Effect of interferon-gamma on macrophage differentiation and response to Toll-like receptor ligands
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE11864 | GEO | 2008/12/31
SECONDARY ACCESSION(S): PRJNA105669
REPOSITORIES: GEO
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Project description:Macrophages are known to be polarized into inflammatory (M1) and immunoregulatory (M2) cells when they are stimulated by agonists such as IFN-gamma and IL-4, respectively. If circulating monocytes may be polarized in response to T cell signals is often misguidedly deduced from macrophage results. Here the transcriptional responses of human CD14+ monocytes to IFN-gamma and IL-4 were analyzed using whole genome microarrays. A principal component analysis and hierarchical clustering showed that monocyte and macrophage responses were distinct. Monocytes stimulated with IFN-gamma and IL-4 for 6 hours exhibited some features of macrophage polarization. Indeed, when 80 genes considered as M1 and M2 genes were analyzed, we found that M1 genes were modulated in response to IFN-gamma and that M2 genes were modulated in response to IL-4. The M1 polarization of monocytes was transient because only M2 genes were modulated when monocytes were stimulated with IFN-gamma and IL-4 for 18 hours. However, the activation of monocytes by IFN-gamma and IL-4 could not be reduced to M1/M2 polarization status. Indeed, monocytes exhibited early specific signatures composed of 46 and 39 up-regulated genes in response to IFN-gamma and IL-4, respectively, and a late signature common to both molecules that consisted of 57 up-regulated genes. Taken together, these results demonstrated the extreme plasticity of human monocytes and suggested the existence of a core transcriptional termination program. Using early and late signatures might be pertinent to investigate monocyte activation in inflammatory or infectious diseases. Monocytes were stimulated with IFN-gamma (20ng/mL) or IL-4 (20ng/mL) for 6 and 18 hours or culture for 6 and 18 hours without agonist (Unstimulated samples). Monocytes-derived-macrophages (MDM) stimulated with IFN-gamma and IL-4 for 18 hours were used as controls. Each microarray is derived from a single biological sample.
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Project description:Synergistic activation of inflammatory cytokine genes by IFN-gamma and TLR signaling is important for innate immunity and inflammatory disease pathogenesis, but underlying mechanisms are not known. By obtaining over three billion bases of sequence from chromatin immunoprecipitated DNA, we generated genome-wide chromatin-state maps of human primary monocytes under IFN-gamma-priming and TLR stimulation. We found that IFN-gamma induced genome-wide sustained occupancy of STAT1, IRF-1 and associated histone acetylation at TSS-proximal and distal regulatory elements and provided a synergy mechanism whereby IFN-gamma creates a primed chromatin environment to augment TLR-induced gene transcription, which suggest therapeutic approaches that selectively target priming mechanisms. Examination and comparison of the changes in TF binding and histone modification in human primary monocytes under different conditions.
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Project description:Macrophages are known to be polarized into inflammatory (M1) and immunoregulatory (M2) cells when they are stimulated by agonists such as IFN-gamma and IL-4, respectively. If circulating monocytes may be polarized in response to T cell signals is often misguidedly deduced from macrophage results. Here the transcriptional responses of human CD14+ monocytes to IFN-gamma and IL-4 were analyzed using whole genome microarrays. A principal component analysis and hierarchical clustering showed that monocyte and macrophage responses were distinct. Monocytes stimulated with IFN-gamma and IL-4 for 6 hours exhibited some features of macrophage polarization. Indeed, when 80 genes considered as M1 and M2 genes were analyzed, we found that M1 genes were modulated in response to IFN-gamma and that M2 genes were modulated in response to IL-4. The M1 polarization of monocytes was transient because only M2 genes were modulated when monocytes were stimulated with IFN-gamma and IL-4 for 18 hours. However, the activation of monocytes by IFN-gamma and IL-4 could not be reduced to M1/M2 polarization status. Indeed, monocytes exhibited early specific signatures composed of 46 and 39 up-regulated genes in response to IFN-gamma and IL-4, respectively, and a late signature common to both molecules that consisted of 57 up-regulated genes. Taken together, these results demonstrated the extreme plasticity of human monocytes and suggested the existence of a core transcriptional termination program. Using early and late signatures might be pertinent to investigate monocyte activation in inflammatory or infectious diseases.
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Project description:Synergistic activation of inflammatory cytokine genes by IFN-gamma and TLR signaling is important for innate immunity and inflammatory disease pathogenesis, but underlying mechanisms are not known. By obtaining over three billion bases of sequence from chromatin immunoprecipitated DNA, we generated genome-wide chromatin-state maps of human primary monocytes under IFN-gamma-priming and TLR stimulation. We found that IFN-gamma induced genome-wide sustained occupancy of STAT1, IRF-1 and associated histone acetylation at TSS-proximal and distal regulatory elements and provided a synergy mechanism whereby IFN-gamma creates a primed chromatin environment to augment TLR-induced gene transcription, which suggest therapeutic approaches that selectively target priming mechanisms.
