Negative regulation of MyD88-dependent signaling by IL-10 in dendritic cells

Chang, JiHoon; Kunkel, Steven L.; Chang, Cheong Hee

doi:10.1073/pnas.0905815106

Cited by 110 publications

(107 citation statements)

References 27 publications

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“…1B). IL-10 negatively regulates cytokine production in DC upon LPS stimulation (18). We tested therefore whether IL-10 participates in the inhibition of IL-23p19 gene expression.…”

Section: Resultsmentioning

confidence: 99%

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Interleukin-23 production in dendritic cells is negatively regulated by protein phosphatase 2A

Chang

Voorhees

Liu

et al. 2010

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

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IL-12 and IL-23 are produced by activated antigen-presenting cells but the two induce distinct immune responses by promoting Th1 and Th17 cell differentiation, respectively. IL-23 is a heterodimeric cytokine consisting of two subunits: p40 that is shared with IL-12 and p19 unique to IL-23. In this study, we showed that the production of IL-23 but not IL-12 was negatively regulated by protein phosphatase 2A (PP2A) in dendritic cells (DC). PP2A inhibits IL-23 production by suppressing the expression of the IL-23p19 gene. Treating DC with okadaic acid that inhibits the PP2A activity or knocking down the catalytic subunit of PP2A with siRNA enhanced IL-23 but not IL-12 production. Unlike PP2A, MAP kinase phosphatase-1 or CYLD did not show an effect on IL-23 production supporting the specificity of PP2A. PP2A-mediated inhibition requires a newly made protein that is likely responsible for bringing PP2A and IKKβ together upon LPS stimulation, which then results in the termination of IKK phosphorylation. Thus, our results uncovered an important role of the protein phosphatase in the regulation of IL-23 production and identified PP2A as a previously uncharacterized inhibitor of IL-23p19 expression in DC.cytokine | NF-κB | TLR

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“…1B). IL-10 negatively regulates cytokine production in DC upon LPS stimulation (18). We tested therefore whether IL-10 participates in the inhibition of IL-23p19 gene expression.…”

Section: Resultsmentioning

confidence: 99%

“…Cytokine concentrations in supernatants were detected by ELISA and mRNA accumulation of cytokines was analyzed by qRT-PCR as previously described (33). The primers used for GAPDH, IL-12p35, IL-12p40, IL-10, IL-6, and IL-23p19 were described previously (18).…”

Section: Methodsmentioning

confidence: 99%

Interleukin-23 production in dendritic cells is negatively regulated by protein phosphatase 2A

Chang

Voorhees

Liu

et al. 2010

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

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“…In this line, it has been demonstrated that adjuvants not only determine IL-10 production by DC, but also dictate their sensitivity to be inhibited by IL-10, modulating thus their functional properties. 39 Indeed, MyD88-independent adjuvants such as poly(I: C), are resistant to IL-10 inhibitory effects, whereas DC activated through MyD88-dependent adjuvants (Imiquimod or CpG) can be inhibited by this cytokine. Thus, these results may suggest DC as a potential IL-10 source and at the same time may explain why anti-IL-10R antibodies, even in the presence of tumor IL-10, do not provide any benefit when using poly(I: C) or anti-CD40 as adjuvants.…”

Section: Discussionmentioning

confidence: 99%

Vaccine-induced but not tumor-derived Interleukin-10 dictates the efficacy of Interleukin-10 blockade in therapeutic vaccination

et al. 2015

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“…It has been described that an in vivo LPS challenge induces hyporesponsiveness to following in vivo or ex vivo LPS challenges. The biochemical mechanisms accounting for this hyporesponsiveness have been demonstrated to involve negative regulators such as IRAK-M, SOCS-1, SHIP, ST2 and IL-10 [2,3,[12][13][14][15][16][17][18] and downregulation of CD14 [19].…”

Section: Introductionmentioning

confidence: 99%

Characterization of inflammation and immune cell modulation induced by low-dose LPS administration to healthy volunteers

et al. 2014

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Human in vivo models of systemic inflammation are used to study the physiological mechanisms of inflammation and the effect of drugs and nutrition on the immune response. Although in vivo lipopolysaccharide (LPS) challenges have been applied as methodological tool in clinical pharmacology studies, detailed information is desired on dose-response relationships, especially regarding LPS hyporesponsiveness observed after low-dose in vivo LPS administration. A study was performed to assess the in vivo inflammatory effects of low intravenous LPS doses, and to explore the duration of the induced LPS hyporesponsiveness assessed by subsequent ex vivo LPS challenges. This was a randomized, double-blind, placebo-controlled study with single ascending low doses of LPS (0.5, 1 and 2 ng/kg body weight) administered to healthy male volunteers (3 cohorts of 8 subjects, LPS:placebo 6:2). The in vivo inflammatory response was assessed by measurement of cytokines and CRP. Ex vivo LPS challenges were performed (at −2, 6, 12, 24, 48 and 72 hours relative to in vivo LPS administration) to estimate the duration and magnitude of LPS hyporesponsiveness by assessment of cytokine release (TNF-α, IL-1β, IL-6, IL-8). LPS administration dose-dependently increased body temperature (+1.5°C for 2 ng/kg LPS), heart rate (+28 bpm for 2 ng/kg LPS), CRP and circulating cytokines which showed clearly distinctive increases from placebo already at the lowest LPS dose level tested (0.5 ng/kg, contrast for timeframe 0-6 hours: TNF-α +413%, IL-6 +288%, IL-8 +254%; all p ≤ 0.0001). In vivo LPS administration dose-dependently induced a period of hyporesponsiveness in the ex vivo LPS-induced cytokine release (IL-1β, IL-6 and TNF-α), with maximal hyporesponsiveness observed at 6 hours, lasting no longer than 12 hours. For IL-6 and IL-8, indications for immune cell priming were observed. We demonstrated that an in vivo LPS challenge, with LPS doses as low as 0.5 ng/kg, elicits a cytokine response that is clearly distinctive from baseline cytokine levels. This study expanded the knowledge about the dose-effect relationship of LPS-induced hyporesponsiveness. As such, the low-dose LPS challenge has been demonstrated to be a feasible methodological tool for future clinical studies exploring pharmacological or nutritional immune-modulating effects.

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Negative regulation of MyD88-dependent signaling by IL-10 in dendritic cells

Cited by 110 publications

References 27 publications

Interleukin-23 production in dendritic cells is negatively regulated by protein phosphatase 2A

Interleukin-23 production in dendritic cells is negatively regulated by protein phosphatase 2A

Vaccine-induced but not tumor-derived Interleukin-10 dictates the efficacy of Interleukin-10 blockade in therapeutic vaccination

Characterization of inflammation and immune cell modulation induced by low-dose LPS administration to healthy volunteers

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