Differential Regulation of Macrophage Ccaat-Enhancer Binding Protein Isoforms by Lipopolysaccharide and Cytokines

Muhammad, Tengku Sifzizul Tengku; Hughes, Timothy R.; Ranki, Harri; Cryer, Anthony; Ramji, Dipak Purshottam

doi:10.1006/cyto.2000.0711

Cited by 79 publications

(64 citation statements)

References 13 publications

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“…The recombinant protein was labeled with [ 35 S]methionine (40 Ci) to aid detection. Nuclear and whole cell extracts were prepared essentially as described previously (12,15,16,40,42). Protease inhibitors (0.5 mM phenylmethylsulfonyl fluoride, 1 g/ml pepstatin A, 10 g/ml aprotinin, 10 g/ml I-S soybean trypsin inhibitor) and DTT (0.5 mM) were added to all buffers before use.…”

Section: Methodsmentioning

confidence: 99%

“…The gels were then dried under vacuum and exposed to x-ray film. For antibody supershift assays, samples of nuclear or whole cell extracts were incubated with the appropriate antiserum for 30 min on ice prior to the addition of the radiolabeled probe (12,15,16,30,32,40,42). For competition assays, a 250 -500-fold molar excess of the double-stranded oligonucleotides was added to the samples of proteins prior to the addition of the radiolabeled probe (12, 15, 16, 30 -32, 40, 42).…”

Section: Methodsmentioning

confidence: 99%

“…Refs. [12][13][14][15][16]. This cytokine is a key modulator of the immune and inflammatory responses along with numerous other cellular actions during physiological and pathophysiological conditions (17,18).…”

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confidence: 99%

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Interferon-γ Stimulates the Expression of the Inducible cAMP Early Repressor in Macrophages through the Activation of Casein Kinase 2

Mead

Hughes

Irvine

et al. 2003

Journal of Biological Chemistry

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Interferon-␥ (IFN-␥) is a pleiotropic cytokine that modulates the immune function, cell proliferation, apoptosis, macrophage activation, and numerous other cellular responses. These biological actions of IFN-␥ are characterized by both the activation and the inhibition of gene transcription. Unfortunately, in contrast to gene activation, the mechanisms through which the cytokine suppresses gene transcription remain largely unclear. We show here for the first time that exposure of macrophages to IFN-␥ leads to a dramatic induction in the expression of the inducible cAMP early repressor (ICER), a potent inhibitor of gene transcription. In addition, a synergistic action of IFN-␥ and calcium in the activation of ICER expression was identified. The IFN-␥-mediated activation of ICER expression was not blocked by H89, bisindoylmaleimide, SB202190, PD98059, W7, and AG490, which inhibit protein kinase A, protein kinase C, p38 mitogen-activated protein kinase, extracellular signal-regulated kinase, calcium-calmodulin-dependent protein kinase, and Janus kinase-2, respectively. In contrast, apigenin, a selective casein kinase 2 (CK2) inhibitor, was found to inhibit response. Consistent with this finding, IFN-␥ stimulated CK2 activity and the level of phosphorylated cAMP response element-binding protein, which is known to induce ICER gene transcription, and this response was inhibited in the presence of apigenin. These studies, therefore, identify a previously uncharacterized pathway, involving the IFN-␥-mediated stimulation of CK2 activity, activation of cAMP response element-binding protein, and increased production of ICER, which may then play an important role in the inhibition of macrophage gene transcription by this cytokine.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Interferon-γ Stimulates the Expression of the Inducible cAMP Early Repressor in Macrophages through the Activation of Casein Kinase 2

Mead

Hughes

Irvine

et al. 2003

Journal of Biological Chemistry

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“…TSC1 controls pro-IL-1b expression via mTORC1-dependent C/EBPb Previous studies showed that C/EBPb protein, which could be induced by LPS (Supplementary Figure 6) 14,38 , is required for the activation of mouse and human IL-1b gene expression [39][40][41][42][43] . We found that TSC1 KO peritoneal macrophages had markedly reduced C/EBPb protein expression compared with WT macrophages ( Figure 5A), whereas its expression was not affected in Rictor KO macrophages ( Figure 5B).…”

Section: Tsc1 Deficiency Does Not Inhibit Activation Of Mapks and Nf-mentioning

confidence: 99%

TSC1 controls IL-1β expression in macrophages via mTORC1-dependent C/EBPβ pathway

et al. 2015

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The tuberous sclerosis complex 1 (TSC1) is a tumor suppressor that inhibits the mammalian target of rapamycin (mTOR), which serves as a key regulator of inflammatory responses after bacterial stimulation in monocytes, macrophages, and primary dendritic cells. Previous studies have shown that TSC1 knockout (KO) macrophages produced increased inflammatory responses including tumor necrosis factor-a (TNF-a) and IL-12 to pro-inflammatory stimuli, but whether and how TSC1 regulates pro-IL-1b expression remains unclear. Here using a mouse model in which myeloid lineage-specific deletion of TSC1 leads to constitutive mTORC1 activation, we found that TSC1 deficiency resulted in impaired expression of pro-IL-1b in macrophages following lipopolysaccharide stimulation. Such decreased pro-IL-1b expression in TSC1 KO macrophages was rescued by reducing mTORC1 activity with rapamycin or deletion of mTOR. Rictor deficiency has no detectable effect on pro-IL-1b synthesis, suggesting that TSC1 positively controls pro-IL-1b expression through mTORC1 pathway. Moreover, mechanism studies suggest that mTORC1-mediated downregulation of the CCAAT enhancer-binding protein (C/EBPb) critically contributes to the defective pro-IL-1b expression. Overall, these findings highlight a critical role of TSC1 in regulating innate immunity by control of the mTOR1-C/EBPb pathway. Cellular & Molecular Immunology

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“…When looking at the molecular mechanism, the induction by IFNα was shown to regulated via a IRF-Stat module in the IL-10 promoter (ZieglerHeitbrock et al, 2003). For IFN mediated suppression of gene expression various mechanisms have been proposed including suppression of Sp3 (Hughes et al, 2002) or down-regulation of C/EBP (Tengku-Muhammad et al, 2000). The main transcription factor used by IFN is Stat1 (Schroder et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Mechanism of Interferon-gamma mediated down-regulation of Interleukin-10 gene expression

Schaefer

Unterberger

Frankenberger

et al. 2009

Molecular Immunology

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Differential Regulation of Macrophage Ccaat-Enhancer Binding Protein Isoforms by Lipopolysaccharide and Cytokines

Cited by 79 publications

References 13 publications

Interferon-γ Stimulates the Expression of the Inducible cAMP Early Repressor in Macrophages through the Activation of Casein Kinase 2

Interferon-γ Stimulates the Expression of the Inducible cAMP Early Repressor in Macrophages through the Activation of Casein Kinase 2

TSC1 controls IL-1β expression in macrophages via mTORC1-dependent C/EBPβ pathway

Mechanism of Interferon-gamma mediated down-regulation of Interleukin-10 gene expression

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