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Query: UNIPROT:P15088 (mast cell)
 14,925 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ultraviolet B radiation (280-320 nm) can initiate skin cancer as well as suppress the immune system, thereby preventing the rejection of ultraviolet-B-induced tumors. Recently we reported that there was not only a correlation but also a functional link between dermal mast cell prevalence and susceptibility to ultraviolet-B-induced systemic immunosuppression in multiple strains of mice. In this study, we investigated whether increased dermal mast cell prevalence is a significant predisposing factor for basal cell carcinoma development in humans. In 21 Danes with a history of basal cell carcinoma and 20 control subjects of similar age, sex, skin phototype, and recreational sun exposure over the past 12 mo, dermal mast cell prevalence was quantified on non-sun-exposed buttock skin. We investigated this skin site in order to avoid any changes in mast cell prevalence caused by sun exposure and assumed that the prevalence of mast cells in buttock skin correlated with that at sun-exposed sites at critical times in the development of basal cell carcinomas. Patients with a history of basal cell carcinoma had a significantly higher median dermal mast cell prevalence than control subjects (p = 0.01, Mann-Whitney U ). No correlation was observed between dermal mast cell prevalence and age of basal cell carcinoma patients and control subjects. These results suggest that increased dermal mast cell prevalence is a predisposing factor for basal cell carcinoma development in humans. We hypothesize that mast cells function in humans, as in mice, by initiating immunosuppression and thereby allowing a permissive environment for basal cell carcinoma development.
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PMID:Communications: high dermal mast cell prevalence is a predisposing factor for basal cell carcinoma in humans. 1095 Dec 53

1. The development into tumours of skin cells transformed by ultraviolet (UV) B radiation of wavelengths 290-320 nm is enhanced by the ability of UVB to suppress an immune response that would otherwise destroy them. Ultraviolet B-induced immunomodulation may be by multiple mechanisms, but generally manifests in an antigen-presenting cell defect and an altered cytokine environment in the draining lymph nodes. 2. Immune responses to microbial or self-antigens may be dysfunctional by similar mechanisms following UVB exposure. 3. Earliest-acting intermediates in the initiation of UVB-induced immunosuppression are the UVB absorbers (photoreceptors) of the skin, notably DNA resulting in immunoregulatory cytokine production, and trans-urocanic acid (UCA), which, upon isomerization to its cis isomer, signals downstream immunosuppressive events. 4. In mice, dermal mast cells are critical to UVB-induced systemic immunomodulation. In mice, there is a functional link as well as a linear relationship between the prevalence of histamine-staining dermal mast cells and the log of the dose of UVB required for 50% immunosuppression. Studies with histamine receptor antagonists support histamine as the main' product of mast cells involved. Histamine acts in large part via a prostanoid-dependent pathway. 5. Approximately 50% of humans and greater than 90% of patients with non-melanoma skin cancer are UVB susceptible for suppression of a contact hypersensitivity response. Neither cytokine polymorphisms nor UVB-induced levels of cis-UCA in irradiated skin have been linked to UVB susceptibility. Patients with basal cell carcinomas (BCC) have an increased dermal mast cell prevalence in non-sun-exposed buttock skin. We propose that mast cells function in humans, as in mice, by initiating immunosuppression and, thereby, allowing a permissive environment for BCC development.
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PMID:Sunlight, immunosuppression and skin cancer: role of histamine and mast cells. 1115 22

We examined the role of mast cell infiltrates and other clinical and histological factors in the prognosis of Merkel cell carcinoma. Mast cells were stained immunohistochemically in 36 Merkel cell carcinomas with an antibody to tryptase. The number of stainable cells was quantified within the tumors and surrounding stroma. Other clinical and histological parameters were examined, statistically analyzed, and compared to subsequent clinical course and prognosis. Patient prognosis was worse with higher tumor mast cell numbers (P < 0.002). Prognosis was also found to be adversely affected by the presence of lymphovascular invasion (P = 0.03) and increased tumor size (P = 0.05). Increased mast cells counts, tumor size, and lymphovascular invasion are associated with an adverse prognosis in Merkel cell carcinomas. Evaluation of mast cell infiltrates may provide useful prognostic data and ultimately could assist in selecting patients that require adjuvant treatment in this aggressive form of skin cancer.
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PMID:Mast cells have prognostic value in Merkel cell carcinoma. 1821 40

