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)

Tacalcitol (1,24(R)(OH)2D3, TV-02) inhibited the TPA-induced inflammatory cell infiltration (largely neutrophils) histopathologically and myeloperoxidase (MPO) activity dose-dependently. Tacalcitol inhibited the mRNA expression and protein production of TPA-induced macrophage inflammatory protein-2 (MIP-2) and KC, the functional analogue of human interleukin (IL)-8, in the skin. Immunohistochemical staining of the TPA-applied skin revealed that mast cells expressed MIP-2, whereas KC was observed in keratinocytes, fibroblasts and outer root sheath of hair follicles. Furthermore, tacalcitol inhibited TPA-induced mast cell degranulation 24 hr after application without influence on the total number of mast cells. In this study, tacalcitol was found to have an inhibitory effect on cutaneous inflammation such as inhibition of neutrophil infiltration, MIP-2 and KC production, and mast cell degranulation in TPA-treated hairless mice. These results suggest that tacalcitol modulates cutaneous inflammation as well as keratinocyte proliferation and differentiation, and the inhibitory effect of tacalcitol on cutaneous inflammation may contribute to clinical the effectiveness in the treatment of psoriasis.
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PMID:Anti-inflammatory effects of tacalcitol (1,24(R)(OH)2D3, TV-02) in the skin of TPA-treated hairless mice. 1518 40

Several inflammatory skin conditions, including atopic dermatitis (AD) and psoriasis, are exacerbated by stress. Recent evidence suggests that crosstalk between mast cells, neurons and keratinocytes might be involved in such exacerbation. Mast cells are distributed widely in the skin, are present in increased numbers in AD and are located in close proximity to substance P- or neurotensin-containing neurons. Corticotropin-releasing factor (CRF), its structurally related peptide urocortin (Ucn) and their receptors are also present in the skin and their levels are increased following stress. Human mast cells synthesize and secrete both CRF and Ucn in response to immunoglobulin E receptor (FcepsilonRI) crosslinking. Mast cells also express CRF receptors, activation of which leads to the selective release of cytokines and other pro-inflammatory mediators. Thus, we propose that CRF receptor antagonists could be used together with natural molecules, such as retinol and flavonoids, to inhibit mast cell activation and provide new therapeutic options for chronic inflammatory conditions exacerbated by stress.
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PMID:Mast cells as targets of corticotropin-releasing factor and related peptides. 1549 78

Mast cells are implicated in stress-induced inflammatory skin diseases such as psoriasis. Mechanisms of stress-induced mast cell degranulation however, are not entirely clear. Here we explore the role of activation of a Substance P (SP) receptor (NK-1) on mast cell degranulation upon exposure to stress in rats. A specific nonpeptide NK-1 antagonist, CP99994 was used to treat the rats either peripherally or intracerebroventricularly. Because increased SP activity in the brain may mediate the stress response, we also examined cutaneous mast cell degranulation after central injection of SP. Stress, as well as SP injected centrally, increased mast cell degranulation. Both central and peripheral injection of CP99994 prevented stress-induced mast cell degranulation. Surprisingly, the combination of stress with SP decreased mast cell degranulation, suggesting that high levels of SP may counteract the stress responses. Results in this animal model suggest that NK-1 antagonists may be used therapeutically to treat stress-induced inflammatory skin diseases; however, drug doses should be chosen carefully.
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PMID:NK-1 antagonist CP99994 inhibits stress-induced mast cell degranulation in rats. 1555 Jan 45

Mast cell chymase is a chymotrypsin-like serine proteinase primarily stored in secretory mast cell granules. Mast cell chymase has various effects on angiotensin, metalloproteases, lipoproteins, procollagen, neuropeptides and cytokines. Recent studies have demonstrated that chymase inhibitors inhibit skin inflammation. In this study we sought to determine the role of mast cell chymase in atopic dermatitis (AD) in comparison with its role in psoriasis and normal skin. Skin biopsy specimens were obtained from non-lesional and lesional skin of patients with chronic AD and psoriasis and from normal skin of non-atopic and non-psoriatic controls. The number of mast cells containing chymase was determined by immunohistochemistry using a chymase-specific monoclonal antibody. A significantly (P < 0.05) enhanced number of chymase-positive cells was found in lesional AD skin as compared to normal skin as well as to lesional and non-lesional skin of patients with psoriasis. A significant (P < 0.05) increase in the number of chymase-positive cells was also found in non-lesional AD skin in comparison to psoriasis. An enhanced, albeit not statistically significant difference was noted in non-lesional AD skin as compared to normal skin. In conclusion, these results suggest that mast cell chymase may play an integral part in eliciting and maintaining cutaneous inflammation in AD but not in psoriasis. The increased proteinase activity of mast cell chymase may also be involved in promoting a skin barrier defect in AD, which subsequently enhances the skin's permeability to allergens and microbes and thereby aggravates the eczema.
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PMID:Mast cell chymase is increased in chronic atopic dermatitis but not in psoriasis. 1570 60

