BCL3 is induced by IL-6 via Stat3 binding to intronic enhancer HS4 and represses its own transcription

Brocke-Heidrich, Katja; Ge, Baosheng; Cvijic, Helena; Pfeifer, Gabriele; Löffler, Dennis; Henze, Christian; McKeithan, Timothy W.; Horn, Friedemann

doi:10.1038/sj.onc.1209711

Cited by 76 publications

(66 citation statements)

References 34 publications

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“…2D). STAT3C expression in primary astrocytes was sufficient to increase the levels of GFAP and Bcl-3, proteins widely reported to be induced by active STAT3 (9,10,13,(37)(38)(39)(40), and these increases were blocked by lithium treatment (Fig. 2E).…”

Section: Gsk3mentioning

confidence: 86%

Differential Regulation of STAT Family Members by Glycogen Synthase Kinase-3

Beurel

Jope

2008

Journal of Biological Chemistry

157

155

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Excessive neuroinflammation contributes to many neurological disorders and is poorly controlled therapeutically. The signal transducer and activator of transcription (STAT) family of transcription factors has a central role in inflammatory reactions, being stimulated by multiple cytokines and interferons and regulating the expression of many proteins involved in inflammation. We found that STAT3 activation is highly dependent on glycogen synthase kinase-3 (GSK3). Inhibitors of GSK3 greatly reduced (>75%) the activating STAT3 tyrosine phosphorylation in mouse primary astrocytes, microglia, and macrophage-derived RAW264.7 cells induced by interferon-␥ (IFN␥), IFN␣, interleukin-6, or insulin. GSK3 inhibitors blocked STAT3 DNA binding activity and the expression of STAT3-induced GFAP and Bcl-3. GSK3 dependence was selective for activation of STAT3 and STAT5, whereas STAT1 and STAT6 activation were GSK3-independent. Knockdown of the two GSK3 isoforms showed STAT3 and STAT5 activation were dependent on GSK3␤, but not GSK3␣. The regulatory mechanism involved GSK3␤ binding STAT3 and promoting its association with the IFN␥ receptor-associated intracellular signaling complex responsible for activating STAT3. Furthermore, GSK3␤ associated with the IFN␥ receptor and was activated by stimulation with IFN␥. Thus, inhibitors of GSK3 reduce the activation of STAT3 and STAT5, providing a mechanism to differentially regulate STATs to modulate the inflammatory response.The brain mounts a crucial inflammatory response to control the detrimental effects of injury, infection, and other insults. This neuroinflammatory response is mediated by astrocytes, the most numerous cells in the brain, and macrophage-derived microglia, which assume the immune surveillance role in the brain. If neuroinflammation is excessive or chronic, neuronal function and survival can be impaired, which contributes to many widespread neurodegenerative diseases, such as Alzheimer disease and multiple sclerosis (1-3). Therefore, clarifying inflammatory signaling pathways in the brain is critical for developing new methods to control the detrimental consequences of neuroinflammation.A central component of inflammatory signaling is the Janus kinase (JAK) 2 /signal transducer and activator of transcription (STAT) cascade (4). Activated by cytokines and interferons, receptor-associated tyrosine kinase JAKs phosphorylate STATs on an activating tyrosine residue (e.g. Tyr 701-STAT1 and Tyr 705 -STAT3). STATs are nucleocytoplasmic shuttling transcription factors that accumulate in the nucleus as a result of tyrosine phosphorylation increasing the STAT binding affinity to DNA, which slows dephosphorylation of STATs that is necessary for nuclear export, leading to regulation of gene expression (reviewed in Ref. 5). Besides regulation by tyrosine phosphorylation, the duration and degree of gene activation by STATs can be regulated by serine phosphorylation, by binding to transcriptional coactivators, and by modulation of the rate of nuclear export, which is required for ren...

