Selective inhibition of interleukin‐1β gene expression in activated RAW 264.7 macrophages by interferon‐γ

Chujor, Chujor S. N.; Klein, Lilian; Lam, Charles

doi:10.1002/eji.1830260611

Cited by 20 publications

(12 citation statements)

References 37 publications

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“…1) observations in the murine macrophage cell line RAW 264.7. (9) The specific effect of IFN was supported by the observation that anti-IFN antibody abrogated the inhibitory effect of IFN on LPS-stimulated IL-1 expression (Fig. 2).…”

Section: Discussionmentioning

confidence: 65%

“…(5) An IFN regulatory cytokine, IL-18 (IL-18), a proximal stimulus of IFN expression, (6) also exists in a proform that requires proteolytic cleavage by caspase-1 to produce a functionally active cytokine. (7,8) Chujor et al (9) observed that IFN could selectively inhibit lyopolysaccharide (LPS)-induced IL-1 in the murine macrophage cell line RAW 264.7. The relevance of this observation to the in vivo control of the inflammatory response was not determined, however.…”

Section: Introductionmentioning

confidence: 99%

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IFN-γInhibits Lipopolysaccharide-Induced Interleukin-1βin Primary Murine Macrophages via a Stat1-Dependent Pathway

Boer

Kalvakolanu

et al. 2001

Journal of Interferon & Cytokine Research

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Interleukin-1 (IL-1) plays an important role in host defenses against microbial pathogens. Excessive production of this cytokine, however, may be responsible in part for the lethality observed during sepsis. Our studies show that interferon-gamma (IFN-gamma) downregulates lipopolysaccharide (LPS)-induced interleukin-1beta (IL-1beta) transcription in primary macrophages. This phenomenon does not occur in splenocytes or bone marrow-derived macrophages from signal transducer and activator of transcription (Stat1)-deficient mice, suggesting that Stat1, a transcription factor involved in IFN signaling, plays a critical role in this process. Moreover, nitric oxide (NO) was also involved in the downregulation of LPS-induced IL-1 by IFN, as addition of the inducible nitric oxide synthase (iNOS) inhibitor L-N(6)-(1-iminoethyl)lysine (NIL) negated the effect. Kinetic analysis of IL-1 and IFN levels in LPS-treated mice in vivo suggests that IFN-mediated inhibition of IL-1 might be an important negative feedback mechanism for limiting IL-1 generation in vivo.

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Section: Discussionmentioning

confidence: 65%

Section: Introductionmentioning

confidence: 99%

IFN-γInhibits Lipopolysaccharide-Induced Interleukin-1βin Primary Murine Macrophages via a Stat1-Dependent Pathway

Boer

Kalvakolanu

et al. 2001

Journal of Interferon & Cytokine Research

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“…In the case of RAW 264.7 cells stimulated with LPS, IFN-␥ was reported to induce hyporesponsiveness to LPS and reduce the production of TNF-␣ (50). Another report also showed that IFN-␥ strongly suppressed the expression of IL-1 ␤ gene stimulated with LPS (51). These data suggest that IFN-␥ acts as inhibitory cytokine under the chronically inflammatory conditions stimulated with LPS.…”

