NF-κB signalling is inhibited by glucocorticoid receptor and STAT6 via distinct mechanisms

Nelson, Glyn; Wilde, Geraint J. C.; Spiller, David G.; Kennedy, Stephanie M.; Ray, David; Sullivan, Elaine; Unitt, John; White, Mike

doi:10.1242/jcs.00461

Cited by 66 publications

(54 citation statements)

References 39 publications

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“…This finding is in agreement with previous studies (34). STAT6 can inhibit gene expression either by acting on the histone acetylation level of target gene promoter (35) or by interfering with the binding or the activity of transcription factors such as NF-B (36,37). For the ccl5 promoter, preliminary results suggest that the acetylation level of histones associated with the promoter is not decreased by IL-4 treatment.…”

Section: Discussionsupporting

confidence: 92%

Cell-Autonomous CCL5 Transcription by Memory CD8 T Cells Is Regulated by IL-4

Marçais

Coupet

Walzer

et al. 2006

The Journal of Immunology

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Immunological memory is associated with the display of improved effector functions. The maintenance by CD8 memory cells of high levels of untranslated CCL5 mRNA allows these cells to immediately secrete this chemokine upon Ag stimulation. Untranslated mRNA storage is a newly described process supporting the immediate display of an effector function by memory lymphocytes. We have tested the capacity of different cytokines to regulate the memorization of CCL5 by memory CD8 T cells. We found that IL-4 treatment of murine CD8 T cells impairs immediate CCL5 secretion capacity by inhibiting CCL5 mRNA transcription through a STAT6-dependent pathway. The inhibition by IL-4 is reversible, as memory CD8 T cells reconstitute their CCL5 mRNA stores and reacquire their immediate CCL5 secretion capacity when IL-4 is withdrawn. This recovery is cell autonomous because it proceeds in culture medium in the absence of exogenous growth factors, suggesting that CCL5 expression by memory CD8 T cells is a default process. Overall, these results indicate that the expression of CCL5 is an intrinsic property acquired by memory CD8 T cells that is regulated by environmental factors.

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Section: Discussionsupporting

confidence: 92%

Cell-Autonomous CCL5 Transcription by Memory CD8 T Cells Is Regulated by IL-4

Marçais

Coupet

Walzer

et al. 2006

The Journal of Immunology

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“…Therefore, different cells participating in IL-13-induced lung tissue response may have: 1) a different STAT6 dependence because of the absence or presence of IL-4R␣ and/or STAT6; 2) a simultaneous induction of different signaling pathways such as STAT6 and ERK1/2 (15), etc., that either enhance or suppress the expression of target genes, especially genes containing composite sites; 3) a consecutive induction of different signaling pathways regulating each other. A possible negative effect of STAT6 on NF-B activation has been reported in vitro (63) and in vivo (64). Moreover, phosphorylated STAT6 can bind both p50 and p65 subunits of NF-B directly and this interaction substantially enhances STAT6 DNA-binding activity and synergistically activates IL-4-responsive gene transcription (65).…”

