Role of Stat3 in Lipopolysaccharide-Induced IL-10 Gene Expression

Benkhart, Elke; Siedlar, Maciej; Wedel, Andrew; Werner, Thomas; Ziegler‐Heitbrock, H. W. L.

doi:10.4049/jimmunol.165.3.1612

Cited by 224 publications

(213 citation statements)

References 25 publications

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“…Another study provided evidence that post-transcriptional regulation of IL-10 gene expression through sequences in the 3'-untranslated region of the IL-10 mRNA contributes to its overall production as well [100,101]. A critical role for Stat3 but not other Stat proteins in LPS-induced IL-10 transcription in a human npg B cell line was reported by Benkhart and colleagues who demonstrated a direct interaction of Stat3 with the human IL-10 promoter at -120 [102]. Since Stat3 is also the mediator of IL-10 signaling via the IL-10 receptor [103], this finding provides a mechanistic explanation for the noted autoregulation of IL-10.…”

Section: Il-10 Gene Expression In Microbe-and Cytokine-activated Macrmentioning

confidence: 93%

Regulation of cytokine production during phagocytosis of apoptotic cells

2006

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Loss of self-tolerance and expansion of auto-reactive lymphocytes are the basis for autoimmunity. Apoptosis and the rapid clearance of apoptotic cells by phagocytes usually occur as coordinated processes that ensure regulated cellularity and stress response with non-pathological outcomes. Defects in clearance of apoptotic cells would contribute to the generation of self-reactive lymphocytes, which drive autoimmune disorders such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). The IL-12 family of cytokines (IL-12, IL-23, and IL-27) and IL-10 are produced by phagocytic macrophages and play critical roles in the regulation of antigen-presenting cells (APCs) and effector lymphocytes during an immune response to pathogens. Inappropriate expression of these cytokines and their dysregulated activities have been strongly implicated in the pathogenesis of several autoimmune diseases. The production of pro-and anti-inflammatory cytokines by phagocytic APCs is delicately regulated during the ingestion of apoptotic cells as part of an intrinsic mechanism to prevent inflammatory autoimmune reactions. How apoptotic cell-derived signals regulate cytokine production is poorly understood. A recent study by our group demonstrated that phagocytosis of apoptotic cells by activated macrophages results in strong inhibition of IL-12 p35 gene expression by activating a novel transcription repressor, which we named GC-binding protein (GC-BP), through tyrosine dephosphorylation. We are also beginning to understand the molecular mechanisms underlying apoptotic cell-triggered production of IL-10 by phagocytes. These studies will help to elucidate some novel immune regulatory mechanisms and explore the regulation of immune responses to autoantigens with potentials to discover new therapeutic targets for the treatment of autoimmune disorders.

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Section: Il-10 Gene Expression In Microbe-and Cytokine-activated Macrmentioning

confidence: 93%

Regulation of cytokine production during phagocytosis of apoptotic cells

2006

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“…76 The more extended promoter construct harboring À1104/ þ 30 was generated by ligating the extra upstream sequence with the À1044/ þ 30-luc reporter construct.…”

Section: Construction Of Luciferase Reporter Gene Vectorsmentioning

confidence: 99%

Differential expression in lupus-associated IL-10 promoter single-nucleotide polymorphisms is mediated by poly(ADP-ribose) polymerase-1

et al. 2007

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Systemic lupus erythematosus (SLE) is a complex, multifactorial autoimmune disease characterized by the dysregulation of T and B cells that leads to hyperactivity of B cells and production of autoantibodies, and involves both environmental and genetic factors. Interleukin-10 (IL-10) is a candidate susceptibility gene in SLE. In particular, three IL-10 promoter singlenucleotide polymorphisms (SNPs; À1082A/G, À819T/C and À592A/C) are strongly associated with the pathogenesis of SLE. We found that the homozygous GCC haplotype linked to greater SLE severity confers higher IL-10 gene transcriptional activity than the ATA haplotype in macrophages that encounter apoptotic cells, because of the differential DNA binding to the À592 SNP by a nuclear protein uniquely induced by apoptotic cells. We identified this protein as poly(ADP-ribose) polymerase-1, confirmed its physiological role and characterized its molecular properties in modulating IL-10 production during phagocytosis of apoptotic cells. This study unveils a novel direct link between DNA damage repair/apoptosis pathways and IL-10-mediated immune regulation.

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“…In vitro, two transcription factors designated SP1 and SP3 have been implicated as important for the regulation of IL-10, suggesting that IL-10 mRNA may be constitutively produced under the influence of SP1/SP3 transcriptional elements and largely regulated by post-transcriptional control mechanisms such as 3 0 mRNA instability sequences present in the IL-10 mRNA transcript [18][19][20]. In addition to these observations, further regulation of IL-10 was suggested by in vitro work that observed decreases in IL-10 production following removal of a putative STAT-3-binding site at position -120 in the IL-10 promoter [21].…”

Section: Introductionmentioning

confidence: 99%

STAT‐1‐mediated repression of monocyte interleukin‐10 gene expression in vivo

et al. 2006

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There have been substantial advances in understanding the events that regulate gene expression at the cellular and molecular level; however, there has been limited progress integrating this information to understand how biological systems function in vivo. For example, the anti‐inflammatory cytokine IL‐10 is thought to down‐regulate the effects of the pro‐inflammatory cytokine IFN‐γ on monocyte activation following LPS stimulation. However, the often‐postulated reciprocal regulation of IL‐10 gene expression by IFN‐γ has not been studied in vivo. Here we demonstrate that the regulation of IL‐10 gene expression has at least two phases following challenge with LPS or a gram‐negative organism. In C57BL/6 mice, early IL‐10 induction occurs independently of STAT‐1, while a delayed active repression of IL‐10 gene expression is critically dependent on STAT‐1, but only partially dependent upon IFN‐α/β and IFN‐γ. This in vivo IL‐10 production comes from blood monocytes, but not tissue macrophages, and cannot be reproduced in vitro. This study provides new insights into the regulation of IL‐10 following challenge with a gram‐negative organism, and highlights the importance of studying these cytokine regulatory pathways in vivo.

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Role of Stat3 in Lipopolysaccharide-Induced IL-10 Gene Expression

Cited by 224 publications

References 25 publications

Regulation of cytokine production during phagocytosis of apoptotic cells

Regulation of cytokine production during phagocytosis of apoptotic cells

Differential expression in lupus-associated IL-10 promoter single-nucleotide polymorphisms is mediated by poly(ADP-ribose) polymerase-1

STAT‐1‐mediated repression of monocyte interleukin‐10 gene expression in vivo

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