The UV radiation in sunlight is the primary cause of skin cancer. UV is also immunosuppressive and numerous studies have shown that UV-induced immune suppression is a major risk factor for skin cancer induction. Previous studies demonstrated that dermal mast cells play a critical role in the induction of immune suppression. Mast cell-deficient mice are resistant to the immunosuppressive effects of UV radiation, and UV-induced immune suppression can be restored by injecting bone marrow-derived mast cells into the skin of mast cell- deficient mice. The exact process however, by which mast cells contribute to immune suppression, is not known. In this study, we show that one of the first steps in the induction of immune suppression is mast cell migration from the skin to the draining lymph nodes. UV exposure, in a dose-dependent manner, causes a significant increase in lymph node mast cell numbers. When GFP(+) skin was grafted onto mast cell-deficient mice, we found that GFP(+) mast cells preferentially migrated into the lymph nodes draining the skin. The mast cells migrated primarily to the B cell areas of the draining nodes. Mast cells express CXCR4(+) and UV exposure up-regulated the expression of its ligand CXCL12 by lymph node B cells. Treating UV-irradiated mice with a CXCR4 antagonist blocked mast cell migration and abrogated UV-induced immune suppression. Our findings indicate that UV-induced mast cell migration to draining lymph nodes, mediated by CXCR4 interacting with CXCL12, represents a key early step in UV-induced immune suppression.
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PMID:Mast cell migration from the skin to the draining lymph nodes upon ultraviolet irradiation represents a key step in the induction of immune suppression. 1835 88

Transplant immunosuppressants have been implicated in the increased incidence of non-melanoma skin cancer in transplant recipients, most of whom harbor considerable UVB-induced DNA damage in their skin prior to transplantation. This study was designed to evaluate the effects of two commonly used immunosuppressive drugs, cyclosporine A (CsA) and sirolimus (SRL), on the development and progression of UVB-induced non-melanoma skin cancer. SKH-1 hairless mice were exposed to UVB alone for 15 weeks, and then were treated with CsA, SRL, or CsA+SRL for 9 weeks following cessation of UVB treatment. Compared with vehicle, CsA treatment resulted in enhanced tumor size and progression. In contrast, mice treated with SRL or CsA+SRL had decreased tumor multiplicity, size, and progression compared with vehicle-treated mice. CsA, but not SRL or combined treatment, increased dermal mast cell numbers and TGF-beta1 levels in the skin. These findings demonstrate that specific immunosuppressive agents differentially alter the cutaneous tumor microenvironment, which in turn may contribute to enhanced development of UVB-induced skin cancer in transplant recipients. Furthermore, these results suggest that CsA alone causes enhanced growth and progression of skin cancer, whereas co-administration of SRL with CsA causes the opposite effect. JID JOURNAL CLUB ARTICLE: For questions, answers, and open discussion about this article please go to http://network.nature.com/group/jidclub
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PMID:Sirolimus reduces the incidence and progression of UVB-induced skin cancer in SKH mice even with co-administration of cyclosporine A. 1878 41

The most prevalent cancer diagnosed in the world is sunlight-induced skin cancer. In addition to being a complete carcinogen, UV radiation, the causative agent of skin cancer, induces immune suppression. Because UV-induced immune suppression is a well-recognized risk factor for skin cancer induction, it is crucial to understand the mechanisms underlying UV-induced immune suppression. Mast cells, which have recently emerged as immune regulatory cells, are particularly important in UV-induced immune suppression. UV exposure does not induce immune suppression in mast cell-deficient mice. We report that UV irradiation blocks germinal center (GC) formation, Ab secretion, and T follicular helper (Tfh) cell function, in part by altering the expression of transcription factors BCL-6 and BLIMP-1. No suppression of GC formation, Tfh cell IL-21 expression, or Ab secretion was observed in UV-irradiated mast cell-deficient (Kit(W-sh/W-sh)) mice. When mast cell-deficient mice were reconstituted with wild type mast cells, immune suppression was restored. Reconstituting the mast cell-deficient mice with bone marrow-derived mast cells from IL-10-deficient mice failed to restore the ability of UV radiation to suppress GC formation. Our findings demonstrate a function for mast cells, suppression of Tfh cell production, GC formation, and Ab production in vivo.
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PMID:Mast cell-derived IL-10 suppresses germinal center formation by affecting T follicular helper cell function. 2109 22

