To date, few studies have been conducted on the relationship between postbiotics and air pollution, and there is limited knowledge if postbiotic and probiotic have synergistic effects. Therefore, we ...created a PM‐induced lung inflammation mice model and demonstrated the effect of probiotic, postbiotic, and their combination treatment on attenuation of PM2.5‐induced lung damage and allergic response. The mice were intratracheally given PM2.5 triggering conditions of acute lung damage and allergic response. Our results showed that individual treatment of probiotic and postbiotic reduced body weight loss by 47.1% and 48.9%, but the results did not show any effect on polarizing IFN‐γ/IL‐4 ratio. In addition, PM2.5‐induced overactive expression of IgE treated by probiotic and postbiotic was reduced by 33.2% and 30.4%, respectively. While combination treatment of probiotic and postbiotic exerted a synergistic effect, especially considerably on improving IgE reduction by 57.1%, body weight loss by 78.3%, and IFN‐γ/IL‐4 ratio boost by 87.5%. To sum up the above functionality, these research findings may help establish a novel platform for postbiotic application, formulation, and mechanistic selection with regard to PM2.5‐induced lung injury.
Practical Application
Allergic inflammation caused by PM2.5 is not like common allergens (ex. Pollens, ovalbumin, dust mites), which simply skewing Th1/Th2 polarization to Th2. Thus using probiotics screened by Th1‐skewing criteria might not be the best choice to treat on PM2.5‐induced symptoms. This research proposed a combination of probiotics and postbiotics on modulating immunity homeostasis, and consequently attenuating complications of PM2.5‐induced lung damage. These research findings may help establish a novel platform for postbiotic application, formulation and mechanistic selection with regard to PM2.5‐induced lung injury.
While 30%-70% of RSV-infected infants develop bronchiolitis, 2% require hospitalization. It is not clear why disease severity differs among healthy, full-term infants; however, virus titers, ...inflammation, and Th2 bias are proposed explanations. While TLR4 is associated with these disease phenotypes, the role of this receptor in respiratory syncytial virus (RSV) pathogenesis is controversial. Here, we evaluated the interaction between TLR4 and environmental factors in RSV disease and defined the immune mediators associated with severe illness. Two independent populations of infants with RSV bronchiolitis revealed that the severity of RSV infection is determined by the TLR4 genotype of the individual and by environmental exposure to LPS. RSV-infected infants with severe disease exhibited a high GATA3/T-bet ratio, which manifested as a high IL-4/IFN-γ ratio in respiratory secretions. The IL-4/IFN-γ ratio present in infants with severe RSV is indicative of Th2 polarization. Murine models of RSV infection confirmed that LPS exposure, Tlr4 genotype, and Th2 polarization influence disease phenotypes. Together, the results of this study identify environmental and genetic factors that influence RSV pathogenesis and reveal that a high IL-4/IFN-γ ratio is associated with severe disease. Moreover, these molecules should be explored as potential targets for therapeutic intervention.
To investigate the expression and function of interleukin-4 receptor alpha (IL-4Ralpha) in human conjunctival epithelial cells (HCjECs).
The presence of IL-4Ralpha mRNA and protein was examined by ...reverse transcription (RT) PCR and immunohistology, respectively. Cell surface expression was examined by flow cytometry. The effects of interleukin (IL)-4 or IL-13 on the tyrosine phosphorylation of signal transducer and the activator of transcription 6 (STAT6) were evaluated by immunoblot analyses. The transcripts upregulated upon IL-4 stimulation were examined using GeneChip, and confirmed by quantitative RT-PCR.
IL-4Ralpha mRNA and protein were detected in human conjunctival epithelium. IL-4Ralpha protein was expressed on the cell surface of HCjECs. IL-4 and IL-13 induced tyrosine phosphorylation of STAT6. GeneChip analysis showed that nine transcripts were upregulated more than fourfold by IL-4 stimulation in the primary HCjECs from two individuals. Quantitative RT-PCR assay confirmed the upregulation of these transcripts: lecithin retinol acyltransferase (LRAT), calpain (CAPN14), tumour necrosis factor alpha-induced protein 6 (TNFAIP6), RAS guanyl-releasing protein 1 (RASGRP1), endothelin receptor type A (EDNRA), hyaluronan synthase 3 (HAS3), cathepsin C (CTSC), carbonic anhydrase II (CA2) and cytokine-inducible SH2-containing protein (CISH).
HCjECs expressed functioning IL-4Ralpha, and IL-4 stimulation induced the expression of several genes.
