rheumatism

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“…In lpr and gld mice, defects in PCD signaling through the Fas pathway appear to predispose to autoimmunity [29]. Whereas mutations of the Fas receptor (FasR) or Fas ligand (FasL) have been associated with a lupus-like autoimmune syndrome in mice with the lpr or gld genetic background [29], Fas-mediated signaling appears to be intact in human SLE [30]. Lupus T cells demonstrate defective activation-induced cell death (AICD) [31].…”

Section: Mhp Increased Roi Production Cytoplasmic Alkalinization Anmentioning

confidence: 99%

“…Cell-surface expression of FasR [39] and FasL is also redox sensitive [40]. Increased ROI levels might be related to increased IL-10 production, release of FasL and overexpression of FasR in SLE [30]. Elevated NO production might also contribute to increased spontaneous apoptosis [41].…”

Section: Mhp Increased Roi Production Cytoplasmic Alkalinization Anmentioning

confidence: 99%

Mitochondrial hyperpolarization: a checkpoint of T-cell life, death and autoimmunity

Perl

Gergely

Nagy

et al. 2004

Trends in Immunology

220

142

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T-cell activation, proliferation and selection of the cell death pathway depend on the production of reactive oxygen intermediates (ROIs) and ATP synthesis, which are tightly regulated by the mitochondrial transmembrane potential (ΔΨ m ). Mitochondrial hyperpolarization (MHP) and ATP depletion represent early and reversible steps in T-cell activation and apoptosis. By contrast, T cells of patients with systemic lupus erythematosus (SLE) exhibit persistent MHP, cytoplasmic alkalinization, increased ROI production and depleted ATP, which mediate enhanced spontaneous and diminished activation-induced apoptosis and sensitize lupus T cells to necrosis. Necrotic, but not apoptotic, cell lysates activate dendritic cells and might account for increased interferon a production and inflammation in lupus patients. MHP is proposed as a key mechanism of SLE pathogenesis and is therefore a target for pharmacological intervention.Innate and adaptive immune responses depend on controlled production of ATP and reactive oxygen intermediates (ROIs) in mitochondria. In response to antigenic stimulation, clonal expansion of T and B cells are continuously downsized and potentially autoreactive cells are eliminated by apoptosis. An array of signals through the T-cell receptor (TCR), costimulatory molecules, cell death receptors, lymphokines, and other circulating metabolites, such as ATP, NAD, cADPR, glucose, glutathione, nitric oxide (NO) and ROIs, determine the fate of T cells [1]. T-cell activation and death pathway selection depend on the production of ROIs and ATP synthesis, which are tightly regulated by the mitochondrial transmembrane potential (ΔΨ m ) (Box 1). Disruption of ΔΨ m has been proposed as the point of no return in apoptotic signaling [2] T-cell activation is regulated by mitochondrial ROI productionROIs modulate T-cell activation, cytokine production and proliferation at multiple levels [12]. The antigen-binding αβ or γδTCR is associated with a multimeric receptor module comprising the CD3γδε and TCRζ chains. The cytoplasmic domains of the CD3 and ζ chains contain a common motif, termed the immunoreceptor tyrosinebased activation motif (ITAM), which is crucial for the coupling of intracellular tyrosine kinases [13]. . Thus, expression of cytokines can be selectively regulated by oxidative stress depending on the relative expression level of transcription factors involved (e.g. IL-2 is expressed through a promoter that has AP-1 and NFAT motifs, and IL-4 is expressed through an AP-1-less NFAT enhancer; Figure 1). Redox control of apoptosis signal processingProgrammed cell death (PCD) or apoptosis is a physiological mechanism for elimination of autoreactive lymphocytes during development. Signaling through the Fas or structurally related TNF family of cell-surface death receptors has emerged as a major pathway in the elimination of unwanted cells under physiological and disease conditions [18]. Fas and TNF receptors mediate cell death through cytoplasmic death domains (DDs) shared by both receptors [19]. They ...

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“…The established facts are that (i) IL-10 favors the maturation of TH2 lymphocytes; (ii) IL-10 prevents tumour antigen presentation to CD8ϩ CTLs by suppressing the expression of MHC class I and II antigens; 31,32 and (iii) in certain clinical conditions, IL-10 may regulate the survival or death of immune cells via the CD95/ CD95L (Fas/Fas-L)-dependent apoptotic pathways. 33,34 It has been demonstrated that IL-10 induces apoptosis not only in CD4ϩ lymphocytes and NK cells [33][34][35] but also in human monocytes. 36 All these immune cells are of central importance in the initiation, development and outcome of the immune response.…”

Section: Il-10 Cytokine Gene Polymorphisms In Different Stages and Dementioning

confidence: 99%

Cancer of the uterine cervix may be significantly associated with a gene polymorphism coding for increased IL-10 production

et al. 2001

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The purpose of our prospective, case-controlled study was to investigate the hypothesis that women who are genetically programmed to produce high or medium levels of IL-10 were more likely to develop cancer of the uterine cervix than individuals genetically predisposed to low IL-10 production. The population was recruited from patients attending gynecological clinics at 2 hospitals in Harare, Zimbabwe. Laboratory tests were performed in the Departments of Immunology, Chemical Pathology and Medical Microbiology, Medical School, University of Zimbabwe, and simultaneously at the Department of Biological Sciences, University of Manchester, United Kingdom. Included in our study were 77 women with histologically proven cancer of the uterine cervix and 69 age-and parity-matched healthy women. All of the patients and healthy controls were from the Shona ethnic group that inhabits northern Zimbabwe. DNA was purified from cervical cytobrush samples obtained from women with cervical cancer. Control DNA was extracted from urine or peripheral blood samples from the healthy women. The Qiagen DNA extraction kit was used. Detection of allele A and/or G at ؊1082 in the promoter region of the IL-10 gene was carried out using the ARMS-PCR technique. Polymorphism in the amplified products was detected by gel electrophoresis in the presence of ethidium bromide and were bands visualized under UV light. The data comprise 77 women who developed invasive cervical cancer and 69 healthy women matched for age and parity. Patients with cancer were significantly (p ‫؍‬ 0.001) more likely to be predisposed to produce higher (A/G) levels of IL-10. The genotype encoding for high (G/G) production of IL-10 was only observed in one cancer patient. The prevalence of low producers of IL-10 in the cancer group was significantly lower than in the healthy women. There were no high producers amongst the healthy women. These data suggest that the genetically acquired ability to produce higher levels of IL-10 may be a significant factor in the development of cervical cancer.

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Interleukin-10 promotes activation-induced cell death of SLE lymphocytes mediated by Fas ligand.

Cited by 166 publications

References 67 publications

Association of a four–amino acid residue insertion polymorphism of the HS1 gene with systemic lupus erythematosus: Molecular and functional analysis

Association of a four–amino acid residue insertion polymorphism of the HS1 gene with systemic lupus erythematosus: Molecular and functional analysis

Mitochondrial hyperpolarization: a checkpoint of T-cell life, death and autoimmunity

Cancer of the uterine cervix may be significantly associated with a gene polymorphism coding for increased IL-10 production

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