Nontraumatic psychological water avoidance stress has been shown to induce mucosal degeneration, inflammatory cell infiltration and mast cell degranulation in stomach, ileum, colon and urinary bladder. Many skin disorders, such as atopic dermatitis and psoriasis, worsen during stress and seem to be related with infiltration and activation of mast cells releasing vasoactive and proinflammatory mediators. Melatonin is a free radical scavenger and has cytoprotective effects in inflammatory conditions. The aim of the present study was to investigate the effects of melatonin on water avoidance stress (WAS)-induced degranulation of mast cells in the dermis. Wistar rats were exposed to acute WAS (aWAS group) or chronic WAS (cWAS group). Before exposing to acute WAS, one group of animals was treated with 10mg/kg melatonin (aWAS+mel group). In the cWAS+mel group, treatment with melatonin lasted for 5 days. Dermal mast cells were stained with toluidine blue and investigated using light microscopy. Numbers of mast cells were increased in both aWAS and cWAS groups, but numbers of degranulated mast cells were increased significantly only in the cWAS group when compared to the control group. Numbers of mature granulated and degranulated mast cells were decreased in the cWAS+mel group when compared to the cWAS group. In conclusion, chronic melatonin treatment reduced WAS-induced infiltration and activation of mast cells in dermis and may provide a useful therapeutic option in stress-induced skin disorders.
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PMID:The protective effects of melatonin against water avoidance stress-induced mast cell degranulation in dermis. 1570 56

Mast cells are critical for allergic reactions, but also for innate or acquired immunity and inflammatory conditions that worsen by stress. Corticotropin-releasing hormone (CRH), which activates the hypothalamic-pituitary-adrenal axis under stress, also has proinflammatory peripheral effects possibly through mast cells. We investigated the expression of CRH receptors and the effects of CRH in the human leukemic mast cell (HMC-1) line and human umbilical cord blood-derived mast cells. We detected mRNA for CRH-R1alpha, 1beta, 1c, 1e, 1f isoforms, as well as CRH-R1 protein in both cell types. CRH-R2alpha (but not R2beta or R2gamma) mRNA and protein were present only in human cord blood-derived mast cells. CRH increased cAMP and induced secretion of vascular endothelial growth factor (VEGF) without tryptase, histamine, IL-6, IL-8, or TNF-alpha release. The effects were blocked by the CRH-R1 antagonist antalarmin, but not the CRH-R2 antagonist astressin 2B. CRH-stimulated VEGF production was mediated through activation of adenylate cyclase and increased cAMP, as evidenced by the fact that the effect of CRH was mimicked by the direct adenylate cyclase activator forskolin and the cell-permeable cAMP analog 8-bromo-cAMP, whereas it was abolished by the adenylate cyclase inhibitor SQ22536. This is the first evidence that mast cells express functional CRH receptors and that CRH can induce VEGF secretion selectively. CRH-induced mast cell-derived VEGF could, therefore, be involved in chronic inflammatory conditions associated with increased VEGF, such as arthritis or psoriasis, both of which worsen by stress.
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PMID:Human mast cells express corticotropin-releasing hormone (CRH) receptors and CRH leads to selective secretion of vascular endothelial growth factor. 1594 67

