Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.3.16 (calcineurin)
 17,112 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This review highlights some of the research advances in allergic skin disease, anaphylaxis, and hypersensitivity reactions to foods, drugs, and insects that were reported primarily in the Journal in 2004. Clinical observations included that gastrointestinal symptoms during anaphylaxis are associated with an increased risk for hypotension; recurrence of peanut allergy can occur for about 8% of children who pass an oral food challenge and is associated with continued avoidance of the food after the challenge; seafood allergy is reported by 2.3% of the US population; and determination of the time to resolution of childhood egg and milk allergy might be predictable by means of serial determination of food-specific IgE levels. The comorbid effects of atopic dermatitis (AD) on asthma and the role of topical calcineurin inhibitors in the therapy of AD were also addressed. Basic and translational research observations indicate that improved diagnosis and therapy might become possible on the basis of reported identification or characterization of allergens such as: lipid transfer proteins and birch pollen-related cross-reactive allergens in plant foods; proteins in scorpion venom that cross-react with proteins from imported fire ant; mosquito saliva proteins responsible for systemic anaphylaxis; and IgE binding to quinolones detectable with an in vitro immunoassay. In addition, advances in understanding immune regulation associated with abrogation of oral tolerance in food allergy and of dendritic cell function, modulation of regulatory T cells, and chemokine expression in AD have elucidated possible targets for future intervention.
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PMID:Advances in allergic skin disease, anaphylaxis, and hypersensitivity reactions to foods, drugs, and insects. 1599 Jul 89

Through its receptor Kit (CD117), stem cell factor (SCF) critically regulates human mast cell (MC) differentiation, survival, priming, and activation. The dominance of SCF in setting these parameters compels stringent contra-regulation to maintain a balanced MC phenotype. We have synthesized a library of bispecific Ab fragments to examine the effect of linking Kit with CD300a. In this study, we report that CD300a exerts a strong inhibitory effect on Kit-mediated SCF-induced signaling, consequently impairing MC differentiation, survival, and activation in vitro. This effect derives from Kit-mediated tyrosine phosphorylation of CD300a and recruitment of the SHIP-1 but not of SH2-containing protein phosphatase 1. CD300a inhibits the constitutive activation of the human leukemic HMC-1 cells but not their survival. Finally, CD300a abrogates the allergic reaction induced by SCF in a murine model of cutaneous anaphylaxis. Our findings highlight CD300a as a novel regulator of Kit in human MC and suggest roles for this receptor as a suppressor of Kit signaling in MC-related disorders.
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PMID:Suppression of normal and malignant kit signaling by a bispecific antibody linking kit with CD300a. 1842 27

Aggregation of the high affinity IgE receptor (Fc epsilonRI) activates a cascade of signaling events leading to mast cell activation. Subsequently, inhibitory signals are engaged for turning off activating signals. We identified that regulator of calcineurin (Rcan) 1 serves as a negative regulator for turning off Fc epsilonRI-mediated mast cell activation. Fc epsilonRI-induced Rcan1 expression was identified by suppression subtractive hybridization and verified by real-time quantitative polymerase chain reaction and Western blotting. Deficiency of Rcan1 led to increased calcineurin activity, increased nuclear factor of activated T cells and nuclear factor kappaB activation, increased cytokine production, and enhanced immunoglobulin E-mediated late-phase cutaneous reactions. Forced expression of Rcan1 in wild-type or Rcan1-deficient mast cells reduced Fc epsilonRI-mediated cytokine production. Rcan1 deficiency also led to increased Fc epsilonRI-mediated mast cell degranulation and enhanced passive cutaneous anaphylaxis. Analysis of the Rcan1 promoter identified a functional Egr1 binding site. Biochemical and genetic evidence suggested that Egr1 controls Rcan1 expression. Our results identified Rcan1 as a novel inhibitory signal in Fc epsilonRI-induced mast cell activation and established a new link of Egr1 and Rcan1 in Fc epsilonRI signaling.
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PMID:Rcan1 negatively regulates Fc epsilonRI-mediated signaling and mast cell function. 1912 55

Tacrolimus (FK506) and cyclosporine A (Cys A) are immunosuppressive drugs used in the treatment of inflammatory diseases and for preventing rejection of allogeneic transplants. Tacrolimus forms a complex with FK506 binding protein (FKBP), and Cys A forms a complex with cyclophilin. These tacrolimus-FKBP and Cys A-cyclophilin complexes interact with calcineurin (CaN), thereby suppressing activation of T cells. In contrast, steroidal anti-inflammatory drugs suppress the immune system mainly via inhibition of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) and the activating protein-1 (AP-1) pathway. Previously, we reported that tacrolimus, but not dexamethasone, reduced scratching behavior in a murine model of atopic dermatitis. To elucidate the mechanism involved in the inhibition of scratching behavior, we used a mouse model of allergic dermatitis to compare the characteristics of tacrolimus and Cys A treatment. We found that Cys A suppressed scratching behavior induced by application of 2,4-dinitrofluorobenzene, as did tacrolimus. In addition, both drugs attenuated increases in vascular permeability and scratching behavior induced by passive cutaneous anaphylaxis. These results indicate that inhibition of the CaN pathway plays an important role in tacrolimus- and Cys A-induced inhibition of scratching behavior in mice. Furthermore, we observed that CaN inhibitors suppressed mast cell-dependent allergic reaction.
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PMID:Comparison of the efficacy of tacrolimus and cyclosporine A in a murine model of dinitrofluorobenzene-induced atopic dermatitis. 2067 65

Anaphylaxis, the most serious and life-threatening allergic reaction, produces the release of inflammatory mediators by mast cells and basophils. Regulator of calcineurin 1 (Rcan1) is a negative regulator of mast-cell degranulation. The action of mediators leads to vasodilation and an increase in vascular permeability, causing great loss of intravascular volume in a short time. Nevertheless, the molecular basis remains unexplored on the vascular level. We investigated Rcan1 expression induced by histamine, platelet-activating factor (PAF), and epinephrine in primary human vein (HV)-/artery (HA)-derived endothelial cells (ECs) and human dermal microvascular ECs (HMVEC-D). Vascular permeability was analyzed in vitro in human ECs with forced Rcan1 expression using Transwell migration assays and in vivo using Rcan1 knockout mice. Histamine, but neither PAF nor epinephrine, induced Rcan1-4 mRNA and protein expression in primary HV-ECs, HA-ECs, and HMVEC-D through histamine receptor 1 (H1R). These effects were prevented by pharmacological inhibition of calcineurin with cyclosporine A. Moreover, intravenous histamine administration increased Rcan1 expression in lung tissues of mice undergoing experimental anaphylaxis. Functional in vitro assays showed that overexpression of Rcan1 promotes barrier integrity, suggesting a role played by this molecule in vascular permeability. Consistent with these findings, in vivo models of subcutaneous and intravenous histamine-mediated fluid extravasation showed increased response in skin, aorta, and lungs of Rcan1-deficient mice compared with wild-type animals. These findings reveal that endothelial Rcan1 is synthesized in response to histamine through a calcineurin-sensitive pathway and may reduce barrier breakdown, thus contributing to the strengthening of the endothelium and resistance to anaphylaxis. These new insights underscore its potential role as a regulator of sensitivity to anaphylaxis in humans.
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PMID:Endothelial Regulator of Calcineurin 1 Promotes Barrier Integrity and Modulates Histamine-Induced Barrier Dysfunction in Anaphylaxis. 2910 73