IL-6 Produced by Dendritic Cells from Lupus-Prone Mice Inhibits CD4+CD25+ T Cell Regulatory Functions

Wan, Suigui; Xia, Chang-Qing; Morel, Laurence

doi:10.4049/jimmunol.178.1.271

Cited by 185 publications

(193 citation statements)

References 51 publications

(62 reference statements)

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“…60 Furthermore, T REG cell suppressive functions are reduced in SLE patients and MRL mice, and it is thought that this is due to elevated levels of IL-6, which inhibits T REG cell function. 42,94,95 T REG cells have significantly higher expression of HSP90 than T cells. The high expression of HSP90 in T REG suggests a role for HSP90 in FoxP3 expression and may explain why we found higher levels of FoxP3 2 CD3 1 CD8 1 T cells.…”

Section: Mature B Cells Were Decreased In Mice Treated With 17-dmagmentioning

confidence: 89%

Heat shock protein 90 inhibition by 17-DMAG lessens disease in the MRL/lpr mouse model of systemic lupus erythematosus

et al. 2012

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Elevated expression of heat shock protein 90 (HSP90) has been found in kidneys and serum of systemic lupus erythematosus (SLE) patients and MRL/Mp-Fas lpr /Fas lpr (MRL/lpr) autoimmune mice. We investigated if inhibition of HSP90 would reduce disease in MRL/ lpr mice. In vitro, pretreatment of mesangial cells with HSP90 inhibitor Geldanamycin prior to immune-stimulation showed reduced expression of IL-6, IL-12 and NO. In vivo, we found HSP90 expression was elevated in MRL/lpr kidneys when compared to C57BL/6 mice and MRL/lpr mice treated with HSP90 inhibitor 17-DMAG. MRL/lpr mice treated with 17-DMAG showed decreased proteinuria and reduced serum anti-dsDNA antibody production. Glomerulonephritis and glomerular IgG and C3 were not significantly affected by administration of 17-DMAG in MRL/lpr. 17-DMAG increased CD8 1 T cells, reduced double-negative T cells, decreased the CD4/CD8 ratio and reduced follicular B cells. These studies suggest that HSP90 may play a role in regulating T-cell differentiation and activation and that HSP90 inhibition may reduce inflammation in lupus.

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Section: Mature B Cells Were Decreased In Mice Treated With 17-dmagmentioning

confidence: 89%

Heat shock protein 90 inhibition by 17-DMAG lessens disease in the MRL/lpr mouse model of systemic lupus erythematosus

et al. 2012

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“…This process could be driven to affinity maturation and isotype class switching by antigen and TLR-dependent signals or by nonspecific activation of DC and hypersecretion of cytokines, such as IL-6. DC from autoimmune B6.Sle1.-Sle2.Sle3 congenic mice have also been shown to suppress Treg cell function in vitro via IL-6 [55]. It is tempting to explain the complexity of human lupus in terms of cumulative effects on antigen-specific and antigen-independent regulation of the immune response.…”

Section: Discussionmentioning

confidence: 99%

MyD88‐dependent autoimmune disease in Lyn‐deficient mice

et al. 2007

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Recent evidence suggests that systemic autoimmune disease depends on signals from TLR ligands, but little is known about how TLR-dependent pathways lead to the loss of self tolerance in vivo. To address this, we have examined the role of TLR signaling in Lyndeficient mice, which develop an autoimmune disease similar to SLE. We found that absence of the TLR signaling adaptor molecule MyD88 suppresses plasma cell differentiation of switched and unswitched B cells, and prevents the generation of antinuclear IgG antibodies and glomerulonephritis. In mixed chimeras the increased IgM and IgG antibody secretion in Lyn-deficient mice is at least partially due to B cellindependent effects of Lyn. We now show that MyD88 deficiency blocks the expansion and activation of DC in which Lyn is also normally expressed, and prevents the hypersecretion of proinflammatory cytokines IL-6 and IL-12 by Lyn-deficient DC. These findings further highlight the important role of TLR-dependent signals in both lymphocyte activation and autoimmune pathogenesis. IntroductionOur understanding of the pathways leading to autoantibody (autoAb) production in systemic lupus erythematosus (SLE) has been greatly enhanced by studies of murine SLE models, including mice with single targeted mutations to negative regulators of BCR signaling, e.g., the src-family protein tyrosine kinase Lyn [1][2][3], phosphatase SHP-1 [4] and coreceptor CD22 [5, 6]. Lyn deficiency manifests as the hypersecretion of IgM, IgA and IgG autoAb, which, by 17-20 weeks of age, develop specificity to nuclear components such as dsDNA, are deposited as immune complexes (IC) in the kidneys and lead to lethal proliferative glomerulonephritis [1][2][3]. Following BCR stimulation, Lyn-deficient B cells have greater and more prolonged intracellular calcium flux, more MAPK activation and hyperproliferate in comparison to WT B cells [1, 7, 8]. These findings, together with the fact that the expression of Lyn is limited to B, NK and myeloid cells [9], have led to the suggestion that B cell intrinsic effects are the main cause of SLE-like autoimmune disease. Growing support for the central role B cells play in the development of autoimmune disease (reviewed in [10]) and the discovery of lower levels of Lyn in B cells of human SLE patients have helped strengthen this idea [11].However, the development of high-affinity pathogenic autoAb, which are targeted at nuclear antigens and potentially damaging to organs including kidneys, depends on somatic hypermutation in the germinal center and collaboration between cells of the adaptive and innate immune systems. T cells play an important role in this process and autoantigen-specific T cells are required for secretion of IgG autoAb specific for nuclear components and end-organ damage in the spontaneous murine models, MRL-lpr/lpr and (NZBÂNZW)F 1 [18]. Disease in the gp96 transgenic mice is dependent on MyD88, an adaptor molecule required for signaling by all TLR except TLR3, which binds dsRNA, and TLR4, which also signals by a MyD88-independent pa...

