Dual Function of Interleukin-1β for the Regulation of Interleukin-6-induced Suppressor of Cytokine Signaling 3 Expression

Xiang, Yang; Albrecht, Ute; Zakowski, Vera; Sobota, Radoslaw M.; Häussinger, Dieter; Heinrich, Peter C.; Ludwig, Stephan; Bode, Johannes G.; Schaper, Fred

doi:10.1074/jbc.m313072200

Cited by 24 publications

(22 citation statements)

References 38 publications

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“…The results indicated that the activation of p50-p65 and the B site at Ϫ69, contributed only partially to the synergistic effect of IL-1 on IL-6-induced CRP gene expression. Our data support the idea that IL-1, besides activating NF-B in Hep3B cells, participates in IL-6 synergy via other pathways, as has been shown in the case of other IL-1-regulated genes (29).…”

Section: Discussionsupporting

confidence: 90%

Regulation of Basal and Induced Expression of C-Reactive Protein through an Overlapping Element for OCT-1 and NF-κB on the Proximal Promoter

Voleti

Agrawal

2005

The Journal of Immunology

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C-reactive protein (CRP) is an acute phase protein produced by hepatocytes. A minor elevation in the baseline levels of serum CRP is considered an indicator of chronic inflammation. In hepatoma Hep3B cells, IL-6 induces CRP expression by activating transcription factors STAT3 and C/EBPβ. IL-1 synergistically enhances the effects of IL-6. The first 157 bp of the CRP promoter are sufficient for IL-1 synergy. Previously, NF-κB, a transcription factor activated by IL-1β in Hep3B cells, has been shown to increase endogenous CRP expression. The purpose of this study was to investigate the possible action of NF-κB on the 157 bp of the proximal promoter. In this study we show that NF-κB requires and acts synergistically with C/EBPβ on the CRP-proximal promoter to regulate CRP expression. We located the regulatory element that consisted of overlapping binding sites for NF-κB (p50-p50 and p50-p65) and OCT-1. The κB site was responsible for the synergy between NF-κB and C/EBPβ and was also necessary for the CRP transactivation by C/EBPβ through the C/EBP site. Mutation of the κB site decreased the synergistic effect of IL-1β on IL-6-induced CRP expression. Basal CRP expression increased dramatically when binding of both OCT-1 and NF-κB was abolished. Combined data from luciferase transactivation assays and EMSA lead us to conclude that the binding of OCT-1 to the promoter, facilitated by p50-p50 in a novel way, represses, whereas replacement of OCT-1 by p50-p65 induces CRP transcription in cooperation with C/EBPβ. This model for CRP expression favors the variation seen in baseline serum CRP levels in a normal healthy population.

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Section: Discussionsupporting

confidence: 90%

Regulation of Basal and Induced Expression of C-Reactive Protein through an Overlapping Element for OCT-1 and NF-κB on the Proximal Promoter

Voleti

Agrawal

2005

The Journal of Immunology

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“…S1 for quantification). We recently reported that IL1b enhances IL-6-induced SOCS3 expression by stabilising SOCS3 mRNA (Yang et al, 2004). However, we could show that IL-1b was able to inhibit IL-6-mediated STAT3 activation independent of de novo protein synthesis (Fig.…”

Section: Il-1b Negatively Regulates Stat Activation By Il-6-type Cytomentioning

confidence: 79%

“…These cells have been extensively characterised and lack NF-kB activation in response to IL-1b [ Fig. 1C, compare lanes 1-5 with lanes 6-10 and Yang et al (Yang et al, 2004)]. Fig.…”

Section: Il-1b Negatively Regulates Stat Activation By Il-6-type Cytomentioning

confidence: 97%

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Cross-regulation of cytokine signalling: pro-inflammatory cytokines restrict IL-6 signalling through receptor internalisation and degradation

