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

SUMMARYGastrointestinal infection with the nematode Trichinella spiralis is accompanied by a rapid and reversible expansion of the mucosal mast cell and goblet cell populations in the intestinal epithelium, which is associated with the release of their mediators into the gut lumen. Both goblet cell and mast cell hyperplasia are highly dependent on mucosal T-cells and augmented by the cytokines IL-4 and IL-13. However, the contribution of both mast and goblet cells, and the mediators they produce, to the expulsion of the adults of T. spiralis is only beginning to be elucidated through studies predominantly employing T. spiralis-mouse models. In the present article, we review the factors proposed to control T. spiralis-induced mucosal mast cell (MMC) and goblet cell differentiation in the small intestine, and focus on some key MMC and goblet cell effector molecules which may contribute to the expulsion of adult worms and/or inhibition of larval development.
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PMID:Innate immune response mechanisms in the intestinal epithelium: potential roles for mast cells and goblet cells in the expulsion of adult Trichinella spiralis. 1841 1

Allergen inhalation by sensitized asthmatics induces an IgE and mast cell dependent bronchoconstriction and a Th2-dependent inflammatory airway reaction, mucus hypersecretion and airway hyperreactivity. The link between T cells and bronchoconstriction remains controversial. Here we analyzed allergen-induced changes in airway tone in ovalbumin-sensitized mice with established allergic airway inflammation. Inhalation of nebulized ovalbumin elicited a dose-dependent and allergen-specific increase in airway resistance and bronchial tone with a concomitant increase of lymphocytes and eosinophils in bronchoalveolar lavage fluid. A Th2 pattern of cytokine expression and increased mRNA expression of MCP-1, RANTES and VCAM-1 were demonstrated. Anti-CD4 monoclonal antibody treatment prior to provocation decreased IL-13 and VCAM-1 mRNA expression and abolished the increase in bronchial tone and the inflammatory response. We conclude that allergen inhalation in sensitized mice induces airway narrowing similar to the late asthmatic reactions in humans and that this phenomenon is based on activation of CD4(+) T cells.
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PMID:T-cell mediated late increase in bronchial tone after allergen provocation in a murine asthma model. 1850 92

The Tec family tyrosine kinase, IL-2-inducible T cell kinase (Itk), is expressed in T cells and mast cells. Mice lacking Itk exhibit impaired Th2 cytokine secretion; however, they have increased circulating serum IgE, but exhibit few immunological symptoms of allergic airway responses. We have examined the role of Itk in mast cell function and FcepsilonRI signaling. We report in this study that Itk null mice have reduced allergen/IgE-induced histamine release, as well as early airway hyperresponsiveness in vivo. This is due to the increased levels of IgE in the serum of these mice, because the transfer of Itk null bone marrow-derived cultured mast cells into mast cell-deficient W/W(v) animals is able to fully rescue histamine release in the W/W(v) mice. Further analysis of Itk null bone marrow-derived cultured mast cells in vitro revealed that whereas they have normal degranulation responses, they secrete elevated levels of cytokines, including IL-13 and TNF-alpha, particularly in response to unliganded IgE. Analysis of biochemical events downstream of the FcepsilonRI revealed little difference in overall tyrosine phosphorylation of specific substrates or calcium responses; however, these cells express elevated levels of NFAT, which was largely nuclear. Our results suggest that the reduced mast cell response in vivo in Itk null mice is due to elevated levels of IgE in these mice. Our results also suggest that Itk differentially modulates mast cell degranulation and cytokine production in part by regulating expression and activation of NFAT proteins in these cells.
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PMID:The Tec family kinase, IL-2-inducible T cell kinase, differentially controls mast cell responses. 1852 50

IL-33 is a novel member of the IL-1 cytokine family and a potent inducer of type 2 immunity, as mast cells and Th2 CD4+ T cells respond to IL-33 with the induction of type 2 cytokines such as IL-13. IL-33 mRNA levels are extremely high in the CNS, and CNS glia possess both subunits of the IL-33R, yet whether IL-33 is produced by and affects CNS glia has not been studied. Here, we demonstrate that pathogen-associated molecular patterns (PAMPs) significantly increase IL-33 mRNA and protein expression in CNS glia. Interestingly, IL-33 was localized to the nucleus of astrocytes. Further, CNS glial and astrocyte-enriched cultures treated with a PAMP followed by an ATP pulse had significantly higher levels of supernatant IL-1beta and IL-33 than cultures receiving any single treatment (PAMP or ATP). Supernatants from PAMP + ATP-treated glia induced the secretion of IL-6, IL-13, and MCP-1 from the MC/9 mast cell line in a manner similar to exogenous recombinant IL-33. Further, IL-33 levels and activity were increased in the brains of mice infected with the neurotropic virus Theiler's murine encephalomyelitis virus. IL-33 also had direct effects on CNS glia, as IL-33 induced various innate immune effectors in CNS glia, and this induction was greatly amplified by IL-33-stimulated mast cells. In conclusion, these results implicate IL-33-producing astrocytes as a potentially critical regulator of innate immune responses in the CNS.
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PMID:Induction of IL-33 expression and activity in central nervous system glia. 2936 Feb 1