Pimecrolimus is a calcineurin inhibitor developed for the topical therapy of inflammatory skin diseases, particularly atopic dermatitis (AD). Pimecrolimus selectively targets T cells and mast cells. Pimecrolimus inhibits T-cell proliferation, as well as production and release of interleukin-2 (IL-2), IL-4, interferon-gamma and tumour necrosis factor-alpha. Moreover, pimecrolimus inhibits mast cell degranulation. In contrast to tacrolimus, pimecrolimus has no effects on the differentiation, maturation and functions of dendritic cells. In contrast to corticosteroids, pimecrolimus does not affect endothelial cells and fibroblasts and does not induce skin atrophy. Given the low capacity of pimecrolimus to permeate through the skin, it has a very low risk of systemic exposure and subsequent systemic side-effects. In different randomised controlled trials, topical pimecrolimus as cream 1% (Elidel) has been shown to be effective, well tolerated and safe in both adults and children with mild to moderate AD. In addition, pimecrolimus has been successfully used in inflammatory skin diseases other than AD, including seborrheic dermatitis, intertriginous psoriasis, lichen planus and cutaneous lupus erythematosus.
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PMID:Pimecrolimus in dermatology: atopic dermatitis and beyond. 1603 22

Pimecrolimus, an ascomycin macrolactam derivative, is an inhibitor of T-cell and mast cell activation under development by Novartis for the potential treatment of psoriasis and allergic dermatitis. Novartis is developing both topical and oral formulations of the compound. By December 1998, the topical form of the compound was in phase III trials and the oral form was in phase II trials. Phase III trials were initiated in July 1999 for the treatment of atopic dermatitis. In December 1998, Warburg Dillon Read predicted sales of SFr 30 million in 2000 rising to SFr 184 million in 2002. In March 1999, Credit Suisse First Boston predicted sales of 10 million USD in 2001 rising to 90 million USD in 2003.
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PMID:Pimecrolimus (Novartis). 1611 91

Skin samples from patients with extra-mammary Paget disease, Bowen's disease, atopic dermatitis, psoriasis and non-lesional skin of nevus pigmentosus were immunohistochemically examined with an anti-soluble erythropoietin receptor antibody (anti-sEPOR antibody), and only the dermal mast cells positively stained in all skin samples were examined. These positively stained dermal cells were proved to be mast cells by double staining with anti-sEPOR antibody and either with anti-bikunin antibody or anti-tryptase antibody. Immunoelectron microscopically these EPOR were found in the secretory granules of the dermal mast cells. Further, EPOR in the mast cells may be consisting of only the extracellular domain of erythropoietin receptor molecule as the mast cells were immunohistochemically not reacted with an antibody to the C-terminal peptide of EPOR. Human mast cell line, HMC-1 cells has immunohistochemically the erythropoietin receptor, which was consisting of a 43 kDa major protein and a 20 kDa minor protein in the immunoelectrophoresis. These data may indicate that EPOR in the mast cells may not be the whole molecule, but probably the soluble one of EPOR.
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PMID:The receptor for erythropoietin is present on cutaneous mast cells. 1642 25

Corticotropin-releasing hormone (CRH) coordinates the systemic stress response via hypothalamic-pituitary-adrenal (HPA) axis activation with subsequent modulation of the inflammatory response. Stress is known to affect expression of immune-mediated inflammatory diseases, many of which are associated with HPA axis abnormalities. HPA axis components including CRH and its receptors (CRH-R) exist in the skin and exhibit differential expression according to cell type, physiological fluctuations and disease states. This confirms a local functioning cutaneous HPA-like system. Peripheral CRH may exhibit proinflammatory effects. Animal studies confirm that peripheral CRH is required for induction of the inflammatory response in vivo. CRH and CRH-R are upregulated in inflammatory arthritis synovium and psoriatic skin. CRH may influence mast cell activation, direct modulation of immune cells, angiogenesis and induction of the novel orphan nuclear receptor NURR1. This transcription factor is part of the steroid/thyroid superfamily of related nuclear receptors that includes receptors for steroids, retinoids and vitamin D; ligands of these receptors are effective in treating psoriasis. The roles of CRH and NURR1 in psoriasis and inflammatory skin diseases, especially those associated with stress, remain to be elucidated. This stress may be psychological or physical. CRH, produced locally or delivered by peripheral nerves, may mediate interactions between a cutaneous HPA axis-like system and the central HPA axis--the "brain-skin axis".
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PMID:The role of corticotropin-releasing hormone in immune-mediated cutaneous inflammatory disease. 1648 Apr 21


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