Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P15088 (mast cell)
 14,925 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Toll-like receptors (TLRs) are a family of pattern recognition receptors that are critical for cellular responses to a variety of bacterial, viral, and fungal products. Mast cells are important to host survival in a number of models of bacterial infection and might act as sentinel cells in host defense. We therefore examined the expression of TLRs and associated molecules by murine bone marrow-derived mast cells (BMMCs). BMMCs and the murine mast cell line MC/9 expressed mRNA for TLR2, TLR4, and TLR6 but not TLR5 and for both adapter molecule MD-2 and signaling molecule MyD88 but lacked surface CD14. After activation with the TLR2- and TLR4-dependent stimuli Staphylococcus aureus-derived peptidoglycan and Escherichia coli-derived lipopolysaccharide (LPS), respectively, mast cells produced significant levels of interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-alpha). To determine whether mast cells require TLR4 for cellular responses to LPS, mast cells were derived from the bone marrow cells of C3H/HeJ and C57Bl/10ScNCr mice containing a point mutation and a null mutation, respectively, in TLR4. Using these models, we demonstrated that the BMMC IL-6 and TNF-alpha responses to LPS were completely dependent on functional TLR4 with no significant LPS response observed in its absence. These findings have important implications for the mechanism of mast cell responses to pathogens and their products and suggest that different TLR4-expressing cells might have different thresholds for activation with LPS.
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PMID:Toll-like receptor 4-mediated activation of murine mast cells. 1173 61

Toll-like receptor 2 (TLR2) and TLR4 play important roles in the early innate immune response to microbial challenge. To clarify the functional roles of TLRs 2 and 4 in mast cells, we examined bone marrow-derived mast cells (BMMCs) from TLR2 or TLR4 gene-targeted mice. Peptidoglycan (PGN) from Staphylococcus aureus stimulated mast cells in a TLR2-dependent manner to produce TNF-alpha, IL-4, IL-5, IL-6, and IL-13, but not IL-1beta. In contrast, LPS from Escherichia coli stimulated mast cells in a TLR4-dependent manner to produce TNF-alpha, IL-1beta, IL-6, and IL-13, but not IL-4 nor IL-5. Furthermore, TLR2- but not TLR4-dependent mast cell stimulation resulted in mast cell degranulation and Ca2+ mobilization. In a mast cell-dependent model of acute sepsis, TLR4 deficiency of BMMCs in mice resulted in significantly higher mortality because of defective neutrophil recruitment and production of proinflammatory cytokines in the peritoneal cavity. Intradermal injection of PGN led to increased vasodilatation and inflammation through TLR2-dependent activation of mast cells in the skin. Taken together, these results suggest that direct activation of mast cells via TLR2 or TLR4 by respective microligands contributes to innate and allergic immune responses.
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PMID:Differential responses of mast cell Toll-like receptors 2 and 4 in allergy and innate immunity. 1202 Dec 51

Mast cells play a critical role in host defense against bacterial infection. Murine mast cells produce cytokines in response to bacterial peptidoglycan and LPS via Toll-like receptor (TLR) TLR2- and TLR4-dependent mechanisms. The expression of TLRs by human mast cells and responses to known TLR activators was examined. Human mast cells expressed mRNA for TLR1, TLR2, and TLR6 but not TLR4. Bacterial peptidoglycan and yeast zymosan were potent inducers of GM-CSF and IL-1beta and also induced substantial short-term cysteinyl leukotriene generation. In contrast, a synthetic triacylated lipopeptide induced short-term degranulation but failed to induce cysteinyl leukotriene production. The TLR4 activator Escherichia coli LPS did not induce a GM-CSF, IL-1beta leukotriene, or degranulation response. These data demonstrate highly selective production of different classes of mast cell mediators in response to distinct TLR activators of potential importance to the host response to bacterial or fungal pathogens.
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PMID:Cutting edge: distinct Toll-like receptor 2 activators selectively induce different classes of mediator production from human mast cells. 1257 23

