Costimulation with interleukin-4 and interleukin-10 induces mast cell apoptosis and cell-cycle arrest: the role of p53 and the mitochondrion

Bouton, L.Andrew; Ramı́rez, C.; Bailey, Daniel; Yeatman, C. Fitzhugh; Yue, Joyce; Wright, Harry V.; Domen, Jos; Rosato, Roberto R.; Grant, Steven; Fischer-Stenger, Krista; Ryan, John

doi:10.1016/j.exphem.2004.09.002

Cited by 35 publications

(26 citation statements)

References 37 publications

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“…We have previously found that IL-4 inhibits the survival of developing mast cells (10), and that combined signaling with IL-4 and IL-10 induces apoptosis of differentiated mast cells (35,36). Given the newly found importance of mast cells in Th1-type pathology, we extended these studies to include the prototypical Th1 cytokine IFN-␥.…”

Section: Discussionmentioning

confidence: 99%

IFN-γ Induces Apoptosis in Developing Mast Cells

Mann-Chandler

Kashyap

Wright

et al. 2005

The Journal of Immunology

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Mast cells are critical effectors of allergic disease, and are now implicated in immune responses observed in arthritis, multiple sclerosis, and heart disease. Because of their role in inflammation, understanding how mast cells develop is of clinical importance. In this study we determined the effects of IFN-γ on mast cell survival. Using in vitro culture of bone marrow cells in IL-3 plus stem cell factor, we found that the addition of IFN-γ induced apoptosis, as exhibited by the presence of subdiploid DNA and caspase activation. IFN-γ-mediated apoptosis was Stat1-dependent, and was accompanied by loss of mitochondrial membrane potential. Apoptosis was reduced in cultures of bone marrow cells derived from p53- or Bax-deficient mice, as well as H2K-Bcl-2 transgenic mice. IFN-γ hyperresponsiveness has been shown to result in inflammatory disease and death in mice lacking the regulatory protein suppressor of cytokine signaling (SOCS)-1. Bone marrow cells from SOCS-1 knockout (KO) mice failed to give rise to viable mast cells after culture in IL-3 plus stem cell factor, with profound apoptosis occurring as the cultures matured. However, bone marrow cells lacking both SOCS-1 and IFN-γ survived normally. This in vitro defect in mast cell development was recapitulated in vivo. SOCS-1 KO mice demonstrated a 67% decrease in peritoneal mast cell numbers relative to wild-type mice, a deficiency that was reversed in SOCS-1/IFN-γ KO mice. These data demonstrate the potent regulatory effects of IFN-γ on mast cell survival and show that this cytokine can elicit mast cell death in vitro and in vivo.

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Section: Discussionmentioning

confidence: 99%

IFN-γ Induces Apoptosis in Developing Mast Cells

Mann-Chandler

Kashyap

Wright

et al. 2005

The Journal of Immunology

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“…Because we have found that the cytokines IL-10 and TGF␤1, which are produced by Treg, can suppress mast cell function (15)(16)(17)(18)(19)(20)(21)(22), we investigated how Tregmast cell interactions affect the mast cell response. Mast cell activation by IgE logically precedes inflammation in atopic disease, suggesting that mast cells could elicit Treg migration.…”

Section: Mast Cells Induce Migration Of Cd25 ϩ and Tconv Cells But Fmentioning

confidence: 99%

“…Given that suppression by preactivated Treg is both Ag and MHC nonspecific, these potent inhibitory cytokines may be critical depending upon the disease model used. We have found that IL-10 and TGF␤1 inhibit mast cell development, function, and survival (15)(16)(17)(18)(19)(20)(21)(22). We have now investigated the role of Treg in controlling the mast cell response.…”

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confidence: 99%

Cutting Edge: CD4 T Cell-Mast Cell Interactions Alter IgE Receptor Expression and Signaling

Kashyap

Thornton

Norton

et al. 2008

The Journal of Immunology

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Mast cell activation is associated with atopic and inflammatory diseases, but the natural controls of mast cell homeostasis are poorly understood. We hypothesized that CD4+CD25+ regulatory T cells (Treg) could function in mast cell homeostasis. In this study, we demonstrate that mast cells can recruit both Treg and conventional CD4+ T cells (Tconv). Furthermore, Treg, but not Tconv, suppress mast cell FcεRI expression. Despite the known inhibitory functions of IL-10 and TGFβ1, FcεRI suppression was independent of IL-10 and TGF-β1 and required cell contact. Surprisingly, coculture with either Treg or Tconv cells suppressed IgE-mediated leukotriene C4 production but enhanced cytokine production by mast cells. This was accompanied by a selective increase in FcεRI-mediated Stat5 phosphorylation, which is a critical mediator of IgE-mediated cytokine secretion. These data are the first direct demonstration that mast cells can recruit Treg and illustrate that T cell interactions can alter the mast cell response.

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“…In the current study, positive staining for IL-10 was present in all groups, with a more obvious response in group 3. Because IL-10 is accepted to be a major component of Th2-mediated mast cell response [25] , a high level of IL-10 in group 3 is not unexpected.…”

Section: Discussionmentioning

confidence: 99%

Inducing Ocular Allergy with β-Lactoglobulin: A New Experimental Model

Sari

Dinç

Yılmaz³

et al. 2010

Ophthalmic Res

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Purpose: To develop a new experimental ocular allergy animal model induced by β-lactoglobulin (BLG), a major cow’s milk allergen, and to discuss the clinical, histopathological and immunohistochemical findings. Methods: Forty Balb/c mice were randomized and separated into groups of 10. Groups were determined according to the different concentrations of BLG drops used. Study groups were immunized with 2.5, 5 or 10 mg/ml topical BLG (groups 2, 3 and 4, respectively) following intraperitoneal injection for the systemic immunization. The control group (group 1) was immunized with aluminium hydroxide (alum) alone within the same intervals. After ocular challenge, all the animals were evaluated clinically, histopathologically (mast cell and eosinophil infiltration) and immunhistochemically in terms of both T helper type 1- (IFNγ, TNFα) and T helper type 2- (IL-3, IL-4, IL-5, IL-10) specific cytokines. Results: Both clinical and immunohistochemical findings showed that an allergic conjunctivitis was induced in all study groups, with an optimized dosage of topical 5 mg/ml BLG. The conjunctivitis was associated with both Th1 and Th2 response, with a slight predominance of Th1 reaction. Conclusion: We describe a new murine model of acute allergic conjunctivitis induced by BLG. We believe that this new preliminary model has the immune parameters of the late phase of acute allergic conjunctivitis and it provides an alternative means for studying the pathogenesis and future treatments of ocular allergy. Our results should be enhanced with more detailed cellular and humoral parameters.

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Costimulation with interleukin-4 and interleukin-10 induces mast cell apoptosis and cell-cycle arrest: the role of p53 and the mitochondrion

Cited by 35 publications

References 37 publications

IFN-γ Induces Apoptosis in Developing Mast Cells

IFN-γ Induces Apoptosis in Developing Mast Cells

Cutting Edge: CD4 T Cell-Mast Cell Interactions Alter IgE Receptor Expression and Signaling

Inducing Ocular Allergy with β-Lactoglobulin: A New Experimental Model

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