Activation of the Murine Interleukin-12 p40 Promoter by Functional Interactions between NFAT and ICSBP

Zhu, Chen; Rao, Kavitha N.; Xiong, Huabao; Gagnidze, Khatuna; Li, Fengling; Horvath, Curt M.; Plevy, Scott E.

doi:10.1074/jbc.m306441200

Cited by 98 publications

(94 citation statements)

References 49 publications

(73 reference statements)

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“…1, and TNF-␣ expression was determined by RT-PCR. (63). In this study we demonstrate that MSP inhibits IL-12 production primarily by repressing the expression of the p40 subunit.…”

Section: Discussionmentioning

confidence: 51%

Macrophage-Stimulating Protein, the Ligand for the Stem Cell-Derived Tyrosine Kinase/RON Receptor Tyrosine Kinase, Inhibits IL-12 Production by Primary Peritoneal Macrophages Stimulated with IFN-γ and Lipopolysaccharide

Morrison¹,

Wilson²,

Ray

et al. 2004

The Journal of Immunology

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IL-12, produced by APCs during the initial stages of an immune response, plays a pivotal role in the induction of IFN-γ by NK and γδT cells and in driving the differentiation of Th1 cells, thus providing a critical link between innate and acquired immunity. Due to the unique position occupied by IL-12 in the regulation of immunity, many mechanisms have evolved to modulate IL-12 production. We have shown previously that macrophage-stimulating protein (MSP), the ligand for the stem cell-derived tyrosine kinase/recepteur d’origine nantais (RON) receptor, inhibits NO production by macrophages in response to IFN-γ and enhances the expression of arginase. Mice lacking RON exhibit increased inflammation in a delayed-type hypersensitivity reaction and increased susceptibility to endotoxic shock. In this study we demonstrate that pretreatment of macrophages with MSP before IFN-γ and LPS results in the complete inhibition of IL-12 production due to suppression of p40 expression. This response is mediated by the RON receptor, and splenocytes from RON−/− animals produce increased levels of IFN-γ. MSP pretreatment of macrophages resulted in decreased tyrosine phosphorylation of Stat-1 and decreased expression of IFN consensus sequence binding protein in response to inflammatory cytokines. In addition to IL-12, the expression of IL-15 and IL-18, cytokines that are also dependent on IFN consensus sequence binding protein activation, is inhibited by pretreatment with MSP before IFN-γ and LPS. We also show that the ability of MSP to inhibit IL-12 production is independent of IL-10. Taken together, these results suggest that MSP may actively suppress cell-mediated immune responses through its ability to down-regulate IL-12 production and thus inhibit classical activation of macrophages.

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“…1, and TNF-␣ expression was determined by RT-PCR. (63). In this study we demonstrate that MSP inhibits IL-12 production primarily by repressing the expression of the p40 subunit.…”

Section: Discussionmentioning

confidence: 51%

Macrophage-Stimulating Protein, the Ligand for the Stem Cell-Derived Tyrosine Kinase/RON Receptor Tyrosine Kinase, Inhibits IL-12 Production by Primary Peritoneal Macrophages Stimulated with IFN-γ and Lipopolysaccharide

Morrison¹,

Wilson²,

Ray

et al. 2004

The Journal of Immunology

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“…The molecular mechanism for this enhancement has been controversial but recently a novel complex between NFAT and IFN regulatory factor (IRF)-8 was shown to bind to the IL-12p40 promoter following LPS plus IFN-␥ macrophage activation (36). IL-10 is known to inhibit IL-12 production by inhibiting IL-12p40 gene expression at the level of transcription (29), and Zhu et al (36) demonstrated that IL-10 interfered with the formation of the IRF-8/NFAT complex. Recent data have demonstrated that pretreatment of BMDCs with IFN-␥ resulted in increased levels of expression of TLR9 (37).…”

Section: Discussionmentioning

confidence: 99%

IFN-γ Negatively Regulates CpG-Induced IL-10 in Bone Marrow-Derived Dendritic Cells

Flores

Diggs

Tait

et al. 2007

The Journal of Immunology

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Dendritic cells (DCs) are important players in the regulation of Th1- and Th2-dominated immune responses. In these studies we showed that IFN-γ, the key mediator of Th1 immunity, actively suppressed the production of IL-10 in murine DCs when activated with LPS or CpG. Our analysis revealed that both LPS and CpG induced IL-10 and IL-12 production but that the presence of IFN-γ, in a dose-dependent manner, suppressed the production of IL-10 while enhancing that of IL-12. The observed inhibition of IL-10 production was independent of IL-12. Experiments performed with STAT-1 knockout mice demonstrated that the primary production of IL-12 induced by CpG was STAT-1 dependent, whereas the production of IL-10 was not. This finding was confirmed by the observation that CpG-induced IL-12 production could be inhibited by anti-IFN-β Abs, whereas CpG-induced IL-10 production could not be inhibited. These data also demonstrated that the inhibitory effect of IFN-γ on IL-10 expression was STAT-1 dependent and transcriptionally regulated. Thus, DCs respond to CpG by producing proinflammatory and anti-inflammatory cytokines such as IL-12 and IL-10, respectively, and IFN-γ acts to not only enhance IL-12 but also to inhibit IL-10 production. The current data demonstrate a novel pathway for IFN-γ-mediated immunoregulation and suggest that IFN-γ-dependent suppression of IL-10 production by DCs may be involved in the antagonism between Th1 and Th2 patterns of immune reactivity.

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“…IRF-8 Ϫ/Ϫ macrophages display selective impairment of IL-12 p40 expression but not other cytokines, such as IL-1, IL-6, and TNF-␣ (32,33). The promoter of the IL-12 p40 gene contains an Ets site as well as a composite IRF-8-nuclear factor of activated T cells DNA-binding element, both of which play an important role for the expression of IL-12 p40 (34,35). In contrast, IRF-4 Ϫ/Ϫ macrophages produce excessive cytokines, including IL-6, TNF-␣, and IL-10, in response to LPS, suggesting that the regulation of cytokine production by IRF-4 is distinct from that by IRF-8.…”

Section: Discussionmentioning

confidence: 99%

Interferon regulatory factor 4 negatively regulates the production of proinflammatory cytokines by macrophages in response to LPS

Honma

Udono

Kohno

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

130

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Activation of the Murine Interleukin-12 p40 Promoter by Functional Interactions between NFAT and ICSBP

Abstract: Interleukin (IL)-12 is a heterodimeric cytokine that is

Cited by 98 publications

References 49 publications

Macrophage-Stimulating Protein, the Ligand for the Stem Cell-Derived Tyrosine Kinase/RON Receptor Tyrosine Kinase, Inhibits IL-12 Production by Primary Peritoneal Macrophages Stimulated with IFN-γ and Lipopolysaccharide

Macrophage-Stimulating Protein, the Ligand for the Stem Cell-Derived Tyrosine Kinase/RON Receptor Tyrosine Kinase, Inhibits IL-12 Production by Primary Peritoneal Macrophages Stimulated with IFN-γ and Lipopolysaccharide

IFN-γ Negatively Regulates CpG-Induced IL-10 in Bone Marrow-Derived Dendritic Cells

Interferon regulatory factor 4 negatively regulates the production of proinflammatory cytokines by macrophages in response to LPS

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