Fc receptor γ-chain, a constitutive component of the IL-3 receptor, is required for IL-3-induced IL-4 production in basophils

Hida, Shigeaki; Yamasaki, Satoshi; Sakamoto, Yuzuru; Takamoto, Masaya; Obata, Koichi; Takai, Toshiyuki; Karasuyama, Hajime; Sugane, Kazuo; Saito, Takashi; Taki, Shinsuke

doi:10.1038/ni.1686

Cited by 87 publications

(99 citation statements)

References 49 publications

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“…It has been suggested that isotype-switched antibodies and FcRγ expression play a role in supporting Heligmosomoides polygyrus-induced expansion of basophils (44). This and other studies suggest that expression of FcRγ plays an instrumental role in basophil responses (24), and here we suggest an additional role for FcRγ that is independent of antibody binding.…”

Section: Discussionsupporting

confidence: 55%

“…Interestingly, the response to papain was enhanced in the cells that were transduced with the mutant that disrupts interaction with the FceRI α-chain (L21A) but was lost in cells transduced with the mutant that disrupts interaction with both FceRI α-chain and IL-3R βc and presumably other transmembrane receptors (D11A). This enhanced signaling in response to papain with the L21A mutant is similar to that seen in response to IL-3, perhaps suggesting that when the FceRI α-chain is not expressed a greater proportion of the pool of FcRγ is free to bind other receptors, including the IL-3R βc (24). The response to papain also required an intact ITAM domain, suggesting that papain does require activation of the ITAM signaling pathway downstream of FcRγ, but, in contrast to IgE, does not require the interaction of FcRγ with the FceRI complex.…”

Section: Resultsmentioning

confidence: 60%

“…This phenomenon is seen particularly in signaling pathways that require calcium fluxes if a receptor does not have the intrinsic ability to elicit such flux on its own (23). It also has been shown that IL-3 stimulation of basophils leads to IL-4 production in a manner that is dependent on the ITAM-containing adaptor FcRγ and is independent of its binding to its classical client immunoreceptor, FceRI α-chain (24). Unexpectedly, we found that papain-induced IL-4 and IL-13 production is FcRγ dependent (Fig.…”

Section: Resultsmentioning

confidence: 98%

“…IL-3 has been shown to play many roles in basophil functioning, because it can lead to direct basophil cytokine production (24), play a key role in basophil expansion and survival (28,29), and also can enhance the stimulatory activity of many basophil activators in vitro (30,31). Because IL-3 is used as a growth factor in our in vitro basophil cultures and because of its published role in signaling through the FcRγ-chain (24), we wanted to determine if IL-3 is required for responsiveness to papain.…”

Section: Resultsmentioning

confidence: 99%

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Signaling pathways activated by a protease allergen in basophils

Rosenstein

Bezbradica

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Allergic diseases represent a significant burden in industrialized countries, but why and how the immune system responds to allergens remain largely unknown. Because many clinically significant allergens have proteolytic activity, and many helminths express proteases that are necessary for their life cycles, host mechanisms likely have evolved to detect the proteolytic activity of helminth proteases, which may be incidentally activated by protease allergens. A cysteine protease, papain, is a prototypic protease allergen that can directly activate basophils and mast cells, leading to the production of cytokines, including IL-4, characteristic of the type 2 immune response. The mechanism of papain's immunogenic activity remains unknown. Here we have characterized the cellular response activated by papain in basophils. We find that papain-induced IL-4 production requires calcium flux and activation of PI3K and nuclear factor of activated T cells. Interestingly, papain-induced IL-4 production was dependent on the immunoreceptor tyrosine-based activation motif (ITAM) adaptor protein Fc receptor γ-chain, even though the canonical ITAM signaling was not activated by papain. Collectively, these data characterize the downstream signaling pathway activated by a protease allergen in basophils.allergen | basophil | signaling

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Section: Discussionsupporting

confidence: 55%

Section: Resultsmentioning

confidence: 60%

Section: Resultsmentioning

confidence: 98%

Section: Resultsmentioning

confidence: 99%

See 2 more Smart Citations

Signaling pathways activated by a protease allergen in basophils

Rosenstein

Bezbradica

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…Basophils from FcR␥-chain Ϫ/Ϫ mice were determined by their expression of CD49b and CD123 instead of CD49b and Fc RI, as previously reported. 32 We first confirmed that BMBAs differentiated normally even in the absence of the FcR␥-chain ( Figure 1E). The PGD2 and PGE2 secretion observed from BMBAs of wild-type C57BL/6 mice was completely abrogated in BMBAs of FcR␥-chain Ϫ/Ϫ mice (Figure 1, F and G).…”

Section: Fc Ri Is Involved In Ige-mediated Pgd2/e2 Secretionsupporting

confidence: 60%

FcεRI, but Not FcγR, Signals Induce Prostaglandin D2 and E2 Production from Basophils