Dupilumab is a fully human antibody to interleukin-4 receptor α that improves the signs and symptoms of moderate to severe atopic dermatitis (AD). To determine the effects of dupilumab on ...Staphylococcus aureus colonization and microbial diversity on the skin, bacterial DNA was analyzed from swabs collected from lesional and nonlesional skin in a double-blind, placebo-controlled study of 54 patients with moderate to severe AD randomized (1:1) and treated with either dupilumab (200 mg weekly) or placebo for 16 weeks. Microbial diversity and relative abundance of Staphylococcus were assessed by DNA sequencing of 16S ribosomal RNA, and absolute S. aureus abundance was measured by quantitative PCR. Before treatment, lesional skin had lower microbial diversity and higher overall abundance of S. aureus than nonlesional skin. During dupilumab treatment, microbial diversity increased and the abundance of S. aureus decreased. Pronounced changes were seen in nonlesional and lesional skin. Decreased S. aureus abundance during dupilumab treatment correlated with clinical improvement of AD and biomarkers of type 2 immunity. We conclude that clinical improvement of AD that is mediated by interleukin-4 receptor α inhibition and the subsequent suppression of type 2 inflammation is correlated with increased microbial diversity and reduced abundance of S. aureus.
Allergic asthma is a significant health burden in western countries, and continues to increase in prevalence. Th2 cells contribute to the development of disease through release of the cytokines IL-4, ...IL-5, and IL-13, resulting in increased airway eosinophils and mucus hypersecretion. The molecular mechanisms behind the disease pathology remain largely unknown. In this study we investigated a potential regulatory role for the
gene family,
,
, and
, genes known to be important in lung development within mesenchymal cell populations. We found that
-mutant mice show exacerbated pathology compared with wild-type controls in a chronic allergen model, with an increased Th2 response and exacerbated lung tissue pathology. Bone marrow chimera experiments indicated that the observed enhanced pathology was mediated by immune cell function independent of mesenchymal cell Hox5 family function. Examination of T cells grown in Th2 polarizing conditions showed increased proliferation, enhanced
expression, and elevated production of IL-4, IL-5, and IL-13 in
-deficient T cells compared with wild-type controls. Overexpression of FLAG-tagged HOX5 proteins in Jurkat cells demonstrated HOX5 binding to the
locus and decreased
and IL-4 expression, supporting a role for HOX5 proteins in direct transcriptional control of Th2 development. These results reveal a novel role for
genes as developmental regulators of Th2 immune cell function that demonstrates a redeployment of mesenchyme-associated developmental genes.
There is increasing evidence that inflammatory cytokines regulate corpus luteum (CL) function in many species. The purpose of the present study was to determine whether interleukin (IL)-4 and IL-6 ...are expressed in the porcine CL, and whether these cytokines influence porcine luteal steroidogenesis. The gene expressions of IL-4, IL-6 and their specific receptors were determined in the CL of Chinese Meishan pigs during the estrous cycle. Moreover, the effects of these cytokines on progesterone (P
4), estradiol-17β (E
2) and prostaglandin (PG) F2α secretion by cultured luteal cells were investigated. IL-4 and IL-6 mRNAs were detected in the CL at all luteal stages. Furthermore, mRNAs of the receptors for IL-4 and IL-6 were clearly expressed in the CL throughout the estrous cycle. Real-time PCR analysis revealed that IL-6 receptor (IL-6R) mRNA expression was higher in the regressed CL (days 19–21 after ovulation) than in the CL at other stages (
P
<
0.01). Exposure of cultured luteal cells obtained from mid-stage CL (days 8–11) to IL-6 (1–100
ng/ml), it inhibited P
4 and E
2 secretion by the cells (
P
<
0.05). Although IL-4 (1–100
ng/ml) did not significantly alter P
4 secretion, it inhibited E
2 secretion by the cells (
P
<
0.05). Neither IL-4 nor IL-6 had any effect on PGF2α secretion by the cells. These results suggest that IL-4 and IL-6 are locally produced in the porcine CL, and that they inhibit steroid production from luteal cells via their specific receptors. Collectively, both IL-4 and IL-6 may play roles in regulating porcine CL function throughout the estrous cycle.
Innate memory-like CD8 thymocytes develop and acquire effector function during maturation in the absence of encounter with Ags. In this study, we demonstrate that enhanced function of transcription ...factors T cell factor (TCF)-1 and β-catenin regulate the frequency of promyelocytic leukemia zinc finger (PLZF)-expressing, IL-4-producing thymocytes that promote the generation of eomesodermin-expressing memory-like CD8 thymocytes in trans. In contrast, TCF1-deficient mice do not have PLZF-expressing thymocytes and eomesodermin-expressing memory-like CD8 thymocytes. Generation of TCF1 and β-catenin-dependent memory-like CD8 thymocytes is non-cell-intrinsic and requires the expression of IL-4 and IL-4R. CD8 memory-like thymocytes migrate to the peripheral lymphoid organs, and the memory-like CD8 T cells rapidly produce IFN-γ. Thus, TCF1 and β-catenin regulate the generation of PLZF-expressing thymocytes and thereby facilitate the generation of memory-like CD8 T cells in the thymus.
