LPS induces IL-10 production by human alveolar macrophages via MAPKinases- and Sp1-dependent mechanisms

Chanteux, Hugues; Guisset, A.; Pilette, Charles; Sibille, Yves

doi:10.1186/1465-9921-8-71

Cited by 137 publications

(114 citation statements)

References 53 publications

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“…40 LPSinduced activation of Sp1 in turn regulates the transcription of the human IL-10 gene. 35,38,39,41 In conclusion, this study demonstrated that the transcription factors PU.1, Spi-B and Sp1 in B cells bound to the À1087 site in the IL-10 promoter region. Using transfection of the DG75 B-cell line, we showed differences in promoter activity for the ACC and GCC haplotypes.…”

Section: Sp1 Transcription Factor Binds To the Il-10 à1087 G-allele Lsupporting

confidence: 52%

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The Sp1 transcription factor binds to the G-allele of the –1087 IL-10 gene polymorphism and enhances transcriptional activation

et al. 2008

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The objectives of this study were to evaluate the influence of the À1087 single nucleotide polymorphism (SNP) on the gene expression of interleukin (IL)-10 and to identify transcription factors binding to this site in B cells. Using electrophoretic mobilityshift assays and nuclear extract from the DG75 B-cell line, we demonstrated that the Sp1 transcription factor bound to the À1087 G-allele of the IL-10 promoter and that the transcription factors PU.1 and Spi-B bound to both the G-and A-alleles. Transient transfections showed that lipopolysaccharide stimulation resulted in a 15-fold increase in promoter activity for the G-allele as compared to a 6-fold increase for the A-allele. Co-transfection with Sp1 expression vector in Sp1-deficient SL2 cells leading to Sp1 binding to the G-allele of the À1087 SNP resulted in increased IL-10 promoter activity. The results suggest a role for Sp1 transcription factor in the activation of IL-10 through the G-allele of the À1087 SNP in response to inflammatory signals.

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Section: Sp1 Transcription Factor Binds To the Il-10 à1087 G-allele Lsupporting

confidence: 52%

“…35,38,39 The mechanism of LPS stimulation involves the binding to proteins, presentation to the cell surface receptor CD14 and subsequently the toll-like receptor 4 (TLR4). 40 LPSinduced activation of Sp1 in turn regulates the transcription of the human IL-10 gene.…”

Section: Sp1 Transcription Factor Binds To the Il-10 à1087 G-allele Lmentioning

confidence: 99%

The Sp1 transcription factor binds to the G-allele of the –1087 IL-10 gene polymorphism and enhances transcriptional activation

et al. 2008

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“…Collectively, these data suggest that C5a-dependent ERK1/2 phosphorylation selectively suppresses LPS-induced IL-6 and TNF production in macrophages. Interestingly, although the literature suggests that ERK1/2 is involved in TLR-induced IL-10 production from human macrophages (15,34), we found in the present study that C5a enhanced LPS-mediated IL-10 production in an ERK1/2-independent, but G ai -dependent, manner (Fig. 3C).…”

Section: Temporal Study Of C5ar/tlr4 Crosstalk In Hmdmscontrasting

confidence: 28%

Inflammatory Responses Induced by Lipopolysaccharide Are Amplified in Primary Human Monocytes but Suppressed in Macrophages by Complement Protein C5a