Ugajin

Satoh

Kanamori

et al. 2011

The American Journal of Pathology

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Prostaglandin (PG) D2 and PGE2 are arachidonic acid metabolites that are generated though an isomerization reaction catalyzed by PG synthases. PGs have been implicated in immunologic reactions in addition to a wide range of physiological functions. It has long been thought that basophils, in contrast to mast cells, do not synthesize PGs, although they do release leukotrienes and platelet-activating factor. Here, we show that basophils function as a source of PGD2 and PGE2. In vitrocultured basophils from mouse bone marrow produced both PGD2 and PGE2 in response to IgE ؉ antigen (Ag), but not to IgG ؉ Ag. Release of PGs was almost completely abrogated in cultured basophils from FcR␥-chain ؊/؊ mice, indicating the involvement of Fc RI. Basophils freshly isolated from bone marrow cells (primary basophils) were also capable of secreting PGD2 and PGE2. Although the amount of PGD2 released from primary basophils was lower than that from mast cells, the capability of primary basophils to generate PGE2 was more potent than that of mast cells. Transcripts and proteins for both hematopoietic-type PGD synthase and PGE synthase were detected in basophils. In addition, human basophils, like mouse basophils, also produced PGD2 through IgE-mediated stimulation. Thus, basophils could be an important source of PGD2/ PGE2 and may contribute to allergic inflammation and immune responses. Prostaglandins, such as PGD2 and PGE2, are cyclooxygenase (COX) metabolites of arachidonic acids. They have a wide range of biological activities, including relaxation and contraction of smooth muscles, and modulation of neuronal activity. 1 PGD2 is principally produced by activated mast cells and, to a lesser extent, by T helper cell 2 (Th2) cells and dendritic cells 2-4 and exerts its effect through D prostanoid 5 and chemoattractant receptor-homologous molecule receptors expressed onTh2 lymphocytes (CRTH2). 6 A number of recent studies have shown that PGD2 is involved in inflammatory reactions. Mast cell-derived PGD2 suppresses IL-12 production by dendritic cells that induce Th2 responses in vivo. 7 PGD2 both activates and induces chemotaxis of Th2 cells, eosinophils, and basophils. 6 A large amount of PGD2 is detected in broncho-alveolar lavage fluid during allergen-induced airway inflammation. 8 Transgenic mice overexpressing human PGD synthase showed exacerbation of ovalbumin (OVA)-induced lung inflammation associated with pronounced eosinophilia and increased Th2 cytokine production. 9 In our previous studies, mice deficient in the CRTH2 gene were characterized by alleviated IgE-mediated cutaneous responses, contact hypersensitivity reactions, 10 and cedar pollen dermatitis. 11 However, PGE2 is produced by a variety of cells, including fibroblasts and macrophages, and exerts its effects via prostaglandin E2 (EP)1, EP2, EP3, and EP4 receptors. 12 PGE2 acts on T cells to enhance production of Th2-type cytokines and to inhibit production of Th1 cytokines in vitro, 13 whereas another study showed that PGE2 facilitates Th1 differentiation via EP...

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Basophils are potent antigen‐presenting cells that selectively induce Th2 cells

Nakanishi

2010

Eur J Immunol

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Basophils and mast cells are important effector cells in helminth-infected host and IgEmediated allergic inflammation. Although they have the same progenitors, basophils and mast cells complete their terminal differentiation in the bone marrow and peripheral tissues, respectively, and only basophils circulate in the blood. Although it is recognized that basophils are important for Th2 responses, and it is also well established that IL-4 is required for Th2 differentiation from naïve CD4 1 T cells, the nature of the cells that produce ''early'' IL-4, remained elusive until recently. Three groups independently demonstrated that basophils are the predominant APC in inducing Th2 response against helminth parasites and allergens. Basophils express MHC class II and CD80/86, have the potential to take-up and process protein Ag (particularly Ag-IgE complex) and to present peptide in the context of MHC class II, and to produce IL-4. These Ag-pulsed basophils induce the development of Th2 cells both in vitro and in vivo. Thus, basophils contribute to Th2/IgE response by the production of IL-4 and presentation of MHC class II/peptide complex to naïve CD4 1 T cells, in contrast to the Th1-inducing action of DC. In this review, we summarize what is known regarding basophil function in allergy and parasite infection, examine the novel Ag-presenting function of basophils and discuss potential clinical implications of this finding.Key words: Ag-IgE complex . Basophils . Helminth infection . Th2 response IntroductionMast cells, basophils and eosinophils are key effector cells in response to parasite infection and allergic inflammation [1][2][3][4][5]. Basophils and eosinophils are granulocytes, which mature in the bone marrow, circulate in the blood and are recruited to allergic inflammatory sites [3][4][5]. In contrast, progenitors of mast cells migrate from the bone marrow to the peripheral tissues and undergo their terminal differentiation in situ; mast cells that complete their differentiation in the skin or intestine develop into connective tissue mast cells and mucosal mast cells, respectively [1,2]. Mast cells and basophils express the high-affinity receptor for IgE and, upon crosslinking of FceR1-bound IgE with multivalent Ag, rapidly produce diverse preformed mediators, cytokines (e.g. IL-4 and IL-13) and lipid mediators, leading to the induction of immediate-type hypersensitivity [1][2][3][4][5]. Here, the author reviews the major functions of basophils as effector cells in the development of allergic inflammation and their novel function as Th2-inducing APC in helminth infection and allergy.Basophil development and its role in allergy Review Series 14th ICIA study by Arinobu et al. [6] has identified a common progenitor of basophils and mast cell precursor (BMCP), which arise from the granulocyte/monocyte progenitor (GMP). Eosinophil precursor also arises from GMP. The development from GMP to eosinophil precursor and BMCP, and from BMCP to basophil precursor or MCP, are regulated by the level and order of expression...

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Fc receptor γ-chain, a constitutive component of the IL-3 receptor, is required for IL-3-induced IL-4 production in basophils

Cited by 87 publications

References 49 publications

Signaling pathways activated by a protease allergen in basophils

Signaling pathways activated by a protease allergen in basophils

FcεRI, but Not FcγR, Signals Induce Prostaglandin D2 and E2 Production from Basophils

Basophils are potent antigen‐presenting cells that selectively induce Th2 cells

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