There have been extensive developments on cellular and molecular mechanisms of immune regulation in allergy, asthma, autoimmune diseases, tumor development, organ transplantation, and chronic ...infections during the last few years. Better understanding the functions, reciprocal regulation, and counterbalance of subsets of immune and inflammatory cells that interact through interleukins, interferons, TNF-α, and TGF-β offer opportunities for immune interventions and novel treatment modalities in the era of development of biological immune response modifiers particularly targeting these molecules or their receptors. More than 60 cytokines have been designated as interleukins since the initial discoveries of monocyte and lymphocyte interleukins (called IL-1 and IL-2, respectively). Studies of transgenic or gene-deficient mice with altered expression of these cytokines or their receptors and analyses of mutations and polymorphisms in human genes that encode these products have provided essential information about their functions. Here we review recent developments on IL-1 to IL-38, TNF-α, TGF-β, and interferons. We highlight recent advances during the last few years in this area and extensively discuss their cellular sources, targets, receptors, signaling pathways, and roles in immune regulation in patients with allergy and asthma and other inflammatory diseases.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
To the Editor: Microbiome-host interactions are believed to significantly influence host immunologic homeostatic mechanisms, whereas microbial dysbiosis has been associated with many inflammatory ...diseases, including asthma.1 In addition to alterations in microbiome composition, the metabolic activity of the microbiome is relevant.2 One such metabolite is histamine, which is a biogenic amine with multiple effects on immunoregulatory and effector responses.3 Secretion of histamine by microbes significantly influences immune responses within the gut, which is mediated in part by histamine type 2 receptor.4-6 Evaluation of histamine secretion by the human gut microbiome has not been previously assessed in healthy human volunteers or patients with asthma. ...bacterial culture supernatants were used to stimulate CHO cells, which possess a histamine receptor 1 (HR1) chemiluminescent reporter.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Histamine exerts its immunoregulatory effects via the activation of 4 different histamine receptors (named H1R to H4R).4 Activation of histamine receptor 2 (H2R) is associated with potent ...immunoregulatory effects, and the anti-inflammatory effects of a histamine-secreting L rhamnosus strain were lost in H2R-deficient animals, suggesting that histamine derived from the microbiota could be immunoregulatory.5 To extend this observation and determine whether this phenomenon is a common feature of histamine-secreting microbes, we performed in vitro and murine studies with another Lactobacillus that is well recognized for its ability to secrete high levels of histamine, L saerimneri strain 30a (ATCC 33222).6 In vitro, the strain performed as expected. In vitro studies have demonstrated that TLR responses to microbial ligands are significantly influenced by histamine signaling through H2R.5,8 In this report, we demonstrate that the H2R is required for IL-6 and IL-17 mucosal responses, suggesting that H2R is a critical immunoregulatory receptor that significantly influences the in vivo immune response to histamine-secreting microbes within the intestine.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Background The induction of tolerance and protective immunity to microbes is significantly influenced by host- and microbiota-derived metabolites, such as histamine. Objective We sought to identify ...the molecular mechanisms for histamine-mediated modulation of pattern recognition receptor signaling. Methods Human monocyte-derived dendritic cells (MDDCs), myeloid dendritic cells, and plasmacytoid dendritic cells were examined. Cytokine secretion, gene expression, and transcription factor activation were measured after stimulation with microbial ligands and histamine. Histamine receptor 2 (H2 R)–deficient mice, histamine receptors, and their signaling pathways were investigated. Results Histamine suppressed MDDC chemokine and proinflammatory cytokine secretion, nuclear factor κB and activator protein 1 activation, mitogen-activated protein kinase phosphorylation, and TH 1 polarization of naive lymphocytes, whereas IL-10 secretion was enhanced in response to LPS and Pam3Cys. Histamine also suppressed LPS-induced myeloid dendritic cell TNF-α secretion and suppressed CpG-induced plasmacytoid dendritic cell IFN-α gene expression. H2 R signaling through cyclic AMP and exchange protein directly activated by cyclic AMP was required for the histamine effect on LPS-induced MDDC responses. Lactobacillus rhamnosus , which secretes histamine, significantly suppressed Peyer patch IL-2, IL-4, IL-5, IL-12, TNF-α, and GM-CSF secretion in wild-type but not H2 R-deficient animals. Conclusion Both host- and microbiota-derived histamine significantly alter the innate immune response to microbes through H2 R.