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Section: Gsk3mentioning

confidence: 86%

Differential Regulation of STAT Family Members by Glycogen Synthase Kinase-3

Beurel

Jope

2008

Journal of Biological Chemistry

157

155

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“…The induction of SOCS3 as a surrogate marker for STAT3 activation (37) was accompanied by the expression of additional genes, including BCL3 and ICAM-1, which are also known to be induced upon STAT3 activation (Fig. 1B) (38,39). STAT3 is phosphorylated within 15 min following CoPPIX treatment (Fig.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Dendritic Cell Maturation and Function Is Independent of Heme Oxygenase 1 but Requires the Activation of STAT3

Mashreghi

Klemz

Knosalla

et al. 2008

The Journal of Immunology

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The induction of heme oxygenase 1 (HO-1) by a single treatment with cobalt protoporphyrin (CoPPIX) protects against inflammatory liver failure and ischemia reperfusion injury after allotransplantation. In this context, the HO-1-mediated inhibition of donor-derived dendritic cell maturation and migration is discussed as one of the key events of graft protection. To investigate the poorly understood mechanism of CoPPIX-induced HO-1 activity in more detail, we performed gene expression analysis in murine liver, revealing the up-regulation of STAT3 after CoPPIX treatment. By using wild-type and HO-1-deficient dendritic cells we demonstrated that LPS-induced maturation is dependent on STAT3 phosphorylation and independent of HO-1 activity. In summary, our observations revise our understanding of the anti-inflammatory properties of HO-1 and highlight the immunomodulatory capacity of STAT3, which might be of further interest for targeting undesired immune responses, including ischemia reperfusion injury.

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“…To further confirm that STAT3 is involved in Bcl3 transcription, we performed chromosome immunoprecipitation assays. Lineage-depleted (Lin -) B6 bone marrow cells were stimulated with G-CSF, IL-6, or IL-3; chromosomal DNA was precipitated with STAT3-specific antibodies; and subsequent PCR amplification was conducted on a highly phylogenetically conserved distal enhancer region within intron 2 of Bcl3, which contains 3 STAT3 binding motifs (26,27) (Figure 5D). We observed STAT3 binding to this enhancer region following stimulation with G-CSF or IL-6, but not with IL-3.…”

Section: Ig (mentioning

confidence: 99%

Bcl3 prevents acute inflammatory lung injury in mice by restraining emergency granulopoiesis

Kreisel¹,

Sugimoto²,

Tietjens³

et al. 2011

J. Clin. Invest.

108

103

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Granulocytes are pivotal regulators of tissue injury. However, the transcriptional mechanisms that regulate granulopoiesis under inflammatory conditions are poorly understood. Here we show that the transcriptional coregulator B cell leukemia/lymphoma 3 (Bcl3) limits granulopoiesis under emergency (i.e., inflammatory) conditions, but not homeostatic conditions. Treatment of mouse myeloid progenitors with G-CSF -serum concentrations of which rise under inflammatory conditions -rapidly increased Bcl3 transcript accumulation in a STAT3-dependent manner. Bcl3-deficient myeloid progenitors demonstrated an enhanced capacity to proliferate and differentiate into granulocytes following G-CSF stimulation, whereas the accumulation of Bcl3 protein attenuated granulopoiesis in an NF-κB p50-dependent manner. In a clinically relevant model of transplant-mediated lung ischemia reperfusion injury, expression of Bcl3 in recipients inhibited emergency granulopoiesis and limited acute graft damage. These data demonstrate a critical role for Bcl3 in regulating emergency granulopoiesis and suggest that targeting the differentiation of myeloid progenitors may be a therapeutic strategy for preventing inflammatory lung injury.

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BCL3 is induced by IL-6 via Stat3 binding to intronic enhancer HS4 and represses its own transcription

Cited by 76 publications

References 34 publications

Differential Regulation of STAT Family Members by Glycogen Synthase Kinase-3

Differential Regulation of STAT Family Members by Glycogen Synthase Kinase-3

Inhibition of Dendritic Cell Maturation and Function Is Independent of Heme Oxygenase 1 but Requires the Activation of STAT3

Bcl3 prevents acute inflammatory lung injury in mice by restraining emergency granulopoiesis

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