IL-21 effects on human IgE production in response to IL-4 or IL-13

134

100

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.

Section: Il-21 Induces Activation-induced Cytidine Deaminase (Aid) Anmentioning

confidence: 92%

Section: Il-21 Induces Activation-induced Cytidine Deaminase (Aid) Anmentioning

confidence: 99%

IL-21: An Executor of B Cell Fate

Konforte

Simard

Paige

2009

134

100

“…This is consistent with the recently reported ability of IL-21 to increase secretion of IL-10 by human PBMC stimulated with anti-CD40 mAb (58) and cytokinestimulated human and mouse NK cells (60,61), respectively. However, the same caveats apply to the effects of IL-21 on cytokine secretion by CD40-stimulated human PBMC as those detailed above for proliferation, because it is possible that monocytes, which constitutively express CD40 and respond to activation with CD40L by secreting cytokines (64), were responsible for the IL-10 secretion noted in these cultures (58).…”

Section: Discussionmentioning

confidence: 99%

Kinetics of Human B Cell Behavior and Amplification of Proliferative Responses following Stimulation with IL-21

Good

Bryant

Tangye

2006

250

237

Although recent studies indicated that IL-21 is an important regulator of human B cell activation, detailed comparison of the effects of IL-21 on distinct B cell subsets have not been performed. Our studies revealed that IL-21R is expressed by naive and germinal center B cells, but not memory or plasma cells. IL-21R was increased on naive and memory B cells following in vitro activation. Investigation into the kinetics and magnitude of responses of human B cells to IL-21 revealed that IL-21 potently augmented proliferation of CD40L-stimulated neonatal, splenic naive, and memory and tonsil germinal center B cells. This response exceeded that induced by IL-4, IL-10, and IL-13, cytokines that also induce B cell proliferation. Remarkably, CD40L/IL-21-stimulated naive B cells underwent the same number of divisions as memory cells and exhibited a greater enhancement in their response compared with CD40L alone than memory B cells. Therefore, IL-21 is a powerful growth factor for naive B cells. This may result from the higher expression of IL-21R on naive, compared with memory, B cells. Stimulation of human B cells with CD40L/IL-21 also induced IL-10 production and activation of STAT3. We propose that IL-21 may have therapeutic application in conditions of immunodeficiency where it could expand naive B cells, the predominant B cell subset in such patients. Conversely, because IL-21 is increased in murine models of lupus, dysregulated IL-21 production may contribute to perturbed B cell homeostasis observed in systemic lupus erythematosus. Thus, antagonizing IL-21 may be a novel strategy for treating Ab-mediated autoimmune diseases.

“…IL-21 decreased serum IgE levels when injected into immunized mice, while the IgE production by LPS plus IL-4-stimulated murine splenic B cells was suppressed by IL-21 in culture through the inhibition of germline C transcription (30). In contrast, Wood et al (31) reported that IL-21 augmented IgE production by unfractionated PBMC or B cells driven by anti-CD40 plus either IL-4 or IL-13, whereas IgE secretion by PBMC was blocked by IL-21 when PHA plus IL-4 were used as the stimuli. Caven et al (32) showed that IL-21 elevated IgE production and the proliferation of IgE-producing B cells when the cytokine was added to PBMC or purified tonsillar B cells provoked by anti-CD40 and IL-4 and that this effect was synergized with IL-10, whereas IgE production was either enhanced or diminished by IL-21 depending on the cell density in case murine B cells were cultured with anti-CD40 and IL-4 with or without IL-21.…”

mentioning

confidence: 95%

IL-21 Administration into the Nostril Alleviates Murine Allergic Rhinitis

Hiromura

Kishida

Nakano

et al. 2007

Type I allergic diseases such as allergic rhinitis are caused by IgE-mediated humoral immune responses, while eosinophils also fulfill important roles in the etiology of IgE-mediated allergy. IL-21 regulates growth, differentiation, and function of T, B, and NK cells, while the production of IgE is also influenced by IL-21. In this study we examined whether IL-21 is capable of controlling IgE-mediated allergic reactions in vivo by using the allergic rhinitis mouse model that was established by repetitive sensitization and intranasal challenge with OVA. Intranasal administration with recombinant mouse IL-21 (rmIL-21) significantly reduced the number of sneezes, as well as the serum concentration of OVA-specific IgE, in comparison with that of untreated allergic mice. The rmIL-21 treatment also suppressed germline Cε transcription in the nasal-associated lymphoid tissues, which may have, at least partly, resulted from the up-regulation of Bcl-6 mRNA caused by IL-21. Local expression of IL-4, IL-5, and IL-13 was also inhibited by the intranasal cytokine therapy whereas, in contrast, the expression of endogenous IL-21 mRNA was induced by exogenous rmIL-21. Moreover, IL-21 acted on nasal fibroblasts to inhibit production of eotaxin. This novel function of IL-21 may be associated with the attenuation of eosinophil infiltration into nasal mucosa that was revealed by histopathological observation. These results indicated that IL-21 nasal administration effectively ameliorated allergic rhinitis through pleiotropic activities, i.e., the prevention of IgE production by B cells and eotaxin production by fibroblasts.