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)

The mechanism of ocular surface allergy in the forms of atopic conjunctivitis and vernal keratoconjunctivitis has been highlighted by specific functions of chemokines. In the context of late-phase allergic responses, these molecules have key roles in recruitment and activation of leukocytes. Their interaction with ligands is redundantly regulated; however, results from strategies to block subsets of chemokines have revealed unexpected or highly organized roles of these mediators. Exemplified by analyses of CCL11 function, current concepts of ocular allergy support CCL11 as central mediator. We emphasize the functions as modulator of mast cell activation/differentiation. With the prospect of understanding these functions, new modalities of drugs specifically developed to target CCL11/CCR3 interaction have been discussed.
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PMID:Roles of chemokines in ocular allergy and possible therapeutic strategies. 1544 80

The selective microlocalization of mast cells within specific airway structures, such as the airway smooth muscle and submucosal glands, in asthma is important in the pathophysiology of inflammatory lung disease. Chemokines are likely candidates mediating mast cell migration into these tissue compartments. In this study, we have defined the chemokine receptor profile of human lung mast cells (HLMC) compared with mast cells derived from human bone marrow (BM) and the human mast cell line HMC-1. CXC chemokine receptor 3 (CXCR3) was the most highly expressed chemokine receptor on ex vivo HLMC analyzed by flow cytometry, and CXCR3 expression by mast cells in the bronchial mucosa was confirmed by immuno-histochemistry. CXCR3 was functional, inducing a rise in cytosolic-free Ca2+, actin reorganization, and chemotaxis in response to the CXC ligands CXCL9, -10, and -11. CXCR3 activation did not induce degranulation or cytokine synthesis. In addition, more than 10% of ex vivo HLMC expressed CC chemokine receptor 3, CXCR1, and CXCR4. It is interesting that CXCR3 was not expressed by human BM-derived mast cells, suggesting its expression is induced during tissue maturation. As CXCR3 ligands are elevated in many pulmonary diseases, CXCR3 may be important for determining the anatomical microlocalization of mast cells within the human lung.
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PMID:Differential expression of CCR3 and CXCR3 by human lung and bone marrow-derived mast cells: implications for tissue mast cell migration. 1567 45

Homing of mast cell progenitors (MCps) to the mouse small intestine involves the interaction of alpha4beta7 integrin with mucosal addressin cellular adhesion molecule-1 (MAdCAM-1). We now demonstrate the dependence of this process on CXC chemokine receptor 2 (CXCR2) and vascular cell adhesion molecule-1 (VCAM-1) using null strains and mice sublethally irradiated and bone marrow (BM) reconstituted (SIBR) with wild-type or null BM or with wild-type BM followed by administration of blocking antibody. The intestinal MCp concentration in CXCR2(-/-) mice was reduced by 67%, but was unaltered in CC chemokine receptor 2(-/-) (CCR2(-/-)), CCR3(-/-), or CCR5(-/-) mice. SIBR mice given CXCR2(-/-) BM had an intestinal MCp concentration that was 76% less than that in BALB/c BM reconstituted mice. Antibody blockade of VCAM-1 or of CXCR2 in SIBR mice reduced intestinal MCp reconstitution, and mice lacking endothelial VCAM-1 also had a marked reduction relative to wild-type mice. Finally, the half-life of intestinal MCps in wild-type mice was less than one week on the basis of a more than 50% reduction by administration of anti-alpha4beta7 integrin or anti-CXCR2. Thus, the establishment and maintenance of MCps in the small intestine is a dynamic process that requires expression of the alpha4beta7 integrin and the alpha-chemokine receptor CXCR2.
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PMID:Constitutive homing of mast cell progenitors to the intestine depends on autologous expression of the chemokine receptor CXCR2. 1570 91

There is a growing interest in the role of chemokines and their receptors in the determination of mast cell tissue localization and how chemokines regulate mast cell function. At least nine chemokine receptors (CXCR1, CXCR2, CXCR3, CXCR4, CX3CR1, CCR1, CCR3, CCR4 and CCR5) have been described to be expressed by human mast cells of different origins. Seven chemokines (CXCL1, CXCL5, CXCL8, CXCL14, CX3CL1, CCL5 and CCL11) have been shown to act on some of these receptors and to induce mast cell migration. Mast cells have a unique expression pattern of CCR3, CXCR1 and CXCR2. These receptors are mainly expressed intracellularly on cytoplasmic membranes. Upon an allergic activation, CCR3 expression is increased on the cell surface and the cell becomes vulnerable for CCL11 treatment. Chemokines do not induce mast cell degranulation but CXCL14 causes secretion of de novo synthesized CXCL8. Because of the expression of CCR3, CCR5 and CXCR4 on mast cell progenitors, these cells are susceptible to HIV infection and mast cells might therefore be a persistent HIV reservoir in AIDS. In this review, we summarize the knowledge about chemokine receptor expression and function on mast cells.
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PMID:Chemokine receptor expression by mast cells. 1610 68