Epigenetic mechanisms, such as DNA methylation, determine immune cell phenotype. To understand the epigenetic alterations induced by helminth coinfections, we evaluated the longitudinal effect of ...ascariasis and schistosomiasis infection on CD4
T cell DNA methylation and the downstream tuberculosis (TB)-specific and bacillus Calmette-Guérin-induced immune phenotype. All experiments were performed on human primary immune cells from a longitudinal cohort of recently TB-exposed children. Compared with age-matched uninfected controls, children with active
and
infection had 751 differentially DNA-methylated genes, with 72% hypermethylated. Gene ontology pathway analysis identified inhibition of IFN-γ signaling, cellular proliferation, and the Th1 pathway. Targeted real-time quantitative PCR after methyl-specific endonuclease digestion confirmed DNA hypermethylation of the transcription factors
,
,
,
,
,
,
and
and cytokines or cytokine receptors
,
,
(TNF receptor),
and
(
< 0.001; Sidak-Bonferroni). Functional blockage of the IFN-γ signaling pathway was confirmed, with helminth-infected individuals having decreased upregulation of IFN-γ-inducible genes (Mann-Whitney
< 0.05). Hypomethylation of the IL-4 pathway and DNA hypermethylation of the Th1 pathway was confirmed by Ag-specific multidimensional flow cytometry demonstrating decreased TB-specific IFN-γ and TNF and increased IL-4 production by CD4+ T cells (Wilcoxon signed-rank
< 0.05). In
-infected individuals, these DNA methylation and immune phenotypic changes persisted at least 6 mo after successful deworming. This work demonstrates that helminth infection induces DNA methylation and immune perturbations that inhibit TB-specific immune control and that the duration of these changes are helminth specific.
miRNAs are ubiquitous regulators of human biology. Parallel profiling of in vitro monocyte-to-Mφ and monocyte-to-DC differentiation revealed static, convergent, and divergent expression of miRNA. ...Bioinformatic and network analysis of differentially expressed miRNAs implicated miR-24, miR-30b, and miR-142-3p as negative regulators of intracellular signaling pathways, triggered not only by differentiation factors (M-CSF/GM-CSF/IL-4) but also from PRRs. Manipulation of miR-24, miR-30b, and miR-142-3p expression during the differentiation of mD-Mφ and mD-DC differentiation had minimal impact on the acquisition of phenotype but significantly abrogated the ability of these cells to mount inflammatory responses to pathogen-associated stimuli. Forced expression of these miRNAs, which are down-regulated during differentiation, inhibited release of inflammatory cytokines TNF-α, IL-12(p40), IL-6 upon stimulation with LPS. Functional analysis revealed overlapping mechanisms of inhibition, including surface expression of TLR4/CD14/MD-1 and intracellular PKCα/NF-κB activation. Potential intermediary targets of the TLR4-NF-κB axis included members of the PI3K and MAPK families and PKC isoforms. These results demonstrate the requirement of miR-24, miR-30b, and miR-142-3p down-regulation for the generation of fully functional Mφs and DCs.
With the hope of understanding how interleukin (IL)-4 and IL-13 modulated quality of anti-viral CD8(+) T cells, we evaluated the expression of receptors for these cytokines following a range of viral ...infections (e.g. pox viruses and influenza virus). Results clearly indicated that unlike other IL-4/IL-13 receptor subunits, IL-4 receptor α (IL-4Rα) was significantly down-regulated on anti-viral CD8(+) T cells in a cognate antigen dependent manner. The infection of gene knockout mice and wild-type (WT) mice with vaccinia virus (VV) or VV expressing IL-4 confirmed that IL-4, IL-13 and signal transducer and activator of transcription 6 (STAT6) were required to increase IL-4Rα expression on CD8(+) T cells, but not interferon (IFN)-γ. STAT6 dependent elevation of IL-4Rα expression on CD8(+) T cells was a feature of poor quality anti-viral CD8(+) T cell immunity as measured by the production of IFN-γ and tumor necrosis factor α (TNF-α) in response to VV antigen stimulation in vitro. We propose that down-regulation of IL-4Rα, but not the other IL-4/IL-13 receptor subunits, is a mechanism by which CD8(+) T cells reduce responsiveness to IL-4 and IL-13. This can improve the quality of anti-viral CD8(+) T cell immunity. Our findings have important implications in understanding anti-viral CD8(+) T cell immunity and designing effective vaccines against chronic viral infections.
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