Section: Discussionmentioning

confidence: 72%

Production of Adrenomedullin in Macrophage Cell Line and Peritoneal Macrophage

Kubo¹,

Minamino²,

Isumi³

et al. 1998

Journal of Biological Chemistry

163

111

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We demonstrate that adrenomedullin (AM) is produced and secreted from cultured murine monocyte/ macrophage cell line (RAW 264.7) as well as mouse peritoneal macrophage. Immunoreactive (IR) AM secreted from RAW 264.7 cells was chromatographically identified to be native AM. To elucidate the regulation mechanism of AM production in macrophage, we examined the effects of various substances inducing differentiation or activation of monocyte/macrophage. Phorbol ester (TPA), retinoic acid (RA), lipopolysaccharide (LPS), and interferon-␥ (IFN-␥) increased AM production 1.5-7-fold in RAW 264.7 cells in a dose-as well as time-dependent manner. By LPS stimulation, the AM mRNA level in RAW 264.7 cells was augmented up to 7-fold after 14 h incubation. RA exerted a synergistic effect when administered with TPA, LPS, or IFN-␥, whereas IFN-␥ completely suppressed AM production in RAW 264.7 cells stimulated with LPS. Dexamethasone, hydrocortisone, estradiol, and transforming growth factor-␤ dosedependently suppressed AM production in RAW 264.7 cells. AM production was also investigated in mouse peritoneal macrophage. Primary mouse macrophage secreted IR-AM at a rate similar to that of RAW 264.7 cells, and its production was enhanced 9-fold by LPS stimulation. AM was found to increase basal secretion of tumor necrosis factor ␣ (TNF-␣) from RAW 264.7 cells, whereas AM suppressed the secretion of TNF-␣ and interleukin-6 from that stimulated with LPS. Thus, macrophage should be recognized as one of the major sources of AM circulating in the blood. Especially in cases of sepsis and inflammation, AM production in macrophage is augmented, and the secreted AM is deduced to function as a modulator of cytokine production. Adrenomedullin (AM)1 is a potent vasorelaxant peptide originally isolated from extracts of human pheochromocytoma by monitoring the elevating activity of platelet cAMP (1). AM shows slight homology with calcitonin gene-related peptide (CGRP) and has a potent and long-lasting depressor effect when injected intravenously into anesthetized rats (1, 2). We have shown that cultured endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) produce and secrete AM into culture medium (3, 4). The production and secretion of AM in VSMC and EC were augmented by interleukin-1 (IL-1), tumor necrosis factor ␣ (TNF-␣), and lipopolysaccharide (LPS) (5, 6), which are known to be major factors inducing septic shock (7-9). In the in vivo study, intravenous administration of LPS into rats actually elevated plasma AM concentration 20-fold and augmented AM gene expression in blood vessels, lung, and intestine (10). Plasma AM levels were also remarkably increased in patients with septic shock compared with those in healthy volunteers (11,12). These data suggest the possibility that AM contributes to induction of refractory hypotension in septic shock. On the other hand, macrophages are activated by exposure to stimuli of foreign bodies such as LPS and then start to produce and secrete various cytokines, such as IL-1 and TNF-␣. These da...

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“…In fact, it has been suggested that the agents that increase cAMP levels could be inhibitors of macrophage activities (21,36). It has also been reported that LPS inhibits, in some cases, certain aspects of IFN-␥-induced macrophage activation, whereas, in other cases, it increases activation (16,(37)(38)(39). Both cAMP-increasing agents and LPS inhibit M-CSF-dependent proliferation of macrophages.…”

Section: Resultsmentioning

confidence: 99%

The Expression of MHC Class II Genes in Macrophages Is Cell Cycle Dependent

Xaus

Comalada

Barrachina

et al. 2000

The Journal of Immunology

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Using different drugs, we stopped the cell cycle of bone marrow-derived macrophages at different points. After IFN-γ stimulation, macrophages arrested at the G1 phase of the cell cycle did not increase cell surface expression of the MHC class II IA. This inhibition is specific, because, under the same conditions, IFN-γ induces the expression of Fcγ receptors and the inducible NO synthase mRNA. Treatments that inhibit macrophage proliferation by blocking the cell cycle at the G1 phase, such as adenosine, forskolin, or LPS, blocked the IFN-γ induction of IA. Under IFN-γ treatment, the steady-state levels of IAα and IAβ mRNA did not increase in cells arrested at the G1 phase and the half-life of the MHC mRNA was not modified. These data suggest that the cell cycle modulation of IFN-γ-induced MHC II gene expression occurs at the transcriptional level. The expression of the class II transactivator mRNA induced by IFN-γ was also blocked when macrophages were arrested at the G1 phase of the cell cycle, suggesting that the lack of IFN-γ response occurs at the early steps of MHC class II expression. Finally, macrophages arrested at the G1 phase showed increased basal levels of cell surface IA due to an increase of the translational efficiency. These data show that the expression of MHC class II genes is regulated by the cell cycle.

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Selective inhibition of interleukin‐1β gene expression in activated RAW 264.7 macrophages by interferon‐γ

Cited by 20 publications

References 37 publications

IFN-γInhibits Lipopolysaccharide-Induced Interleukin-1βin Primary Murine Macrophages via a Stat1-Dependent Pathway

IFN-γInhibits Lipopolysaccharide-Induced Interleukin-1βin Primary Murine Macrophages via a Stat1-Dependent Pathway

Production of Adrenomedullin in Macrophage Cell Line and Peritoneal Macrophage

The Expression of MHC Class II Genes in Macrophages Is Cell Cycle Dependent

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