Allergic inflammation manifests as one of a number of diseases, including asthma, dermatitis, food allergy, vernal keratoconjunctivitis, and systemic anaphylaxis. Together these diseases affect nearly 25% of the Western world and are a leading health-care problem. The diseases are often biphasic, with an early phase driven primarily by mast cell degranulation and a late phase characterized by leukocyte recruitment. While chemokines are well known to be critical for leukocyte recruitment, their importance in early-phase reactions is poorly defined. We show here that administration of a single oral dose of a high affinity and highly selective CCR3 antagonist ablates both the early and late phase reactions in a mouse model of allergic conjunctivitis. A direct analysis of mast cells in the conjunctiva demonstrates that antagonism of the CCR3 receptor stabilizes the mast cell in vivo, thereby leading to the impaired early phase reaction. The late phase reaction is also strongly inhibited as characterized by both reduced eosinophilia and neutrophilia. These results constitute the first direct evidence that antagonism of CCR3 has clear potential for the treatment of allergic diseases.
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PMID:A specific CCR3 chemokine receptor antagonist inhibits both early and late phase allergic inflammation in the conjunctiva. 1646 99

CC chemokine receptor (CCR) 3 is a chemokine receptor implicated in recruiting cells, particularly eosinophils (EPhi), to the lung in episodes of allergic asthma. To investigate the efficacy of selective, small molecule antagonists of CCR3, we developed a murine model of EPhi recruitment to the lung. Murine eotaxin was delivered intranasally to mice that had previously received i.p. injections of ovalbumin (OVA), and the effects were monitored by bronchoalveolar lavage. A selective eosinophilic influx was produced in animals receiving eotaxin but not saline. Furthermore, the number of EPhi was concentration- and time-dependent. Although anti-CCR3 antibody reduced the number of EPhi, the effect of eotaxin in OVA-sensitized mice was not a direct chemotactic stimulus because mast cell deficiency (in WBB6F1-Kitw/Kitw-v mice) significantly reduced the response. Two representative small molecule CCR3 antagonists from our program were characterized as being active at mouse CCR3. They were administered p.o. to wild-type mice and found to reduce eotaxin-elicited EPhi selectively in a dose-dependent manner. Pump infusion of one of the inhibitors to achieve steady-state levels showed that efficacy was not achieved at plasma concentrations equivalent to the in vitro chemotaxis IC90 but only at much higher concentrations. To extend the results from our recruitment model, we tested one of the inhibitors in an allergenic model of airway inflammation, generated by adoptive transfer of OVA-sensitive murine T helper 2 cells and aerosolized OVA challenge of recipient mice, and found that it inhibited EPhi recruitment. We conclude that small molecule CCR3 antagonists reduce pulmonary eosinophilic inflammation elicited by chemokine or allergenic challenge.
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PMID:Selective inhibition of eosinophil influx into the lung by small molecule CC chemokine receptor 3 antagonists in mouse models of allergic inflammation. 1661 69

Mast cells are well known as effector cells in a variety of inflammatory diseases, including asthma as well as other allergic disorders. The precise role of 9-cis retinoic acid (9CRA) in mast cells is not understood despite the accepted fact that 9CRA regulates inflammatory responses and neutrophil differentiation. In this study, we investigated the effects of 9CRA on the expression of CC chemokine receptors in the human mast cell line, HMC-1. 9CRA selectively inhibits the CCR2 mRNA level and increases the CCR3 mRNA level in both a time and dose dependent manner. Other CC chemokine receptors, including CCR1, CCR4 and CCR5 are not altered by treatment with 9CRA. Both TNF-alpha and LPS, known pro-inflammatory molecules, have no effect on mRNA levels of CC chemokine receptors. For surface expression, 9CRA decreased the CCR2 level but had no effect on the CCR3 level. 9CRA inhibited the chemotactic activity in response to the CCR2-dependent chemokine, MCP-1/CCL2 but not in response to CCR3-specific chemokine, eotaxin/CCL11. 9CRA decreased spontaneous homotype clustering. Therefore, our results demonstrate that 9CRA differentially decreases both CCR2 expression and chemotactic ability of HMC-1 cells, and may regulate the inflammatory effects of mast cells.
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PMID:Differential regulation of CC chemokine receptors by 9-cis retinoic acid in the human mast cell line, HMC-1. 1671 75