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Project description:TLRs are considered important for innate immune responses that combat bacterial infections. Here, the role of TLRs in severe septic peritonitis using the colon ascendens stent peritonitis (CASP) model was examined. We demonstrate that mice deficient for MyD88 and TRIF had markedly reduced bacterial numbers both in peritoneal cavity and peripheral blood, indicating that bacterial clearance in this model is inhibited by TLR signals. Moreover, survival of Myd88-/-;TrifLps2/Lps2 mice was significantly improved. The lack of TLR signals prevented the excessive induction of inflammatory cytokines and of IL 10. Notably, the expression of IFN-gamma, which has an essential protective role in septic peritonitis, and of IFN-regulated genes including several p47 and p65 GTPases as well as IP 10 was independent of TLR signaling. These results provide evidence that, in severe septic peritonitis, TLR deficiency balances the innate immune response in a favorable manner by attenuating deleterious responses such as excessive cytokine release, while leaving intact protective IFN-gamma production. In this dataset, expression data of genes induced by septic peritonitis in spleens from TLR-deficient and wildtype mice are included. 3 groups (septic TLR-deficient mice, septic wildtype mice, and untreated wildtype mice) with 4 replicates each.
2011-06-27 | E-GEOD-24327 | biostudies-arrayexpress
Project description:A growing body of evidence suggests that inflammatory cytokines have a dualistic role in immunity. In this study, we sought to determine the direct effects IFN-gamma on the differentiation and maturation of human peripheral blood monocyte-derived dendritic cells (moDC). Here, we report that following differentiation of human peripheral-blood monocytes into moDCs with granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL-4, interferon-gamma (IFN-gamma) induces moDC maturation and up-regulates the co-stimulatory markers CD80, CD86, CD95, and MHC Class I, enabling moDCs to effectively generate antigen-specific CD4+ and CD8+ T cell responses for multiple viral and tumor antigens. Interestingly, early exposure of monocytes to high concentrations of IFN-gamma promotes monocyte differentiation into macrophages, despite the presence of GM-CSF and IL-4. However, under low concentrations of IFN-gamma, monocytes continue to differentiate into dendritic cells possessing a unique gene-expression profile, resulting in impairments in subsequent maturation by IFN-gamma and an inability to generate effective antigen-specific CD4+ and CD8+ T cell responses compared to standard moDCs. Monocytes differentiated in the presence of low levels of IFN-gamma downregulate IFN-gamma receptor expression, impairing their response to an inflammatory rechallenge. These findings demonstrate the ability of IFN-gamma to impart differential programs on human moDCs which shape the antigen-specific T cell responses they induce. Timing and intensity of exposure to IFN-gamma can thus determine whether moDCs are tolerogenic or immunostimulating.
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Project description:Macrophages are major effector cells and antigen presenting cells of the innate immune system and classical activation of macrophage function requires interferon–γ (IFN-γ) pretreatment (priming) and TLR stimuli, which promotes inflammatory responses though high levels of pro-inflammatory cytokines and lower level of the anti-inflammatory cytokines, resulting in microbicidal and tumoricidal effect. However, the underlying molecular mechanism of IFN-γ priming remains elusive. In this study, we explored the effect of IFN-γ on macrophages at miRNA level and discovered that miR-3473b, which was down-regulated after IFN-γ priming, could attenuate the priming effect of IFN-γ. Molecular study revealed that miR-3473b promoted Akt/GSK3 signaling and IL-10 production through directly targeting PTEN to suppress inflammatory response and tumor-suppressing capability of macrophages. In summary, our data demonstrate that IFN-γ beef up macrophage inflammatory response and tumor suppressing capacity by limiting miR-3473b-mediated PTEN suppression. Our work identified an IFN-γ/miR-3473b/Akt axis in the regulation of macrophage function and activation. the assay was performed with 5 μg total RNA samples from both normal BMM (labeled by Cy3) and BMM primed by IFN-γ (100U/ml) for 4 h(labeled by Cy5), normal BMM serves as control.
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Project description:TLRs are considered important for innate immune responses that combat bacterial infections. Here, the role of TLRs in severe septic peritonitis using the colon ascendens stent peritonitis (CASP) model was examined. We demonstrate that mice deficient for MyD88 and TRIF had markedly reduced bacterial numbers both in peritoneal cavity and peripheral blood, indicating that bacterial clearance in this model is inhibited by TLR signals. Moreover, survival of Myd88-/-;TrifLps2/Lps2 mice was significantly improved. The lack of TLR signals prevented the excessive induction of inflammatory cytokines and of IL 10. Notably, the expression of IFN-gamma, which has an essential protective role in septic peritonitis, and of IFN-regulated genes including several p47 and p65 GTPases as well as IP 10 was independent of TLR signaling. These results provide evidence that, in severe septic peritonitis, TLR deficiency balances the innate immune response in a favorable manner by attenuating deleterious responses such as excessive cytokine release, while leaving intact protective IFN-gamma production.
2011-06-28 | GSE24327 | GEO