Deficiency of the transcription factor c-fos increases lipopolysaccharide-induced macrophage interleukin 12 production

Roy, Sabita; Charboneau, Richard; Cain, Kelly; DeTurris, Stanley; Melnyk, Dean; Barke, Roderick A.

doi:10.1016/s0039-6060(99)70161-3

Cited by 25 publications

(22 citation statements)

References 20 publications

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“…AP-1 activation has been previously related to the inhibition of IL-12p70 in different studies. First, macrophages from c-fos knockout mice produced significantly more IL-12p70 as compared with macrophages from wild type mice (41). Second, transfection of RAW264.7 cells with a dominant-negative mutant of AP-1 dramatically enhanced IL-12p40 production (40).…”

Section: Discussionmentioning

confidence: 99%

Histamine H4 Receptor Stimulation Suppresses IL-12p70 Production and Mediates Chemotaxis in Human Monocyte-Derived Dendritic Cells

Gutzmer

Diestel

Mommert

et al. 2005

The Journal of Immunology

222

249

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There is increasing evidence that histamine as an important mediator of immediate type allergic reactions also effects professional APCs. Recent reports showed effects of histamine on human monocyte-derived dendritic cells (MoDC) mediated primarily via histamine H1 receptors (H1R) and H2R. We show here that MoDC also express H3R and H4R at the mRNA and protein level. mRNA of the H3R is down-regulated and mRNA of the H4R is up-regulated during the differentiation from monocytes to MoDC. H4R or H2R stimulation suppressed IL-12p70 production in MoDC. Induction of cAMP was necessary for IL-12p70 inhibition mediated via the H2R. In contrast, H4R stimulation did not affect cAMP production but induced the transcription factor AP-1, and U0126, an inhibitor of AP-1 transactivation and MEK, rescued H4R mediated IL-12p70 suppression. Moreover, MoDC responded to a H4R agonist (and also to a H2R agonist) with increased F-actin polymerization and migration in modified Boyden chamber assays, suggesting a chemotactic effect of histamine via the H2R and the H4R. Thus, H4R stimulation on MoDC results in immunomodulatory and chemotactic effects. Histamine induces chemotaxis and IL-12p70 suppression via different receptors using different signaling pathways, which might be important for the pathogenesis of and therapeutic interventions in allergic diseases.

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Section: Discussionmentioning

confidence: 99%

Histamine H4 Receptor Stimulation Suppresses IL-12p70 Production and Mediates Chemotaxis in Human Monocyte-Derived Dendritic Cells

Gutzmer

Diestel

Mommert

et al. 2005

The Journal of Immunology

222

249

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“…Because c-Fos is also a negative regulator in LPS-induced expression of proinflammatory cytokines (7,(22)(23)(24)(25)(26)(27)(28), we examined the effect of c-Fos disruption in DSS-induced colitis. Fos 2/2 mice exhibited higher susceptibility to DSS-induced colitis associated with higher levels of proinflammatory cytokines and NF-kB activity than did wt mice.…”

Section: Discussionmentioning

confidence: 99%

Fos Proteins Suppress Dextran Sulfate Sodium-Induced Colitis through Inhibition of NF-κB