In order to investigate immunological changes over time in pigs infected with Trichuris suis, we inoculated 40 pigs with 5000 infective T. suis eggs and left 40 pigs as uninfected controls. Equal numbers of pigs from both groups were sacrificed every other week from 1 to 11 weeks p.i. At necropsy tissue samples were collected from all pigs and their worm burdens were determined. In the proximal colon of T. suis-infected pigs infiltration of eosinophils peaked 5 weeks p.i. and mast cell infiltration developed from 5 to 11 weeks p.i. Histological evaluation of the proximal colon revealed that the presence of T. suis was closely associated with intestinal histopathological changes such as crypt hyperplasia, goblet cell hyperplasia and a general hypertrophy of mucosa. The crypt lengths were positively associated with worm burdens. Real-time PCR analysis of genes related to immune function indicate a local increased transcription of genes coding for CCR3, ARG1, MUC5AC, IL-4, IL-5, IL-13, FcepsilonR1alpha, and IL-13Ralpha2 and decreased expression of genes coding for iNOS, TNF-alpha, IL-10, CD3epsilon, CD80, CD86, IL-4Ralpha, IL-13Ralpha1 and CD40 in the proximal colon of pigs infected with T. suis. This local T-helper cell Type 2-like gene-expression pattern indicates that the Type 2 immune response characteristic of helminth infections in both mouse and humans also develops in pigs infected with T. suis. The results from this study expand our knowledge of the immunomodulatory effect of T. suis, a parasite that has proven effective in treating inflammatory bowel disease, when its eggs are administered regularly to patients.
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PMID:A time course study of immunological responses in Trichuris suis infected pigs demonstrates induction of a local type 2 response associated with worm burden. 1675 May 34

Chemokine receptors regulate the trafficking of leukocytes by mediating chemotaxis and by their influence on the expression and/or affinity of leukocyte integrins. Using blocking mAb, we showed that antigen-induced recruitment of mast cell progenitors (MCp) to the lung requires interaction of a4 integrins on the MCp with endothelial vascular cell adhesion molecule 1 (VCAM-1). In seeking a chemokine component, we found that CXCR2-deficient but not CCR3- or CCR5-deficient sensitized and antigen-challenged mice have significantly fewer lung MCp 1 day after challenge and fewer tracheal intraepithelial MC 1 week after challenge, implying that recruited MCp provide the source for these mature MC. Unexpectedly, reconstitution of sensitized, sublethally irradiated +/+ and -/- mice with bone marrow cells of either genotype indicated that expression of CXCR2 by the migrating MCp was not required. Instead, receptor function by resident lung cells was required because normal BM did not reconstitute MCp recruitment in irradiated CXCR2(-/-) mice. The reduced MCp influx into the lung of CXCR2(-/-) mice was accompanied by reduced induction of VCAM-1 transcripts and reduced endothelial surface expression. Thus, these studies demonstrate a role for a chemokine receptor in regulating endothelial VCAM-1 expression, MCp migration, and the level of intraepithelial MC in the lung of aerosolized, antigen-challenged mice.
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PMID:Pulmonary CXCR2 regulates VCAM-1 and antigen-induced recruitment of mast cell progenitors. 1807 23

Progenitor mast cells (prMCs), derived from CD34(+) precursors are CD4(+)/CCR5(+)/CXCR4(+) and susceptible to CCR5(R5)-tropic virus but only marginally susceptible to CXCR4(X4)-tropic HIV. As infected prMCs mature within extravascular compartments, they become both latently infected and HIV-infection resistant, and thus capable of establishing an inducible reservoir of CCR5-tropic infectious clones. In this report we provide the first evidence that IgE-FcepsilonRI interactions, occurring during a unique period of mast cell (MC) ontogeny, enhance prMC susceptibility to X4 and R5X4 virus. IgE-FcepsilonRI interactions significantly increased expression of CXCR4 mRNA ( approximately 400- to 1800-fold), enhanced prMC susceptibility to X4 and R5X4 virus ( approximately 3000- to 16,000-fold), but had no significant effect on CD4, CCR3, or CCR5 expression, susceptibility to R5 virus, or degranulation. Enhanced susceptibility to infection with X4 virus occurred during the first 3-5 wk of MC ontogeny and was completely inhibited by CXCR4-specific peptide antagonists and omalizumab, a drug that inhibits IgE-FcepsilonRI interactions. IgE-FcepsilonRI coaggregation mediated by HIVgp120 or Schistosoma mansoni soluble egg Ag accelerated maximal CXCR4 expression and susceptibility to X4 virus by prMCs. Our findings suggest that for HIV-positive individuals with atopic or helminthic diseases, elevated IgE levels could potentially influence the composition of CXCR4-tropic and R5X4-tropic variants archived within the long-lived tissue MC reservoir created during infection.
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PMID:IgE-FcepsilonRI interactions determine HIV coreceptor usage and susceptibility to infection during ontogeny of mast cells. 1941 93


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