IL-4 Suppresses the Responses to TLR7 and TLR9 Stimulation and Increases the Permissiveness to Retroviral Infection of Murine Conventional Dendritic Cells

Sriram, Uma; Xu, Jun; Chain, Robert; Varghese, Linda; Chakhtoura, Marita; Bennett, Heather; Zoltick, Philip W.; Gallucci, Stefania

doi:10.1371/journal.pone.0087668

Cited by 17 publications

(14 citation statements)

References 71 publications

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“…We studied the effect of E2 on the induction of cytokines in cDCs by CpG and found that E2 has a major impact on the response of cDCs to CpG (Figures 3(c) and 3(d) ). Indeed, cDCs generated in the absence of E2 produced moderate levels of IL-12p70 and undetectable levels of TNF α , while those generated in diestrus levels of E2 responded to CpG by producing significantly higher amounts of IL-12p70 and TNF α , similar to those that we see in cDCs generated in the presence of a standard fetal bovine serum containing physiological levels of hormones [ 44 , 45 ]. These results suggest that the optimal induction of proinflammatory cytokines by TLR9 stimulation occurs only in cDCs differentiated in the presence of E2.…”

Section: Resultssupporting

confidence: 65%

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Bisphenol A Does Not Mimic Estrogen in the Promotion of the In Vitro Response of Murine Dendritic Cells to Toll-Like Receptor Ligands

Chakhtoura

Sriram

Heayn

et al. 2017

Mediators of Inflammation

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Sex hormones affect immune responses and might promote autoimmunity. Endocrine disrupting chemicals such as bisphenol A (BPA) may mimic their immune effects. Conventional dendritic cells (cDCs) are pivotal initiators of immune responses upon activation by danger signals coming from pathogens or distressed tissues through triggering of the Toll-like receptors (TLRs). We generated in vitro murine cDCs in the absence of estrogens and measured the effects of exogenously added estrogen or BPA on their differentiation and activation by the TLR ligands LPS and CpG. Estrogen enhanced the differentiation of GM-CSF-dependent cDCs from bone marrow precursors in vitro, and the selective estrogen receptor modulators (SERMs) tamoxifen and fulvestrant blocked these effects. Moreover, estrogen augmented the upregulation of costimulatory molecules and proinflammatory cytokines (IL-12p70 and TNFα) upon stimulation by TLR9 ligand CpG, while the response to LPS was less estrogen-dependent. These effects are partially explained by an estrogen-dependent regulation of TLR9 expression. BPA did not promote cDC differentiation nor activation upon TLR stimulation. Our results suggest that estrogen promotes immune responses by increasing DC activation, with a preferential effect on TLR9 over TLR4 stimulation, and highlight the influence of estrogens in DC cultures, while BPA does not mimic estrogen in the DC functions that we tested.

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Section: Resultssupporting

confidence: 65%

“…Gene expression in cDCs was analyzed by real-time quantitative reverse transcriptase-PCR (qRT-PCR) using TaqMan probes as described before [ 44 , 45 ]. Briefly, RNA was extracted using Qiagen RNasy plus kit (Qiagen Inc., Valencia, CA, USA), following the manufacturer's protocols.…”

Section: Methodsmentioning

confidence: 99%

Bisphenol A Does Not Mimic Estrogen in the Promotion of the In Vitro Response of Murine Dendritic Cells to Toll-Like Receptor Ligands

Chakhtoura

Sriram

Heayn

et al. 2017

Mediators of Inflammation

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“…Antiretroviral therapy has to a great extent reduced mother-to-child transmission, however, many children continue to become infected vertically; especially in resource limited settings. In 2016, 160,000 children acquired HIV-1 infection, majority being from low- and middle-income countries ( 42 ). Furthermore, only 43% of eligible children received HAART in 2016.…”

Section: Discussionmentioning

confidence: 99%

Alterations in B Cell Compartment Correlate with Poor Neutralization Response and Disease Progression in HIV-1 Infected Children