Section: Discussionmentioning

confidence: 95%

Inhibition of NF-κB Activation Reduces the Tissue Effects of Transgenic IL-13

Chapoval

Al-Garawi²,

Lora³

et al. 2007

The Journal of Immunology

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IL-13 is a major Th2 cytokine that is capable of inducing inflammation, excessive mucus production, airway hyperresponsiveness, alveolar remodeling, and fibrosis in the murine lung. Although IL-13 through its binding to IL-4Rα/IL-13Rα1 uses the canonical STAT6-signaling pathway to mediate these tissue responses, recent studies have demonstrated that other signaling pathways may also be involved. Previous studies from our laboratory demonstrated that IL-13 mediates its tissue effects by inducing a wide variety of downstream genes many of which are known to be regulated by NF-κB. As a result, we hypothesized that NF-κB activation plays a critical role in the pathogenesis of IL-13-induced tissue alterations. To test this hypothesis, we compared the effects of transgenic IL-13 in mice with normal and diminished levels of NF-κB activity. Three pharmacologic approaches were used to inhibit NF-κB including 1) PS1145, a small molecule inhibitor of IκBα kinase (IKK2), 2) antennapedia-linked NF-κB essential modulator-binding domain (NBD) peptide (wild-type NBD), and 3) an adenoviral construct expressing a dominant-negative version of IKK2. We also crossed IL-13-transgenic mice with mice with null mutations of p50 to generate mice that overproduced IL-13 in the presence and absence of this NF-κB component. These studies demonstrate that all these interventions reduced IL-13-induced tissue inflammation, fibrosis and alveolar remodeling. In addition, we show that both PS1145 and wild-type NBD inhibit lung inflammatory and structural cell apoptosis. PS1145 inhibits caspase activation and up-regulates inhibitor of apoptosis protein cellular-inhibitor of apoptosis protein 1 (c-IAP-1). Therefore, NF-κB is an attractive target for immunotherapy of IL-13-mediated diseases.

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“…The mechanisms underlying the reduction of NFkB activation by anti-inflammatory cytokines, which may account for the decreased iNOS expression, range from de novo synthesis of IkBa (Molina-Holgado et al 2002), interactions between STAT6 and upstream factors in signalling cascades activated by pro-inflammatory cytokines (Nelson et al 2003) and transcription blockade by STAT6-mediated inhibition of NFkB binding to the promoter regions of the genes coding NFkB subunits (Bennett et al 1997, Abu-Amer 2001 or prevention of NFkB translocation to the nuclear compartment (Ohmori & Hamilton 2000, Molina-Holgado et al 2002, Al-Ashy et al 2006.…”

Section: Discussionmentioning

confidence: 99%

Interaction between pro-inflammatory and anti-inflammatory cytokines in insulin-producing cells

Souza

Gurgul-Convey

Elsner

et al. 2008

Journal of Endocrinology

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Pro-inflammatory cytokines cause b-cell dysfunction and death. The aim of this study was to investigate the interactions between different pro-and anti-inflammatory cytokines and their effects on apoptotic b-cell death pathways. Insulin-producing RINm5F cells were exposed to different combinations of cytokines. Gene expression analyses of manganese superoxide dismutase (MnSOD) and inducible nitric oxide synthase (iNOS) were performed by real-time RT-PCR. Cell viability was measured by the MTT assay, NFkB activation using a SEAP reporter gene assay, protein expression by western blotting and caspase-3 activity using the DEVD cleavage method. IL-1b, tumour necrosis factor a (TNFa) and a combination of all three pro-inflammatory cytokines increased while IFNg alone did not affect NFkB activity and iNOS gene and protein expression. Interestingly, the anti-inflammatory cytokines IL-4, IL-13 and IL-10 decreased IL-1b-stimulated NFkB activation and iNOS expression. IL-1b, TNFa and the pro-inflammatory cytokine combination also increased MnSOD gene and protein expression. But IL-4, IL-13 and IL-10 did not affect MnSOD expression and did not modulate IL-1b-stimulated MnSOD expression. Caspase-3 activity was increased by IL-1b and the pro-inflammatory cytokine combination, and to a lesser extent by TNFa. In contrast, IFNg had no effect on caspase-3 activity. IL-4, IL-13 and IL-10 decreased caspase-3 activity and increased viability of insulin-producing cells treated with pro-inflammatory cytokines. The anti-inflammatory cytokines counteracted the cytotoxic effects of proinflammatory cytokines in insulin-producing cells. This was achieved through the reduction of nitrosative stress. Thus, a balance between the anti-inflammatory and the proinflammatory cytokines is of crucial importance for the prevention of pancreatic b-cell destruction.

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NF-κB signalling is inhibited by glucocorticoid receptor and STAT6 via distinct mechanisms

Cited by 66 publications

References 39 publications

Cell-Autonomous CCL5 Transcription by Memory CD8 T Cells Is Regulated by IL-4

Cell-Autonomous CCL5 Transcription by Memory CD8 T Cells Is Regulated by IL-4

Inhibition of NF-κB Activation Reduces the Tissue Effects of Transgenic IL-13

Interaction between pro-inflammatory and anti-inflammatory cytokines in insulin-producing cells

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