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“…These studies provided thus a plausible explanation for the systemic nature of the disease. A lack of Treg-mediated immune regulation in lupus is now a general consensus, although there have been differences in the findings as to whether a reduced Treg frequency [40-46, 49-53, 58-61, 68, 71-75, 82-84, 88, 90], defective Treg functions [44,48,53,57,59,60,66,70,76,80,89,90] or both, or alternatively an insensitivity of the Treg target cells [66,67,70,89,99], are truly accountable. By using CD25 as the marker, an early study by Crispin and colleagues first showed that, in lupus patients with active disease, the frequencies of Treg (CD4+CD25 +/bright ) were significantly decreased, while T cells with an activated T helper (Th) effector phenotype (CD4 + CD69 + ) increased [40].…”

Section: Aberrant Treg Frequencies and Functions Associated With Lupumentioning

confidence: 99%

“…However, there have also been controversial findings from other studies showing that the frequency of Treg cells, either defined as CD4 + CD25 bright or CD4 + Foxp3 + , could be normal www.intechopen.com [48,66,67,70,85,86] or even increased [47, 54-56, 58, 62-65, 69, 74, 76-79, 81] in lupus disease. Instead, some of these studies suggested that Treg were functionally defective and less capable of suppressing those potentially auto-reactive lymphocytes in lupus patients [44,48,53,57,59,60,66,76,80], and the mouse models [70,89,90]. Again, alternative findings demonstrating lupus Treg being functionally normal [49,50,62,67,85], or at least normal in majority of patients tested [48,64], or even enhanced in some way [68,80,87] added further confusion as well as interest to the matter.…”

Section: Aberrant Treg Frequencies and Functions Associated With Lupumentioning

confidence: 99%

“…This was attributed to the induction of tolerogenic DC which produced enhanced levels of TGF-, but decreased IL-6 expression [115]. Another study by Wan et al also pointed to the role of IL-6 produced by DC in blocking Treg function, and its genetic linkage (sle1) in mice originated from the NZM2410 lupus mouse strain [90]. In addition, aberrant expression of Type 1 interferon (IFN-) by APC has also been shown to block Treg functions contributing to the Treg versus Teff imbalance in lupus disease [65,81,116].…”

Section: Roles Of DCmentioning

confidence: 99%

See 1 more Smart Citation

Regulatory T Cell Deficiency in Systemic Autoimmune Disorders – Causal Relationship and Underlying Immunological Mechanisms

Huang¹,

Sattler²

2011

Autoimmune Disorders - Pathogenetic Aspects

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IL-6 Produced by Dendritic Cells from Lupus-Prone Mice Inhibits CD4+CD25+ T Cell Regulatory Functions

Cited by 185 publications

References 51 publications

Heat shock protein 90 inhibition by 17-DMAG lessens disease in the MRL/lpr mouse model of systemic lupus erythematosus

Heat shock protein 90 inhibition by 17-DMAG lessens disease in the MRL/lpr mouse model of systemic lupus erythematosus

MyD88‐dependent autoimmune disease in Lyn‐deficient mice

Regulatory T Cell Deficiency in Systemic Autoimmune Disorders – Causal Relationship and Underlying Immunological Mechanisms

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