Toll-like receptors have a critical role in innate immunity and host defence. However their role in allergic disease has not been studied in great detail. The presence of these receptors on mast cells opens up new possibilities concerning the role of Toll-like receptors in the pathogenesis of asthma and atopic dermatitis. The current review examines the biology of Toll-like receptors expressed on mast cells. In particular, mast cell expression of Toll-like receptors and the diverse responses observed following Toll-like receptor-mediated activation are considered. Several pathogens such as Staphylococcus aureus and respiratory syncytial virus are known to contribute to the development or maintenance of allergic disease and also express potent activators of the Toll-like receptor pathways. The importance of such interactions and the full role of pathogens in chronic allergic disease remain to be elucidated. The unusual ability of Toll-like receptor 2 activators to selectively induce leukotriene production by mast cells opens up new possibilities concerning mechanisms of disease exacerbation during infection.
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PMID:Toll-like receptor-mediated activation of mast cells: implications for allergic disease? 1460 Apr 20

Recent studies have revealed that murine bone marrow-derived cultured mast cells (BMMC), which are phenotypically immature mast cells, express functional TLR2 and TLR4 that recognize distinct pathogen-associated molecules. However, it remains relatively uncertain whether mast cells express other TLR. We recently established a method to obtain large numbers of murine fetal skin-derived cultured mast cells (FSMC); these cells exhibit important features of connective tissue type mast cells. Working with FSMC and BMMC, the TLR mRNA expression profiles were compared between both cell types. Although TLR2 and TLR4 mRNA were detected in both cells at comparable levels, TLR3, TLR7, and TLR9 mRNA were expressed by FSMC at higher levels than by BMMC, suggesting distinct TLR expression profiles among different mast cell populations. With respect to their functional aspects, FSMC, but not BMMC, dose dependently produced proinflammatory cytokines (TNF-alpha and IL-6) and chemokines (RANTES, MIP-1alpha, and MIP-2) in response to poly(I:C), R-848, and CpG oligodeoxynucleotide, which are TLR3, TLR7, and TLR9 activators, respectively. Interestingly, these TLR activators failed to induce degranulation and IL-13 production by both mast cells, although peptidoglycan and LPS (TLR2 and TLR4 activators, respectively) induced IL-13 production by both cells. Mast cells, thus, may have potential to recruit other immune cells to the infected sites by responding to various bacterial and viral components through TLR signaling pathways, presumably being involved in initiating innate immunity and subsequently linking innate and acquired immune responses.
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PMID:TLR3-, TLR7-, and TLR9-mediated production of proinflammatory cytokines and chemokines from murine connective tissue type skin-derived mast cells but not from bone marrow-derived mast cells. 1521 Aug 14

To address the role played by MD-2 in mast cell recognition of LPS, we examined bone marrow-derived mast cells (BMMCs) from MD-2 gene-targeted mice. BMMCs from MD-2-/- mice showed impaired cytokine production (TNF-alpha, IL-6, IL-13, and IL-1beta) in response to LPS from Escherichia coli, but not to peptidoglycan (PGN) from Staphylococcus aureus. In a mast cell-dependent acute septic model, MD-2 deficiency of mast cell resulted in significantly higher mortality due to defective neutrophil recruitment and the production of cytokines in the peritoneal cavity, which was similar to mice with TLR4-deficient mast cells. The TLR2-dependent activation of skin mast cells by PGN was not altered by the absence of MD-2 in vivo. Collectively, MD-2 is essential for the recognition of LPS by TLR4 but not for that of PGN by TLR2 of mast cells.
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PMID:MD-2 is required for the full responsiveness of mast cells to LPS but not to PGN. 1536 78

Histamine is a major inflammatory molecule released from the mast cell, and is known to activate endothelial cells. However, its ability to modulate endothelial responses to bacterial products has not been evaluated. In this study we determined the ability of histamine to modulate inflammatory responses of endothelial cells to Gram-negative and Gram-positive bacterial cell wall components and assessed the role of Toll-like receptors (TLR) 2 and 4 in the co-operation between histamine and bacterial pathogens. Human umbilical vein endothelial cells (HUVEC) were incubated with lipopolysaccharide (LPS), lipoteichoic acid (LTA), or peptidoglycan (PGN) in the presence or absence of histamine, and the expression and release of interleukin-6 (IL-6), and NF-kappaB translocation were determined. The effect of histamine on the expression of mRNA and proteins for TLR2 and TLR4 was also evaluated. Incubation of HUVEC with LPS, LTA and PGN resulted in marked enhancement of IL-6 mRNA expression and IL-6 secretion. Histamine alone markedly enhanced IL-6 mRNA expression in HUVEC, but it did not stimulate proportional IL-6 release. When HUVEC were incubated with LPS, LTA, or PGN in the presence of histamine marked amplification of both IL-6 production and mRNA expression was noted. HUVEC constitutively expressed TLR2 and TLR4 mRNA and proteins, and these were further enhanced by histamine. The expression of mRNAs encoding MD-2 and MyD88, the accessory molecules associated with TLR signalling, were unchanged by histamine treatment. These results demonstrate that histamine up-regulates the expression of TLR2 and TLR4 and amplifies endothelial cell inflammatory responses to Gram-negative and Gram-positive bacterial components.
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PMID:Histamine induces Toll-like receptor 2 and 4 expression in endothelial cells and enhances sensitivity to Gram-positive and Gram-negative bacterial cell wall components. 1537 83

