IL-21 Induces Inhibitor of Differentiation 2 and Leads to Complete Abrogation of Anaphylaxis in Mice

Kishida, Tsunao; Hiromura, Yayoi; Shin‐Ya, Masaharu; Asada, Hidetsugu; Kuriyama, Hiroko; Sugai, Manabu; Shimizu, Akira; Yokota, Yoshifumi; Hama, Takemitsu; Imanishi, Jirô; Hisa, Yasuo; Mazda, Osam

doi:10.4049/jimmunol.179.12.8554

Cited by 47 publications

(39 citation statements)

References 59 publications

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“…Indeed, administration of IL-21 in vivo efficiently attenuated symptoms in animal models of allergic rhinitis and anaphylaxis. 15,55 In striking contrast to its effect on murine B cells, we identified IL-21 as an inducer of IgE production by CD40L-stimulated human B cells. Furthermore, IL-4 and IL-21 synergized to increase IgE secretion by all B-cell subsets by more than 10-fold.…”

Section: Discussionmentioning

confidence: 83%

STAT3 is required for IL-21–induced secretion of IgE from human naive B cells

Avery

Cindy

Bryant

et al. 2008

Blood

120

111

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The production of immunoglobulin E (IgE) is tightly regulated. This is evidenced by the fact that it comprises less than 0.0001% of serum Ig, and aberrant production causes atopic conditions, including allergy, rhinitis, and anaphylaxis. Interleu IntroductionIn normal individuals, the concentration of serum immunoglobulin E (IgE) is approximately 100 ng/mL, 10 4 to 10 5 times lower than IgG and IgA, making it the least abundant serum Ig. 1 However, aberrant production of IgE, often resulting from dysregulated Th2 or deficient Th1 responses, is associated with numerous diseases, including atopy, allergy, asthma, eczema/ dermatitis, and parasitic infections. 2 Furthermore, extraordinarily high levels of IgE are present in patients with hyper-IgE syndrome (HIES), Ommen syndrome, Wiskott-Aldrich syndrome, Comel-Netherton syndrome, and immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome, diseases also associated with eczema, allergy, and atopy. 2,3 Thus, to maintain IgE at normal (nonpathogenic) levels, its production must be strictly regulated. Identification of modulators of IgE production is therefore critical for understanding the pathogenesis of, and designing novel therapeutics for, conditions such as allergy and atopy.It is well established that interleukin-4 (IL-4) induces IgE production by human and murine B cells. 4,5 Human B cells also produce IgE when stimulated with IL-13. 2,6,7 Several factors, such as interferon-␥ (IFN-␥), IFN-␣, transforming growth factor-␤, IL-10, and prostaglandins, have been identified that antagonize IL-4-induced IgE production by human and murine B cells. 2,4,5,[8][9][10] Recent studies have also revealed that IL-21 inhibits IL-4-induced IgE secretion by murine B cells. [11][12][13][14][15] The increased levels of serum IgE in IL-21R-or IL-21-deficient mice 11,13 most probably results from the ability of IL-21 to directly inhibit isotype switching to IgE by their B cells. 12 Despite these findings, the effects of IL-21 on IgE secretion by human B cells remain incompletely characterized. On one hand, IL-21 inhibited IL-4-induced IgE secretion in cultures of total peripheral blood mononuclear cells (PBMCs) 16,17 by inducing apoptosis of B cells committed to producing IgE and/or inducing IFN-␥ production by non-B cells in the PBMCs. 14,17 On the other hand, IL-21 had no effect on IgE secretion by human B cells stimulated with anti-CD40 monoclonal antibody (mAb), 18,19 yet it did enhance IgE secretion induced by anti-CD40 mAb and IL-4. [16][17][18]20 Because of conflicting reports on the role of IL-21 in switching to IgE by human B cells, and potential differences in regulating IgE by human and murine B cells, we examined the effect of IL-21 on IgE secretion by human naive B cells. IL-21 induced IgE secretion by CD40L-stimulated naive B cells. Furthermore, addition of both IL-4 and IL-21 to CD40L-stimulated human B cells resulted in potent synergy, inducing 10-to 100-fold higher levels of IgE than those induced by IL-4 or IL-21 alone. One explanation for the int...

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Section: Discussionmentioning

confidence: 83%

STAT3 is required for IL-21–induced secretion of IgE from human naive B cells

Avery

Cindy

Bryant

et al. 2008

Blood

120

111

View full text Add to dashboard Cite

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“…IL-21 receptor (IL-21R) knockout mice have lower serum levels of IgG1 and higher levels of IgE than wild-type mice [37]. Injecting mice with IL-21 decreases serum IgE levels and is therapeutic in mouse models of peanut allergy and allergic rhinitis [38,39]. Finally IL-21 transgenic mice have elevated serum IgM and IgG1 and have increased surface IgG1 + B cells in the spleen [40].…”

Section: Box 1 Interleukin-21 Controls B-cell Functionmentioning

confidence: 98%

Interleukin-21: a critical regulator of the balance between effector and regulatory T-cell responses

Monteleone

Pallone

MacDonald

2008

Trends in Immunology

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“…(Table I). Some insight into the role of IL-21 in allergic responses came from studies showing that exposure to IL-21 resulted in decreased IgE production in an OVA-induced mouse model of allergic rhinitis and in a mouse food allergy model (54,55). In humans, diminution of IgE production has been reported following vaccination with Mycobacterium bovis bacillus Calmette Guerin, BCG (56).…”

Section: Il-21 In Diseasementioning

confidence: 99%

IL-21: An Executor of B Cell Fate

Konforte

Simard

Paige

2009

The Journal of Immunology

131

100

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IL-21 is a type I cytokine that shares the common receptor γ-chain with IL-2, IL-4, IL-7, IL-9, and IL-15. B cells are one of the lymphoid cell types whose development and function are regulated by IL-21. Depending on the interplay with costimulatory signals and on the developmental stage of a B cell, IL-21 can induce proliferation, differentiation into Ig-producing plasma cells, or apoptosis in both mice and humans. Alone and in combination with Th cell-derived cytokines IL-21 can regulate class switch recombination to IgG, IgA, or IgE isotypes, indicating its important role in shaping the effector function of B cells. This review highlights the role of IL-21 in B cell development, function, and disease and provides some perspectives on the future studies in this area.

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IL-21 Induces Inhibitor of Differentiation 2 and Leads to Complete Abrogation of Anaphylaxis in Mice

Cited by 47 publications

References 59 publications

STAT3 is required for IL-21–induced secretion of IgE from human naive B cells

STAT3 is required for IL-21–induced secretion of IgE from human naive B cells

Interleukin-21: a critical regulator of the balance between effector and regulatory T-cell responses

IL-21: An Executor of B Cell Fate

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