Radtke

Wüller

Xiang

et al. 2010

Journal of Cell Science

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The inflammatory response involves a complex interplay of different cytokines which act in an auto- or paracrine manner to induce the so-called acute phase response. Cytokines are known to crosstalk on multiple levels, for instance by regulating the mRNA stability of targeted cytokines through activation of the p38-MAPK pathway. In our study we discovered a new mechanism that answers the long-standing question how pro-inflammatory cytokines and environmental stress restrict immediate signalling of interleukin (IL)-6-type cytokines. We show that p38, activated by IL-1β, TNFα or environmental stress, impairs IL-6-induced JAK/STAT signalling through phosphorylation of the common cytokine receptor subunit gp130 and its subsequent internalisation and degradation. We identify MK2 as the kinase that phosphorylates serine 782 in the cytoplasmic part of gp130. Consequently, inhibition of p38 or MK2, deletion of MK2 or mutation of crucial amino acids within the MK2 target site or the di-leucine internalisation motif blocks receptor depletion and restores IL-6-dependent STAT activation as well as gene induction. Hence, a novel negative crosstalk mechanism for cytokine signalling is described, where cytokine receptor turnover is regulated in trans by pro-inflammatory cytokines and stress stimuli to coordinate the inflammatory response.

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“…Although IL-6-induced STAT-3 phosphorylation was reduced to ϳ70% by IL-1␤ in the absence of SB202190, pretreatment with this inhibitor efficiently blocked the inhibitory effect of IL-1␤ ( Figure 4B). It has previously been shown that proinflammatory cytokines such as TNF␣ and IL-1␤ can enhance IL-6-induced feedback via SOCS-3 by stabilizing SOCS-3 mRNA (20,21). Therefore we investigated whether IL-1␤ could reduce IL-6-induced STAT-3 activation independent of de novo protein synthesis and, thus, SOCS-3 expression.…”

Section: Honke Et Almentioning

confidence: 97%

The p38‐Mediated Rapid Down‐Regulation of Cell Surface gp130 Expression Impairs Interleukin‐6 Signaling in the Synovial Fluid of Juvenile Idiopathic Arthritis Patients

Honke

Ohl

Wiener

et al. 2014

Arthritis & Rheumatology

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Objective. Interleukin-6 (IL-6) signaling plays an important proinflammatory role, but this role is restricted by regulatory mechanisms that, for example, reduce the cell surface availability of the signaltransducing chain of the IL-6 receptor, gp130. The aim of this study was to determine whether the inflammatory environment in arthritic joints has an impact on monocytic gp130 surface expression and the extent to which regulatory processes in the synovial fluid (SF) can be reproduced in an in vitro model.Methods. Flow cytometry and live cell imaging were used to measure the cell surface expression and internalization of gp130. STAT-3 phosphorylation was monitored by flow cytometry and Western blotting.Results. In patients with juvenile idiopathic arthritis (JIA), levels of cell surface gp130 expression in SF monocytes were reduced compared to those in peripheral blood (PB) monocytes. These reduced levels were reproduced when PB monocytes from healthy donors were stimulated with SF, and this reduction was dependent on p38 MAPK. The induction of p38 by IL-1␤ in PB monocytes interfered with IL-6 signaling due to the reduced cell surface expression of gp130.Conclusion. These results suggest that p38-mediated proinflammatory stimuli induce the downregulation of gp130 on monocytes and thus restrict gp130-mediated signal transduction. This regulatory mechanism could be of relevance to processes in the inflamed joints of patients with JIA.

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Dual Function of Interleukin-1β for the Regulation of Interleukin-6-induced Suppressor of Cytokine Signaling 3 Expression

Cited by 24 publications

References 38 publications

Regulation of Basal and Induced Expression of C-Reactive Protein through an Overlapping Element for OCT-1 and NF-κB on the Proximal Promoter

Regulation of Basal and Induced Expression of C-Reactive Protein through an Overlapping Element for OCT-1 and NF-κB on the Proximal Promoter

Cross-regulation of cytokine signalling: pro-inflammatory cytokines restrict IL-6 signalling through receptor internalisation and degradation

The p38‐Mediated Rapid Down‐Regulation of Cell Surface gp130 Expression Impairs Interleukin‐6 Signaling in the Synovial Fluid of Juvenile Idiopathic Arthritis Patients

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