Seow

Lim

Iyer

et al. 2013

The Journal of Immunology

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Monocytes and macrophages are important innate immune cells equipped with danger-sensing receptors, including complement and Toll-like receptors. Complement protein C5a, acting via C5aR, is shown in this study to differentially modulate LPS-induced inflammatory responses in primary human monocytes versus macrophages. Whereas C5a enhanced secretion of LPS-induced IL-6 and TNF from primary human monocytes, C5a inhibited these responses while increasing IL-10 secretion in donor-matched human monocyte-derived macrophages differentiated by GM-CSF or M-CSF. Gαi/c-Raf/MEK/ERK signaling induced by C5a was amplified in macrophages but not in monocytes by LPS. Accordingly, the Gαi inhibitor pertussis toxin and MEK inhibitor U0126 blocked C5a inhibition of LPS-induced IL-6 and TNF production from macrophages. This synergy was independent of IL-10, PI3K, p38, JNK, and the differentiating agent. Furthermore, C5a did not inhibit IL-6 production from macrophages induced by other TLR agonists that are selective for Toll/IL-1R domain–containing adapter inducing IFN-β (polyinosinic-polycytidylic acid) or MyD88 (imiquimod), demonstrating selectivity for C5a regulation of LPS responses. Finally, suppression of proinflammatory cytokines IL-6 and TNF in macrophages did not compromise antimicrobial activity; instead, C5a enhanced clearance of the Gram-negative bacterial pathogen Salmonella enterica serovar Typhimurium from macrophages. C5aR is thus a regulatory switch that modulates TLR4 signaling via the Gαi/c-Raf/MEK/ERK signaling axis in human macrophages but not monocytes. The differential effects of C5a are consistent with amplifying monocyte proinflammatory responses to systemic danger signals, but attenuating macrophage cytokine responses (without compromising microbicidal activity), thereby restraining inflammatory responses to localized infections.

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“…LPS-induced activation of Sp1 expression is involved in the regulation of the transcription of the human IL-10 gene [34][35][36][37] and one Sp1-binding site was identified in the region immediately upstream of À571 in the IL-10 promoter. 38 LPS activates the three mitogen-activated protein kinase (MAPK9) pathways ERK, JNK and p38 and, thereby, transcription factors that are involved in gene regulation.…”

Section: Discussionmentioning

confidence: 99%

“…38 LPS activates the three mitogen-activated protein kinase (MAPK9) pathways ERK, JNK and p38 and, thereby, transcription factors that are involved in gene regulation. 35 Chanteux et al 35 showed that ERK, p38, JNK as well as Sp1 are essential in LPS-induced IL-10 expression in human alveolar macrophages. In a study by Perkins et al 39 on HIV transcription activation, it was shown that Sp1 specifically interacted with the amino-terminal of p65.…”

Section: Discussionmentioning

confidence: 99%

Sp1 binds to the G allele of the−1087 polymorphism in the IL-10 promoter and promotes IL-10 mRNA transcription and protein production

2010

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Interleukin (IL)-10 is an important cytokine in immune regulation and promotes B-cell proliferation and antibody production. High levels of IL-10 were found in subjects with autoimmune diseases. The A to G single nucleotide polymorphism at -1087 of the IL-10 promoter is associated with differences in promoter activity and IL-10 production. The objectives of this study were to analyze differences in the transcription factor binding to the -1087 IL-10 gene polymorphism in B-cells, the influence of the A to G transition on the IL-10 and Sp1 gene expression in B-cells after lipopolysaccharide (LPS) stimulation and the effect of knockdown of Sp1 on IL-10 gene expression. Using B-cell lines obtained from subjects with GG and AA genotypes for the À1087 polymorphism and chromatin immunoprecipitation assay, we showed that the transcription factors PU.1 and Spi-B bound to both G and A alleles, whereas the transcription factor Sp1 only bound to the G allele. LPS stimulation of the B-cells resulted in a larger increase in IL-10 and Sp1 gene expression for GG genotypes than AA genotypes and knockdown of Sp1 gene expression resulted in a decrease in IL-10 mRNA transcription. IL-10 production was higher for the GG genotype than for the AA genotype.

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LPS induces IL-10 production by human alveolar macrophages via MAPKinases- and Sp1-dependent mechanisms

Abstract: Background: IL-10 is a cytokine mainly produced by macrophages that plays key roles in tolerance to inhaled antigens and in lung homeostasis. Its regulation in alveolar macrophages (HAM), the resident lung phagocytes, remains however unknown.

Cited by 137 publications

References 53 publications

The Sp1 transcription factor binds to the G-allele of the –1087 IL-10 gene polymorphism and enhances transcriptional activation

The Sp1 transcription factor binds to the G-allele of the –1087 IL-10 gene polymorphism and enhances transcriptional activation

Inflammatory Responses Induced by Lipopolysaccharide Are Amplified in Primary Human Monocytes but Suppressed in Macrophages by Complement Protein C5a

Sp1 binds to the G allele of the−1087 polymorphism in the IL-10 promoter and promotes IL-10 mRNA transcription and protein production

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