Takada

Ray²,

Ikeda

et al. 2009

The Journal of Immunology

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The Fos family proteins, c-Fos and Fra-1, are components of the dimeric transcription factor AP-1, which is typically composed of Fos and Jun family proteins. We have previously shown that mice lacking c-Fos (Fos−/− mice) respond more strongly to LPS injection than do wild-type (wt) controls. We then examined the sensitivity of Fos−/− mice to acute inflammatory stress in a dextran sulfate sodium (DSS)-induced colitis model. We found that Fos−/− mice exhibited more severe weight loss, bleeding, diarrhea, and colon shortening than did wt mice, in association with higher TNF-α production and NF-κB activity in colon segments of DSS-treated Fos−/− mice. Furthermore, NF-κB inhibition suppressed severe DSS-induced colitis in Fos−/− mice. In contrast, Fra-1 transgenic (Tg) mice responded poorly to LPS injection, and Fra-1–overexpressing macrophages and fibroblasts showed reduced production of proinflammatory cytokines, NO, and NF-κB activity. Remarkably, in the DSS-induced colitis model, Fra-1 Tg mice showed less severe clinical scores of colitis than did wt mice. Consistently, proinflammatory cytokine production and NF-κB activity in colon segments of DSS-treated Fra-1 Tg mice were lower than in wt controls. These findings reveal that the absence of c-Fos and overexpression of Fra-1 respectively enhance and suppress the activation of NF-κB in DSS-induced inflammatory stress. In this paper, we propose that AP-1 transcription factors containing c-Fos or Fra-1 are negative regulators of NF-κB–mediated stress responses.

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“…Human AM are significantly more deficient in AP-1 DNA binding activity than PM due to a lack of REF-1; differentiation of PM into AM is associated with the loss of REF-1 and AP-1 activities [31]. In addition, a lack of the transcriptional factor c-fos in AM alters the post-transcriptional modification factor complex, thereby changing the AP-1 DNA binding characteristics and the transcriptional performance with respect to IL-12 gene expression in macrophages [32]. These factors may explain some of the functional differences between AM and PM.…”

Section: Discussionmentioning

confidence: 99%

Regulation of LPS induced IL-12 production by IFN-γand IL-4 through intracellular glutathione status in human alveolar macrophages

Dobashi

Aihara

Araki

et al. 2001

Clinical and Experimental Immunology

112

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SUMMARYInterleukin-12 (IL-12) is secreted from monocytes and macrophages; it exerts pleiotropic effects on T cells and natural killer (NK) cells, and stimulates interferon-g (IFN-g ) secretion. Glutathione tripeptide regulates the intracellular redox status and other aspects of cell physiology. We examined whether IFNg and IL-4 affect the balance between intracellular reduced glutathione (GSH) and oxidized (GSSG) glutathione, as this may affect IL-12 production in human alveolar macrophages (AM). We used both AM from healthy non-smokers obtained by bronchoalveolar lavage and the monocytic THP-1 cell line in this study. Incubation of AM for 2 h with the GSH precursor N-acetylcysteine (NAC) increased the intracellular GSH/GSSG ratio, and enhanced lipopolysaccharide (LPS)-induced IL-12 secretion by AM. In THP-1 cells, NAC increased the GSH/GSSG ratio and the expression of LPS-induced IL-12 mRNA, whereas l-buthionine-[S,R]-sulphoximine (BSO) decreased these. NAC and BSO offset their own effects on the intracellular GSH/GSSG ratio and the expression of LPS-induced IL-12 mRNA. Furthermore, exposure of AM to the helper T cell type 1 (Th1) cytokine IFN-g or the helper T cell type 2 (Th2) cytokine IL-4 for 72 h increased and decreased the GSH/GSSG ratio, respectively. Lipopolysaccharide (LPS)-induced secretion of IL-12 in AM was enhanced by IFN-g but inhibited by IL-4. These results suggest that IFN-g and IL-4 oppositely affect the GSH/GSSG balance, which may regulate IL-12 secretion from AM in response to LPS.

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Deficiency of the transcription factor c-fos increases lipopolysaccharide-induced macrophage interleukin 12 production

Cited by 25 publications

References 20 publications

Histamine H4 Receptor Stimulation Suppresses IL-12p70 Production and Mediates Chemotaxis in Human Monocyte-Derived Dendritic Cells

Histamine H4 Receptor Stimulation Suppresses IL-12p70 Production and Mediates Chemotaxis in Human Monocyte-Derived Dendritic Cells

Fos Proteins Suppress Dextran Sulfate Sodium-Induced Colitis through Inhibition of NF-κB

Regulation of LPS induced IL-12 production by IFN-γand IL-4 through intracellular glutathione status in human alveolar macrophages

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