In order to better understand the mechanisms governing the display of mast cell characteristics in human mast cells (MCs), such as cord blood (CB)-derived cultured mast cells, peripheral blood (PB)-derived cultured MCs, and differentiated adult-lung cultured MCs, we examined the transcriptomes of these three types MCs using oligonucleotide microarray (GeneChip) and hierarchical clustering analysis. The expression profile of CB-derived MCs substantially differed from those of PB- and lung-derived MCs. In CB-derived MCs, we identified 132 up-regulated transcripts, such as MARCKS, KRT1, TIMP2, SERPINA1, and TLR2, and 428 down-regulated transcripts, such as LTBP3, CDC42BPA, DDO, DICER1, and FCER1A. Moreover, using RT-PCR and FACS analysis, we confirmed the expression of TLR2, which plays an important role in innate immunity, in CB-derived MCs but not in PB-derived MCs. In addition, it was observed that CB-derived MCs uniquely release histamine and CCL1, which are produced by human MCs but not by human monocytes, in response to peptidoglycan (PGN), although it had been controversy issue whether CB-derived MCs could, in fact, induce degranulation in response to PGN. These results indicated that in innate immunity MCs derived from neonatal hemopoietic cells might have unique functions compared to their adult counterparts because of different gene profiles.
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PMID:Differential gene expression profile between cord blood progenitor-derived and adult progenitor-derived human mast cells. 1586 Feb 27

Mast cells are important cells of the immune system, and their secretory products regulate many vascular functions. Although considerable interest is focused on the role of mast cells and infectious agents in atherosclerosis, whether or not mast cell mediators act in concert with bacterial agents to regulate endothelial activation is not known. Here, we have described experimental techniques and presented related results to demonstrate how mast cell granule (MCG) mediators and bacterial products synergize endothelial cell inflammatory responses. The described methods outline: (1) the collection of rat peritoneal mast cells; (2) preparation of MCGs; (3) co-culture of human endothelial cells with mast cell granules; (4) determination of the regulation of endo- thelial cell inflammatory responses; (5) demonstration of the role of MCG protease and histamine in the regulation of endothelial cell function; (6) amplification of lipopolysaccharide-induced signal transduction pathways by mast cell granules; (7) elucidation of histamine-induced amplification of endothelial cell responses to Gram-negative and Gram-positive bacterial cell wall components; and (8) determination of the expression of Toll-like receptor 2 and 4. We hope the techniques described here can be used for designing experiments focusing on the regulatory role of mast cell mediators on cell functions.
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PMID:Endothelial cell activation by mast cell mediators. 1611 Jan 64

Mast cells mediate both IgE-dependent allergic reactions and protective responses against acute infections, possibly through the activation of Toll-like receptors (TLRs). We find that antigen interacts synergistically with TLR2 and TLR4 ligands to markedly enhance production of cytokines in murine mast cell lines. However, the TLR ligands neither stimulated degranulation and release of arachidonic acid nor influenced such responses to antigen, probably because these ligands failed to generate a necessary calcium signal. The enhanced cytokine production could be attributed to synergistic activation of mitogen-activated protein kinases in addition to the engagement of a more effective repertoire of transcription factors for cytokine gene transcription. The synergistic interactions of TLR ligands and antigen might have relevance to the exacerbation of IgE-mediated allergic diseases by infectious agents.
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PMID:FcepsilonR1 and toll-like receptors mediate synergistic signals to markedly augment production of inflammatory cytokines in murine mast cells. 1617 56


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