Cloning of a type I cytokine receptor most related to the IL-2 receptor β chain

Ozaki, Katsutoshi; Kikly, Kristine; Michalovich, David; Young, Peter R.; Leonard, Warren J.

doi:10.1073/pnas.200360997

Cited by 298 publications

(356 citation statements)

References 25 publications

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“…IL-21R is expressed in lymphoid tissues, in particular by NK, B, T, and dendritic cells, macrophages, and endothelial cells (1) (data not shown). IL-21R has the highest sequence homology to IL-2R␤ chain and IL-4R␣ chain (2), which associates with the common ␥ cytokine receptor chain (␥c) 3 (2,3) upon ligand binding. The widespread lymphoid distribution of IL-21R suggests that IL-21 may potentially play a substantial role in immune regulation.…”

Section: Il-21 Activates Both Innate and Adaptive Immunity To Generatmentioning

confidence: 99%

IL-21 Activates Both Innate and Adaptive Immunity to Generate Potent Antitumor Responses that Require Perforin but Are Independent of IFN-γ

Ma¹,

Whitters²,

Konz³

et al. 2003

The Journal of Immunology

162

148

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IL-21 is a key factor in the transition between innate and adaptive immune responses. We have used the cytokine gene therapy approach to study the antitumor responses mediated by IL-21 in the B16F1 melanoma and MethA fibrosarcoma tumor models in mice. Retrovirally transduced tumor cells secreting biologically functional IL-21 have growth patterns in vitro similar to that of control green fluorescent protein-transduced cells, but are completely rejected in vivo. We show that IL-21 activates NK and CD8+ T cells in vivo, thus mediating complete rejection of poorly immunogenic tumors. Rejection of IL-21-secreting tumors requires the presence of cognate IL-21R and does not depend on CD4+ T cell help. Interestingly, perforin, but not IFN-γ or other major Th1 and Th2 cytokines (IL-12, IL-4, or IL-10), is required for the IL-21-mediated antitumor response. Moreover, IL-21 results in 50% protection and 70% cure of nonimmunogenic tumors when given before and after tumor challenge, respectively, in C57BL/6 mice. We conclude that IL-21 immunotherapy warrants clinical evaluation as a potential treatment for cancer.

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Section: Il-21 Activates Both Innate and Adaptive Immunity To Generatmentioning

confidence: 99%

IL-21 Activates Both Innate and Adaptive Immunity to Generate Potent Antitumor Responses that Require Perforin but Are Independent of IFN-γ

Ma¹,

Whitters²,

Konz³

et al. 2003

The Journal of Immunology

162

148

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“…IL-21R, expressed on both NK and T cells (1), is related to IL-2R␤ (3). It was recently shown that the common ␥-chain (␥ c ), 3 shared by the receptors for IL-2, IL-4, IL-7, IL-9, and IL-15, is also the functional component of the IL-21R complex (2). Mice lacking the IL-2/IL-15R␤ chain do not have NK and T cells.…”

Section: Il-21 Up-regulates the Expression Of Genes Associated Withmentioning

confidence: 99%

IL-21 Up-Regulates the Expression of Genes Associated with Innate Immunity and Th1 Response

Strengell

Sareneva

Foster

et al. 2002

The Journal of Immunology

229

180

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IL-21 is a recently characterized T cell-derived cytokine that regulates NK and T cell function. IL-21R shares the common γ-chain (γc) with the receptors for IL-2, IL-4, IL-7, IL-9, and IL-15. Despite the same γc, these cytokines have different effects on diverse cells. In this study, we have studied IL-15- and IL-21-induced gene expression in human primary NK and T cells and the NK-92 cell line. Both IL-15 and IL-21 rapidly induced mRNA synthesis for IFN-γ, T-bet, IL-2Rα, IL-12Rβ2, IL-18R, and myeloid differentiation factor 88 (MyD88), the genes that are important in activating innate immunity and Th1 response. IL-15 induced STAT5 DNA binding to the IL-2Rα IFN-γ-activated sequence (GAS), MyD88 GAS, and c-sis-inducible elements, whereas IL-21 induced STAT3 DNA binding to MyD88 GAS and c-sis-inducible elements. IL-21-induced STAT3 activation was verified by immunoprecipitation and Western blotting with anti-phosphotyrosine Ab. In addition, pretreatment of NK-92 cells with IL-15 or IL-21 strongly enhanced IL-12-induced STAT4 DNA binding to IL-2Rα GAS. The induction of IFN-γ, T-bet, IL-12Rβ2, and IL-18R gene expression in NK cells, along with STAT3 activation, suggests that IL-21 is involved in the activation of innate immune responses. Moreover, the enhanced transcription of these genes in T cells establishes a significant role for IL-21 also in the Th1 response.

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“…In contrast to the cytokine, IL-21R is expressed on multiple cell types in the immune system (2,5,12), including T cells, B cells, NK cells, macrophages, and dendritic cells (13,14).…”

mentioning

confidence: 99%

Blockade of the interleukin‐21/interleukin‐21 receptor pathway ameliorates disease in animal models of rheumatoid arthritis

Young¹,

Hegen²,

Margery³

et al. 2007

Arthritis & Rheumatism

256

203

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Objective. Interleukin-21 (IL-21) is a T cellderived cytokine that modulates T cell, B cell, and natural killer cell responses. In this study, the effects of blocking IL-21 were examined in 2 rodent models of rheumatoid arthritis (RA) to determine whether IL-21 contributes to their pathologic processes.Methods. DBA/1 mice were immunized with bovine type II collagen and then treated with murine IL-21 receptor Fc fusion protein (IL-21R.Fc), which was initiated after the onset of arthritis symptoms in 10% of the cohort. The mice were assessed 3 times per week for signs of disease, including histologic features as well as serum cytokine, Ig, and cytokine messenger RNA (mRNA) levels in the paws. In a separate experiment, Lewis rats were immunized with Freund's complete adjuvant followed by administration of IL-21R.Fc at the peak of inflammation in the joints. Rats were assessed daily for histologic features and for scoring of arthritis severity. In addition, the effects of IL-21R.Fc on the production of interferon-␥ (IFN␥) by T cells were examined.Results Conclusion. These findings demonstrate a pathogenic role for IL-21 in animal models of RA, and support consideration of IL-21 as a therapeutic target in human RA.

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Cloning of a type I cytokine receptor most related to the IL-2 receptor β chain

Cited by 298 publications

References 25 publications

IL-21 Activates Both Innate and Adaptive Immunity to Generate Potent Antitumor Responses that Require Perforin but Are Independent of IFN-γ

IL-21 Activates Both Innate and Adaptive Immunity to Generate Potent Antitumor Responses that Require Perforin but Are Independent of IFN-γ

IL-21 Up-Regulates the Expression of Genes Associated with Innate Immunity and Th1 Response

Blockade of the interleukin‐21/interleukin‐21 receptor pathway ameliorates disease in animal models of rheumatoid arthritis

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