Ionizing gamma radiation has several therapeutic indications including bone marrow transplantation and tumor ablation. Among immune cells, susceptibility of lymphocytes to gamma radiation is well known. However, there is little information on the effects of gamma radiation on mast cells, which are important in both innate and acquired immunity. Previous studies have suggested that mast cells may release histamine in response to high doses of gamma radiation, whereas other reports suggest that mast cells are relatively radioresistant. No strong link has been established between gamma radiation and its effect on mast cell survival and activation. We examined both human and murine mast cell survival and activation, including mechanisms related to innate and acquired immune responses following gamma radiation. Data revealed that human and murine mast cells were resistant to gamma radiation-induced cytotoxicity and, importantly, that irradiation did not directly induce beta-hexosaminidase release. Instead, a transient attenuation of IgE-mediated beta-hexosaminidase release and cytokine production was observed which appeared to be the result of reactive oxygen species formation after irradiation. Mast cells retained the ability to phagocytose Escherichia coli particles and respond to TLR ligands as measured by cytokine production after irradiation. In vivo, there was no decrease in mast cell numbers in skin of irradiated mice. Additionally, mast cells retained the ability to respond to Ag in vivo as measured by passive cutaneous anaphylaxis in mice after irradiation. Mast cells are thus resistant to the cytotoxic effects and alterations in function after irradiation and, despite a transient inhibition, ultimately respond to innate and acquired immune activation signals.
"Once released, Type2-cytokines promote growth, migration and activation of EOs (IL5) and MCs (IL4) as well as IgE production (being candidate mediators of pathologic abnormalities in atopic diseases), exerting a prompt antibacterial and antiviral program (Fukushima, 2007). On the other side, infiltrating EOs/activated MCs contribute to keep high Th2-cytokine array (allowing inflammation and tissue remodeling) and modulate the adaptive response, providing a double-faced outcome in chronic inflammatory disorders (asthma, allergy, autoimmunity or neoplasm) (Kulka et al., 2004; Soule et al., 2007). In mice, TLR4, TLR2/6, and TLR7 have immune-stimulating properties, while TLR3 activation occurs later and appears to down-regulate immune responses; activation of TLR-signaling leads to antiviral cytokine production, such as TNFa and IFNs. "
[Show abstract][Hide abstract] ABSTRACT: The Toll-like Receptor (TLR) family ensures prompt response towards pathogens, protecting the host against infections, and guarantees a realistic balance between protective and detrimental activities. Multiple regulating mechanisms characterize TLR activity that is not limited to innate and adaptive antimicrobial immune responses, as observed in the inflammatory (either infective, allergic or autoimmune) responses associated with tissue remodeling. Following the insult and the arise of inflammatory response, tissue remodeling takes place and might develop in fibrosis, depending on microenvironment as a result of imbalanced fibroblasts (FBs) and myofibroblasts (myoFBs) activation/survival. The process is driven by an epithelial-fibroblast-immune cell cross-talk. While the main FB function is the matrix metabolism for tissue homeostasis or repair, the myoFB differentiation represents a crucial step in attempting repair of injury. FBs/myoFBs provide more than structural support at site of injury, synthesizing and/or reacting to different cytokines, growth factors, neuromediators and soluble/lipid mediators. TLR-bearing FBs/myoFBs might contribute at the innate immune level, providing a second line of protection/defense as well as being a target/effector cell of tissue remodeling. TLRs might also interfere with acute inflammation as well as with established fibrosis, triggering structural/functional changes in agreement with the genetic background, the site of lesion, the entity of associated infection, the poor blood circulation or the pharmacological treatments, all together strictly influencing tissue repair/remodeling process. This review will focus on the recent findings on TLRs at launch and long-lasting tissue remodeling process, that strongly suggest TLRs as optional targets for future therapies. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
Journal of Cellular Physiology 08/2015; DOI:10.1002/jcp.25124 · 3.84 Impact Factor
"This coupled with immunoadjuvants such as TLRs, other innate immune receptor activators or cytokines can augment anti-tumor immunity (reviewed in Ma et al., 2011). In contrast to other immune cells, mast cells are relatively radioresistant (Soule et al., 2007). Mast cells have a slow rate of cell division, which will likely also make them more resistant to several common classes of chemotherapeutic drugs than rapidly dividing immune cells. "
[Show abstract][Hide abstract] ABSTRACT: Mast cells have historically been studied mainly in the context of allergic disease. In recent years, we have come to understand the critical importance of mast cells in tissue remodeling events and their role as sentinel cells in the induction and development of effective immune responses to infection. Studies of the role of mast cells in tumor immunity are more limited. The pro-tumorigenic role of mast cells has been widely reported. However, mast cell infiltration predicts improved prognosis in some cancers, suggesting that their prognostic value may be dependent on other variables. Such factors may include the nature of local mast cell subsets and the various activation stimuli present within the tumor microenvironment. Experimental models have highlighted the importance of mast cells in orchestrating the anti-tumor events that follow immunotherapies that target innate immunity. Mast cells are long-lived tissue resident cells that are abundant around many solid tumors and are radiation resistant making them unique candidates for combined treatment modalities. This review will examine some of the key roles of mast cells in tumor immunity, with a focus on potential immunotherapeutic interventions that harness the sentinel role of mast cells.
"First, CBMC were viable for several days in hypoxia (Fig. 1), secondly there was no spontaneous degranulation in response to hypoxia (Fig. 2A), and thirdly mast cells were still reactive to stimuli under hypoxia. This confirms that mast cells are stable to certain physical environmental changes , . In order to exclude that the results were biased by pH differences we also analysed the pH of the medium in hypoxia and normoxia after 24–96 h and found no differences in pH levels between the two conditions (data not shown). "
[Show abstract][Hide abstract] ABSTRACT: Tissue hypoxia is a consequence of decreased oxygen levels in different inflammatory conditions, many associated with mast cell activation. However, the effect of hypoxia on mast cell functions is not well established. Here, we have investigated the effect of hypoxia per se on human mast cell survival, mediator secretion, and reactivity. Human cord blood derived mast cells were subjected to three different culturing conditions: culture and stimulation in normoxia (21% O(2)); culture and stimulation in hypoxia (1% O(2)); or 24 hour culture in hypoxia followed by stimulation in normoxia. Hypoxia, per se, did not induce mast cell degranulation, but we observed an increased secretion of IL-6, where autocrine produced IL-6 promoted mast cell survival. Hypoxia did not have any effect on A23187 induced degranulation or secretion of cytokines. In contrast, cytokine secretion after LPS or CD30 treatment was attenuated, but not inhibited, in hypoxia compared to normoxia. Our data suggests that mast cell survival, degranulation and cytokine release are sustained under hypoxia. This may be of importance for host defence where mast cells in a hypoxic tissue can react to intruders, but also in chronic inflammations where mast cell reactivity is not inhibited by the inflammatory associated hypoxia.
PLoS ONE 08/2010; 5(8):e12360. DOI:10.1371/journal.pone.0012360 · 3.23 Impact Factor
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