Advances of the interleukin-21 signaling pathway in immunity and angiogenesis

Yuan, Mingjie; Wang, Tao

doi:10.3892/br.2016.665

Cited by 14 publications

(15 citation statements)

References 44 publications

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“…Although IL-17 does not rely directly on JAK/STAT3 signaling, blockade of upstream IL-23 via JAK inhibitors leads to an overall decrease in IL-17 levels [ 101 , 102 ]. Moreover, IL-6, IL-21, IL-22, IL-26, and IL-29, which participate to the amplification and maintenance of the inflammatory loop in psoriasis, all signal via STAT3 [ 46 , 52 , 53 , 55 , 56 , 59 , 103 ]. Therefore, the development and clinical testing of small-molecule inhibitors targeted to upstream JAK enzymes in psoriasis management is an area of active investigation in the field.…”

Section: Biological Therapeutic Strategies (Anti-il-17 -23 -22) mentioning

confidence: 99%

Psoriasis: A STAT3-Centric View

Calautti

Avalle

Poli

2018

IJMS

183

105

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Signal Transducer and Activator of Transcription (STAT)3 has recently emerged as a key player in the development and pathogenesis of psoriasis and psoriatic-like inflammatory conditions. Indeed, STAT3 hyperactivation has been reported in virtually every cell type involved in disease initiation and maintenance, and this factor mediates the signal of most cytokines that are involved in disease pathogenesis, including the central Interleukin (IL)-23/IL-17/IL-22 axis. Despite the recent availability of effective biological agents (monoclonal antibodies) against IL-17 and IL-23, which have radically changed the current standard of disease management, the possibility of targeting either STAT3 itself or, even better, the family of upstream activators Janus kinases (JAK1, 2, 3, and TYK2) offers additional therapeutic options. Due to the oral/topical administration modality of these small molecule drugs, their lower cost, and the reduced risk of eliciting adverse immune responses, these compounds are being actively scrutinized in clinical settings. Here, we summarize the main pathological features of psoriatic conditions that provide the rationale for targeting the JAK/STAT3 axis in disease treatment.

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Section: Biological Therapeutic Strategies (Anti-il-17 -23 -22) mentioning

confidence: 99%

Psoriasis: A STAT3-Centric View

Calautti

Avalle

Poli

2018

IJMS

183

105

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“…IL-21 signals through its heterodimeric receptor consisting of IL-21R and the common cytokine receptor γ chain, and it activates the Janus family tyrosine kinases as well as members of the signal transducer and activator of transcription (STAT) protein family (37). IL-21 preferentially activates STAT3, although STAT1 and STAT5 activation by IL-21 have also been reported (38,39).…”

Section: Introductionmentioning

confidence: 99%

Murine models of Pneumocystis infection recapitulate human primary immune disorders

Elsegeiny¹,

Zheng²,

Eddens³

et al. 2018

JCI Insight

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Despite the discovery of key pattern recognition receptors and CD4+ T cell subsets in laboratory mice, there is ongoing discussion of the value of murine models to reflect human disease. Pneumocystis is an AIDS-defining illness, in which risk of infection is inversely correlated with peripheral CD4+ T cell counts. Due to medical advances in the control of HIV, the current epidemiology of Pneumocystis infection is predominantly due to primary human immunodeficiencies and immunosuppressive therapies. To this end, we found that every human genetic immunodeficiency associated with Pneumocystis infection that has been tested in mice recapitulated susceptibility. For example, humans with a loss-of-function IL21R mutation are severely immunocompromised. We found that IL-21R, in addition to CD4+ T cell intrinsic STAT3 signaling, were required for generating protective antifungal class-switched antibody responses, as well as effector T cell-mediated protection. Furthermore, CD4+ T cell intrinsic IL-21R/STAT3 signaling was required for CD4+ T cell effector responses, including IL-22 production. Recombinant IL-22 administration to Il21r-/- mice induced the expression of a fungicidal peptide, cathelicidin antimicrobial peptide, which showed in vitro fungicidal activity. In conclusion, SPF laboratory mice faithfully replicate many aspects of human primary immunodeficiency and provide useful tools to understand the generation and nature of effector CD4+ T cell immunity.

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“…Interleukin (IL)-21, identified as a member of the IL-2 family, is involved in biological activities in cancer and autoimmunity by binding to its receptor, IL-21R ( 7 ), which is highly expressed in hematological malignancies ( 8 , 9 ) and enhances the aggressiveness of follicular lymphoma ( 10 ). IL-21/IL-21R axis results in the pathogenesis of leukemia and large cell lymphoma through activation of the JAK/STAT signaling pathway ( 11 , 12 ), indicating that IL-21R may present a potential therapeutic target for cancer therapy.…”

Section: Introductionmentioning

confidence: 99%

IL-21R functions as an oncogenic factor and is regulated by the lncRNA MALAT1/miR-125a-3p axis in gastric cancer

et al. 2018

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Interleukin-21 receptor (IL-21R) is involved in the immunological regulation of immune cells and tumor progression in multiple malignancies. However, the potential molecular mechanisms through which non-coding RNAs (ncRNAs) modulate IL-21R signaling in gastric cancer (GC) remain elusive. In this study, the expression of IL-21R was detected by RT-qPCR and western blot analysis in GC cell lines. The association between IL-21R expression and clinicopathological characteristics and the prognosis of patients with GC was analyzed by immunohistochemistry and Kaplan-Meier plotter analysis. The biological functions of IL-21R were analyzed by a series of in vitro and in vivo experiments, and its regulation by ncRNAs was predicted by bioinformatics analysis and confirmed by luciferase assays and rescue experiments. As a result, the expression of IL-21R was found to be significantly increased in GC cell lines and tissues as compared with normal tissues, and was associated with tumor size and lymphatic metastasis, acting as an independent prognostic factor of poor survival and recurrence in patients with GC. The knockdown of IL-21R markedly suppressed GC cell proliferation and invasion, and IL-21R expression was further validated to be negatively regulated by miR-125a-3p (miR-125a). The overexpression of IL-21R reversed the tumor suppressive effects of miR-125a in vitro and in vivo. Moreover, lncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) acted as a sponge of miR-125a to modulate the IL-21R signaling pathway in GC cells and represented a risk factor for survival and recurrence in patients with GC. Taken together, the findings of this study reveal an oncogenic role for IL-21R in gastric tumorigenesis and verify that its activation is partly due to the dysregulation of the lncRNA MALAT1/miR-125a axis. These findings may provide a potential prognostic marker for patients with GC.

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Advances of the interleukin-21 signaling pathway in immunity and angiogenesis

Cited by 14 publications

References 44 publications

Psoriasis: A STAT3-Centric View

Psoriasis: A STAT3-Centric View

Murine models of Pneumocystis infection recapitulate human primary immune disorders

IL-21R functions as an oncogenic factor and is regulated by the lncRNA MALAT1/miR-125a-3p axis in gastric cancer

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