Stem cell factor (SCF) is not only critical for mast cell development, but also an important mast cell functional regulator. However, roles of transcription factors involved in SCF-induced effects remain incompletely defined. Early growth response factor-1 (Egr-1) is a member of zinc-finger transcription factor family. Mouse bone marrow-derived mast cells (BMMC) were used to examine a role of Egr-1 in SCF-induced mast cell activation and growth. SCF induced a strong and rapid expression of Egr-1 mRNA as tested by real-time PCR analysis. SCF-induced Egr-1 nuclear translocation and DNA binding were demonstrated by electrophoretic mobility shift assay (EMSA) and immunofluorescence assay. To examine if Egr-1 is required for SCF-induced IL-13 expression, Egr-1-deficient BMMC were used. Levels of SCF-induced IL-13 mRNA and protein were reduced in Egr-1 deficient BMMC when compared with wild-type BMMC. Although Egr-1 is required for macrophage and lymphocyte development, SCF-induced mast cells growth was not affected by Egr-1 deficiency. Interestingly, SCF-induced Egr activation was blocked by a tyrosine kinase inhibitor PP2, suggesting a role of tyrosine phosphorylation in SCF-induced Egr-1 activation. Taken together, our results suggest that Egr-1 is required for SCF-induced IL-13 expression, but not mast cell growth.
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PMID:The early growth response factor-1 contributes to interleukin-13 production by mast cells in response to stem cell factor stimulation. 1856 87

Previous studies have shown that leukotriene B4 (LTB4), a proinflammatory lipid mediator, is linked to the development of airway hyperresponsiveness through the accumulation of IL-13-producing CD8+ T cells, which express a high affinity receptor for LTB4, BLT1 (Miyahara et al., Am J Respir Crit Care Med 2005;172:161-167; J Immunol 2005;174:4979-4984). By using leukotriene A4 hydrolase-deficient (LTA4H-/-) mice, which fail to synthesize LTB4, we determined the role of this lipid mediator in allergen-induced airway responses. Two approaches were used. In the first, LTA4H-/- mice and wild-type (LTA4H+/+) mice were systemically sensitized and challenged via the airways to ovalbumin. In the second, mice were passively sensitized with anti-ovalbumin IgE and exposed to ovalbumin via the airways. Mast cells were generated from bone marrow of LTA4H+/+ mice or LTA4H-/- mice. After active sensitization and challenge, LTA4H-/- mice showed significantly lower airway hyperresponsiveness compared with LTA4H+/+ mice, and eosinophil numbers and IL-13 levels in the bronchoalveoloar lavage of LTA4H-/- mice were also significantly lower. LTA4H-/- mice also showed decreased airway reactivity after passive sensitization and challenge. After LTA4H+/+ mast cell transfer, LTA4H-/- mice showed increased airway reactivity after passive sensitization and challenge, but not after systemic sensitization and challenge. These data confirm the important role for LTB4 in the development of altered airway responses and suggest that LTB4 secretion from mast cells is critical to eliciting increased airway reactivity after passive sensitization with allergen-specific IgE.
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PMID:Leukotriene B4 release from mast cells in IgE-mediated airway hyperresponsiveness and inflammation. 1902 19

SP600125 is used as a specific inhibitor of c-Jun N-terminal kinase (JNK). We initially aimed to examine physiological roles of JNK in mast cells that play a central role in inflammatory and immediate allergic responses. We found that Fc receptor for IgE (FcepsilonRI)-induced degranulation (serotonin release) and cytokine gene expression [interleukin (IL)-6, tumour necrosis factor-alpha and IL-13] in bone marrow-derived mast cells, were almost completely inhibited by SP600125. However, the time course of FcepsilonRI-induced JNK activation did not correlate with that of serotonin release. Furthermore, FcepsilonRI-induced degranulation and cytokine gene expression were not impaired in a JNK activator, MKK7-deficient mast cells, in which JNK activation was lost. These results indicate that the inhibitory effects by SP600125 are not due to impaired JNK activation. Instead, we found that SP600125 markedly inhibited the FcepsilonRI-induced activation of phosphatidylinositol 3-kinase (PI3K) and Akt, the same as a PI3K inhibitor, wortmannin. Finally, we found that SP600125 specifically inhibits delta form of p110 catalytic subunit (p110delta) of PI3K. Thus, SP600125 exerts its influence on mast cell functions by inhibiting the kinase activity of PI3K, but not JNK.
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PMID:Blockage by SP600125 of Fcepsilon receptor-induced degranulation and cytokine gene expression in mast cells is mediated through inhibition of phosphatidylinositol 3-kinase signalling pathway. 2155 88