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Background Increased airway smooth muscle (ASM) mass is an essential component of airway remodeling and asthma development, and there is no medication specifically against it. Tight junction (TJ) ...proteins, which are expressed in endothelial and epithelial cells and affect tissue integrity, might exist in other types of cells and display additional functions in the asthmatic lung. Objective The aim of this study was to investigate the existence, regulation, and function of TJ proteins in ASM in asthmatic patients. Methods The expression and function of TJ proteins in primary ASM cell lines, human bronchial biopsy specimens, and a murine model of asthma were analyzed by means of RT-PCR, multispectral imaging flow cytometry, immunohistochemistry, Western blotting, 5-(and-6)-carboxyfluorescein diacetate succinimidyl ester staining, tritiated thymidine incorporation, wound-healing assay, and luminometric bead array. Results Increased claudin-1 expression was observed in ASM of asthmatic patients, as well as in a murine model of asthma-like airway inflammation. Whereas IL-1β and TNF-α upregulated claudin-1 expression, it was downregulated by the TH 2 cytokines IL-4 and IL-13 in primary human ASM cells. Claudin-1 was localized to the nucleus and cytoplasm but not to the cell surface in ASM cells. Claudin-1 played a central role in ASM cell proliferation, as demonstrated by increased ASM cell proliferation seen with overexpression and decreased proliferation seen with small interfering RNA knockdown of claudin-1. Overexpression of claudin-1 induced vascular endothelial growth factor and downregulated IL-6, IL-8, and IFN-γ–induced protein 10 production by ASM cells. Claudin-1 upregulation by IL-1β or TNF-α was suppressed by dexamethasone but not by rapamycin, FK506, or salbutamol. Conclusion These results demonstrate that claudin-1 might play a role in airway remodeling in asthmatic patients by means of regulation of ASM cell proliferation, angiogenesis, and inflammation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Abstract Background Childhood exposure to a farm environment has been shown to protect against the development of inflammatory diseases such as allergy, asthma, and inflammatory bowel disease. ...Objective We sought to investigate whether besides exposure to microbes also exposure to structures of non-microbial origin such as the sialic acid N -Glycolylneuraminic acid (Neu5Gc) may play a significant role. Methods Exposure to Neu5Gc was evaluated by quantifying anti-Neu5Gc antibody levels in the sera of children enrolled in two farm studies: the PARSIFAL study (n=299) and the PASTURE birth cohort (cord blood (n=836), 1 year (n=734), 4.5 years (n=700) and 6 years (n=728)), and we associated them with asthma and wheeze. The effect of Neu5Gc was examined in murine airway inflammation and colitis models and the role of Neu5Gc in regulating immune activation was assessed by T helper cells and regulatory T cell activation in mice. Results In children, anti-Neu5Gc IgG levels positively correlated with living on a farm and increased peripheral blood Foxp3 expression and inversely correlated with wheezing and asthma in non-atopic subjects. Exposure to Neu5Gc in mice resulted in reduced airway hyperresponsiveness and inflammatory cell recruitment to the lung. Furthermore, Neu5Gc administration to mice reduced the severity of a colitis model. Mechanistically, we found that Neu5Gc exposure reduced IL-17 positive T cells and supported differentiation of regulatory T cells. Conclusions In addition to microbial exposure, increased exposure to non-microbial-derived Neu5Gc may contribute to the protective effects associated with the farm environment.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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