BackgroundHigh concentrations of plasmatic IgE have been related to distinct systemic inflammatory conditions that frequently predispose individuals to hypersensitivity reactions. Although effects of IgE have been suggested to relay on the low-intensity activation of distinct effector elements of the immune system, such as mast cells (MC), experimental evidence on the role of IgE-induced production of inflammatory mediators on specific pathologies is scarce. MC are an important component in tumor microenvironment where they seem to secrete a number of immunomodulatory and angiogenic mediators, such as the Vascular Endothelial Growth Factor (VEGF) by not well-described mechanisms. In this work, we investigated the effect of monomeric IgE (in the absence of antigen) on the production of VEGF in MC, analyzed if monomeric IgE could exacerbate the pro-tumorigenic properties of that cell type and characterized some of the molecular mechanisms behind the effects of IgE on VEGF production and tumor growth.MethodsFor in vitro studies, murine bone marrow-derived mast cells (BMMCs) were used. Pharmacological inhibitors and phosphorylation of key elements controlling VEGF secretion and protein translation were used to characterize the mechanism of VEGF production triggered by IgE.In vivo, the effect of a single i.v. administration of monomeric IgE on B16 melanoma tumor weight, intratumoral blood vessel formation and tumor-associated MC was assessed in four groups of mice: MC-proficient (WT), MC-deficient (Wsh), Wsh reconstituted with MC derived from WT mice (Wsh Rec WT) and Wsh reconstituted with MC derived from Fyn −/− mice (Wsh Rec Fyn −/−).ResultsMonomeric IgE induced VEGF secretion through a Fyn kinase-dependent mechanism and modulated de novo protein synthesis modifying the activity of the translational regulator 4E-BP1 in BMMCs. In vivo, monomeric IgE increased melanoma tumor growth, peritumoral MC and blood vessel numbers in WT but not in Wsh mice. The positive effects of IgE on melanoma tumor growth were reproduced after reconstitution of Wsh mice with WT but not with Fyn −/− BMMCs.ConclusionOur data suggest that monomeric IgE, in the absence of antigen, induces VEGF production in MC and in vivo contributes to melanoma tumor growth through a Fyn kinase-dependent mechanism.
The evolutionarily conserved protein kinase p38 mediates innate resistance to environmental stress and microbial infection. Four p38 isoforms exist in mammals and may have been co-opted for new roles in adaptive immunity. Murine T cells deficient in p38α, the ubiquitously expressed p38 isoform, showed no readily apparent cell-autonomous defects while expressing elevated amounts of another isoform, p38β. Mice with T cells simultaneously lacking p38α and p38β displayed lymphoid atrophy and elevated Foxp3+ regulatory T cell frequencies. Double deficiency of p38α and p38β in naïve CD4+ T cells resulted in an attenuation of MAPK-activated protein kinase (MK)-dependent mTOR signaling after T cell receptor engagement, and enhanced their differentiation into regulatory T cells under appropriate inducing conditions. Pharmacological inhibition of the p38-MK-mTOR signaling module produced similar effects, revealing potential for therapeutic applications.
fredrik.wermeling@ki.se.
Atopy is a condition characterized by the increase of total serum immunoglobulin E (IgE) levels and a tendency to develop allergic reactions. Allergy in general and specifically atopic dermatitis seems to be associated with an increased risk of melanoma development, but those findings are not conclusive. Mast cells play a central role in allergic reactions because they can be activated by IgE-antigen-dependent crosslinking of the Fc Rl receptor. Since mast cells have been found in the periphery of solid tumors and their presence correlates with tumor angiogenesis and growth, it has been proposed that activation of mast cells may facilitate blood vessel formation and tumor development. We evaluated the melanoma growth in atopic states and the role of mast cells in this process. Since hyper-responsiveness is a critical condition in atopic states, we developed a murine model of atopic condition that allowed us to quantify the increase in the inflammatory state in mice. C57BL/6J mice were sensitized with intravenous (i.v) injection of different concentrations of a monoclonal anti-DNP IgE (SPE-7 clone). Twenty-four hours after IgE administration, atopic condition was evaluated by cutaneous passive anaphylaxis (PCA) assays. A specific antigen for the SPE-7 IgE (DNP-HSA) was i.v. injected together with in Evans blue colorant and extravasation of the colorant was quantified by standard methods. C57BL/6J control and atopic mice were inoculated subcutaneously with 0.5×106B16-BL6 melanoma cells in serum-free Tyrode's buffer 24 hours after vehicle or IgE (750 ng i.v.) administration. Tumor weight was assessed during 4 weeks after inoculation of tumor cells in the ear. Results shown that tumor growth was faster in atopic than non-atopic mice. To investigate the role of mast cells in melanoma growth in atopic condition, we evaluated the tumor weight gain in mast cell deficient Kit (Wsh/Wsh) (W-sh) and mast cell reconstituted (W-sh-rec) mice in normal and atopic conditions. Melanoma tumor growth was impaired in non-atopic and atopic W-sh mice and restored in non-atopic W-sh rec. Interestingly, melanoma growth was greater in W-sh rec atopic mice than in all the groups tested. Our results suggest that atopic condition facilitates melanoma tumor growth and that mast cells participate in this effect. This work was supported by CONACyT Grants 83079 and 79162. Scholarship 210067. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr A7.
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