The mechanisms by which immunologically activated mast cells stimulate the production of proinflammatory cytokines by T helper type 2 (Th2) lymphocytes were investigated in a human cell culture system. Supernatants collected from cord blood-derived mast cells after treatment with immunoglobulin E (IgE)/anti-IgE contained an activity that stimulated the production of interleukin (IL)-4, IL-5 and IL-13 (both mRNA and protein) by Th2 lymphocytes. This activity was not detected in supernatants from unactivated mast cells and its production was inhibited by treatment of activated mast cells with the cyclo-oxygenase inhibitor diclofenac. The concentration of diclofenac used inhibited completely the production of prostaglandin D(2) (PGD(2)) but did not inhibit the release of histamine or leukotriene C(4). The effect of supernatants from activated mast cells was mimicked by exogenous PGD(2) at concentrations similar to those detected in the cultures of activated mast cells, and addition of exogenous PGD(2) to supernatants from diclofenac-treated mast cells restored their ability to stimulate Th2 cytokine production. The ability of the mast cell supernatants to stimulate production of Th2 cytokines was not affected by addition of diclofenac to the Th2 cells directly, indicating that the production, but not the action, of the factor was sensitive to diclofenac treatment. Inhibition of chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2) abolished the effect of the mast cell supernatants on Th2 cytokine production. These data indicate that mast cells have the ability to stimulate Th2 cells to elaborate cytokines independently of T cell receptor activation or co-stimulation and this response is mediated by PGD(2) acting upon CRTH2 expressed by Th2 cells.
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PMID:Interaction between prostaglandin D and chemoattractant receptor-homologous molecule expressed on Th2 cells mediates cytokine production by Th2 lymphocytes in response to activated mast cells. 1922 Mar 24

Despite being first described in humans nearly 130 years ago, the basophil granulocyte has received little recognition other than being the least common leukocyte circulating in blood. Even after its identity as the source of histamine released by blood cells in response to reaginic IgE, its role in allergic disease has largely been viewed as redundant to that of the tissue mast cell. This line of thought, however, is changing with evidence that has emerged during the last 15 years. Not only have these rare cells been shown to constitute a significant source of cytokines (IL-4 and IL-13) vital to the pathogenesis of allergic disease, but by doing so, may very well modulate T-helper 2-type inflammation at the level of T-cell/dendritic cell interactions. This novel concept combined with the fact that basophils selectively infiltrate allergic lesion sites has sparked greater interest in this once overlooked immune cell, both in adaptive as well as in innate immunity.
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PMID:Basophils beyond effector cells of allergic inflammation. 1923 94

Pigs infected with Ascaris suum or controls were given 100 microg (low-dose) or 1,000 microg (high-dose) all-trans retinoic acid (ATRA)/kg body weight in corn oil or corn oil alone per os on days after inoculation (DAI) -1, +1, and +3 with infective eggs. Treatment with ATRA increased interleukin 4 (IL4) and IL12p70 in plasma of infected pigs at 7 DAI and augmented bronchoalveolar lavage (BAL) eosinophilia observed at 7 and 14 DAI. To explore potential molecular mechanisms underlying these observations, a quantitative real-time reverse transcription (RT)-PCR array was used to examine mRNA expression in tissue. Ascaris-infected pigs had increased levels of liver mRNA for T-helper-2 (Th2)-associated cytokines, mast cell markers, and T regulatory (Treg) cells, while infected pigs given ATRA had higher IL4, IL13, CCL11, CCL26, CCL17, CCL22, and TPSB1 expression. Gene expression for Th1-associated markers (IFNG, IL12B, and TBX21), the CXCR3 ligand (CXCL9), IL1B, and the putative Treg marker TNFRSF18 was also increased. Expression of IL4, IL13, IL1B, IL6, CCL11, and CCL26 was increased in the lungs of infected pigs treated with ATRA. To determine a putative cellular source of eosinophil chemoattractants, alveolar macrophages were treated with IL4 and/or ATRA in vitro. IL4 induced CCL11, CCL17, CCL22, and CCL26 mRNA, and ATRA increased the basal and IL4-stimulated expression of CCL17 and CCL22. Thus, ATRA augments a diverse Th1-, Th2-, Treg-, and inflammation-associated response in swine infected with A. suum, and the increased BAL eosinophilia may be related to enhanced induction of eosinophil chemokine activity by alveolar macrophages.
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PMID:Localized Th1-, Th2-, T regulatory cell-, and inflammation-associated hepatic and pulmonary immune responses in Ascaris suum-infected swine are increased by retinoic acid. 1933 34


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