Ultraviolet (UV) radiation contained in sunlight is considered a major risk in the induction of skin cancer. While mast cells are best known for their role in allergic responses, they have also been shown to play a crucial role in suppressing the anti-tumour immune response following UV exposure. Evidence is now emerging that UV may also trigger mast cell release of cutaneous tissue remodelling and pro-angiogenic factors. In this review, we will focus on the cellular and molecular mechanisms by which UV recruits and then activates mast cells to initiate and promote skin cancer development.
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PMID:Dermal mast cells affect the development of sunlight-induced skin tumours. 2227 60

The UVB (290-320 nm) radiation in sunlight is responsible for inducing skin cancer. Exposure to UV radiation is also immunosuppressive, and the systemic immune suppression induced by UV is a well-recognized risk factor for cancer induction. As UVB radiation is absorbed within the upper layers of the skin, indirect mechanisms must play a role in activating systemic immune suppression. One prominent example is mast cell migration, which from the skin to the draining LN is an essential step in the cascade of events leading to immune suppression. What triggers mast cell migration is not entirely clear. Here, we tested the hypothesis that PAF, a lipid mediator of inflammation produced by the skin in response to UV exposure, is involved. Mast cell-deficient mice (Kit(W-sh/W-sh)) are resistant to the suppressive effect of UV radiation, and reconstituting mast cell-deficient mice with normal bone marrow-derived mast cells restores susceptibility to immunosuppression. However, when mast cells from PAFR-/- mice were used, the reconstituted mice were not susceptible to the suppressive effects of UV. Furthermore, PAFR-/- mice showed impaired UV-induced mast cell migration when compared with WT mice. Finally, injecting PAF into WT mice mimicked the effect of UV irradiation and induced mast cell migration but not in PAFR-/- mice. Our findings indicate that PAFR binding induces mast cells to migrate from the skin to the LNs, where they mediate immune suppression.
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PMID:An essential role for platelet-activating factor in activating mast cell migration following ultraviolet irradiation. 2400 77

One way sunlight causes skin cancer is by suppressing anti-tumor immunity. A major mechanism involves altering mast cell migration via the C-X-C motif chemokine receptor 4-C-X-C motif chemokine ligand 12 (CXCR4-CXCL12) chemokine pathway. We have discovered that pharmacologically blocking this pathway with the CXCR4 antagonist AMD3100 prevents both UV radiation-induced immune suppression and skin cancer. The majority of control mice receiving UV-only developed histopathologically confirmed squamous cell carcinomas. In contrast, skin tumor incidence and burden was significantly lower in AMD3100-treated mice. Perhaps most striking was that AMD3100 completely prevented the outgrowth of latent tumors that occurred once UV irradiation ceased. AMD3100 protection from UV immunosuppression and skin cancer was associated with reduced mast cell infiltration into the skin, draining lymph nodes, and the tumor itself. Thus a major target of CXCR4 antagonism was the mast cell. Our results indicate that interfering with UV-induced CXCL12 by antagonizing CXCR4 significantly inhibits skin tumor development by blocking UV-induced effects on mast cells. Hence, the CXCR4-CXCL12 chemokine pathway is a novel therapeutic target in the prevention of UV-induced skin cancer.
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PMID:Pharmacologically antagonizing the CXCR4-CXCL12 chemokine pathway with AMD3100 inhibits sunlight-induced skin cancer. 2422 5

The growth and differentiation factor activin A is a key regulator of tissue repair, inflammation, fibrosis, and tumorigenesis. However, the cellular targets, which mediate the different activin functions, are still largely unknown. In this study, we show that activin increases the number of mature mast cells in mouse skin in vivo. To determine the relevance of this finding for wound healing and skin carcinogenesis, we mated activin transgenic mice with CreMaster mice, which are characterized by Cre recombinase-mediated mast cell eradication. Using single- and double-mutant mice, we show that loss of mast cells neither affected the stimulatory effect of overexpressed activin on granulation tissue formation and reepithelialization of skin wounds nor its protumorigenic activity in a model of chemically induced skin carcinogenesis. Furthermore, mast cell deficiency did not alter wounding-induced inflammation and new tissue formation or chemically induced angiogenesis and tumorigenesis in mice with normal activin levels. These findings reveal that mast cells are not major targets of activin during wound healing and skin cancer development and also argue against nonredundant functions of mast cells in wound healing and skin carcinogenesis in general.
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PMID:Mast cells are dispensable for normal and activin-promoted wound healing and skin carcinogenesis. 2422 81


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