et al. 2017

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Several B cell defects are reported in HIV-1 infected individuals including variation in B cell subsets, polyclonal B cell activation and exhaustion, with broadly neutralizing antibodies elicited in less than 10–20% of the infected population. HIV-1 disease progression is faster in children than adults. B Lymphocyte Stimulator (BLyS), expressed on dendritic cells (DCs), is a key regulator of B cell homeostasis. Understanding how DCs influence B cell phenotype and functionality (viral neutralization), thereby HIV-1 disease outcome in infected children, is important to develop interventional strategies for restoration of B cell function. In this study, a total of 38 vertically transmitted HIV-1 infected antiretroviral therapy (ART) naïve children and 25 seronegative controls were recruited. Based on the CD4 counts and years post-infection, infected children were categorized as long-term non-progressors (LTNPs) (n = 20) and progressors (n = 18). Eight of these progressors were followed up at 6–12 months post-ART. Percentages (%) of DCs, B cell subsets, and expression of BLyS on DCs were analyzed by flow-cytometry. Plasma levels of B cell growth factors were measured by ELISA and viral neutralization activity was determined using TZM-bl assay. Lower (%) of myeloid DCs (mDCs), plasmacytoid DCs, and high expression of BLyS on mDCs were observed in HIV-1 infected progressors than seronegative controls. Progressors showed lower % of naive B cells, resting memory B cells and higher % of mature activated, tissue-like memory B cells as compared to seronegative controls. Higher plasma levels of IL-4, IL-6, IL-10, and IgA were observed in progressors vs. seronegative controls. Plasma levels of IgG were high in progressors and in LTNPs than seronegative controls, suggesting persistence of hypergammaglobulinemia at all stages of disease. High plasma levels of BLyS in progressors positively correlated with poor viral neutralizing activity. Interestingly on follow up, treatment naïve progressors, post-ART showed increase in resting memory B cells along with reduction in plasma BLyS levels that correlated with improvement in viral neutralization. This is the first study to demonstrate that reduction in plasma BLyS levels correlates with restoration of B cell function, in terms of viral neutralization in HIV-1-infected children.

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“…As a model of cDCs, bone marrow-derived DCs were generated as previously described (42, 45). Briefly, bone marrow precursors were flushed from femurs and tibias of mice and then seeded at 5 × 10 5 /well in complete IMDM (Mediatech, Manassas, VA, USA) (10% FBS, penicillin/streptomycin, gentamicin, and 2-ME) (Life Technologies, Grand Island, NY, USA) enriched with 3.3 ng/ml GM-CSF (BD Biosciences, San Jose, CA, USA) in 48-well plates or at 10 6 /well in 24-well plates.…”

Section: Methodsmentioning

confidence: 99%

“…Gene expression in cDCs was analyzed by quantitative real-time Reverse Transcriptase-PCR (qRT-PCR) using Taqman probes as described before (42, 45). Briefly, RNA was extracted using Qiagen RNasy plus kit (Qiagen Inc. Valencia, CA, USA) or Zymo quick kit (Zymo Research), following the manufacturer's protocols.…”

Section: Methodsmentioning

confidence: 99%

STAT2 Is Required for TLR-Induced Murine Dendritic Cell Activation and Cross-Presentation

Lee

Chakhtoura

et al. 2016

The Journal of Immunology

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TLR-stimulated cross-presentation by conventional dendritic cells (cDCs) is important in host defense and antitumor immunity. We recently reported that cDCs lacking the type I IFN signaling molecule STAT2 are impaired in cross-presenting tumor Ags to CD8+ T cells. To investigate how STAT2 affects cross-presentation, we determined its requirements for dendritic cell activation. In this study, we report that STAT2 is essential for the activation of murine female cDCs upon TLR3, -4, -7, and -9 stimulation. In response to various TLR ligands, Stat2−/− cDCs displayed reduced expression of costimulatory molecules and type I IFN-stimulated genes. The cDC responses to exogenous IFN-α that we evaluated required STAT2 activation, indicating that the canonical STAT1–STAT2 heterodimers are the primary signaling transducers of type I IFNs in cDCs. Interestingly, LPS-induced production of IL-12 was STAT2 and type I IFN receptor (IFNAR) dependent, whereas LPS-induced production of TNF-α and IL-6 was STAT2 and IFNAR independent, suggesting a specific role of the IFNAR–STAT2 axis in the stimulation of proinflammatory cytokines by LPS in cDCs. In contrast, R848- and CpG-induced cytokine production was less influenced by the IFNAR–STAT2 axis. Short kinetics and IFNAR blockade studies showed that STAT2 main function is to transduce signals triggered by autocrine type I IFNs. Importantly, Stat2−/− cDCs were deficient in cross-presenting to CD8+ T cells in vitro upon IFN-α, CpG, and LPS stimulation, and also in cross-priming and licensing cytotoxic T cell killers in vivo. We conclude that STAT2 plays a critical role in TLR-induced dendritic cell activation and cross-presentation, and thus is vital in host defense.

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IL-4 Suppresses the Responses to TLR7 and TLR9 Stimulation and Increases the Permissiveness to Retroviral Infection of Murine Conventional Dendritic Cells

Cited by 17 publications

References 71 publications

Bisphenol A Does Not Mimic Estrogen in the Promotion of the In Vitro Response of Murine Dendritic Cells to Toll-Like Receptor Ligands

Bisphenol A Does Not Mimic Estrogen in the Promotion of the In Vitro Response of Murine Dendritic Cells to Toll-Like Receptor Ligands

Alterations in B Cell Compartment Correlate with Poor Neutralization Response and Disease Progression in HIV-1 Infected Children

STAT2 Is Required for TLR-Induced Murine Dendritic Cell Activation and Cross-Presentation

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