IL‐Y, a synthetic member of the IL‐12 cytokine family, suppresses the development of type 1 diabetes in NOD mice

Flores, Rafael R.; Kim, Eun; Zhou, Lei; Yang, Chenjie; Zhao, Jing; Gambotto, Andrea; Robbins, Paul D.

doi:10.1002/eji.201445403

Cited by 27 publications

(27 citation statements)

References 52 publications

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“…However, IL-30 was demonstrated to function as an agonistic cytokine via the gp130 signaling pathway similar to IL-6, either by itself or associated with other molecules, such as IL-12p40 (15, 16), cytokine-like factor 1 (CLF) (61), IL-6Rα (62), forming p28/IL-6Rα classic signaling, p28/sIL-6Rα trans -signaling, and p28 signaling (Figure 4). …”

Section: Il-y (P28/p40)mentioning

confidence: 99%

“…These suppressive effects seemed to be ascribed to antagonizing the activation of STAT1 and STAT3 pathways induced by IL-27 and IL-6, both of which signal through the gp130 receptor (15). Moreover, recent studies using adenovirus vector expressing p28/p40 (IL-Y) suggested that treatment of prediabetic non-obese diabetic mice prevented the onset of hyperglycemia with reduced expression of inflammatory mediators such as IFN-γ (16). Interestingly, in this study, p28/p40 was demonstrated to be able to significantly stimulate a unique cytokine and chemokine expression profile as well as to activate STAT3, in part, through a pathway involving WSX-1 (16).…”

Section: Il-y (P28/p40)mentioning

confidence: 99%

“…Moreover, recent studies using adenovirus vector expressing p28/p40 (IL-Y) suggested that treatment of prediabetic non-obese diabetic mice prevented the onset of hyperglycemia with reduced expression of inflammatory mediators such as IFN-γ (16). Interestingly, in this study, p28/p40 was demonstrated to be able to significantly stimulate a unique cytokine and chemokine expression profile as well as to activate STAT3, in part, through a pathway involving WSX-1 (16). These results implicate that the p28/p40 might be a bioactive immunosuppressive cytokine and not a mere competitive inhibitor against IL-27, IL-12, or IL-23.…”

Section: Il-y (P28/p40)mentioning

confidence: 99%

“…IL-39, which was most recently discovered, consists of EBI3 and p19 and signals via IL-12Rβ1 and IL-23R (14). p40 also binds to p28 to form p28/p40, tentatively called IL-Y, but this complex was demonstrated to be an antagonist to the signaling by IL-12 and IL-27 (15, 16). In addition, biological activities of monomeric forms of p28 (17), EBI3 (18), and p19 (19) and generation of soluble receptors of WSX-1 (20) and IL-23R (21) as antagonists to IL-27 and IL-23, respectively, were reported as well.…”

Section: Introductionmentioning

confidence: 99%

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Expanding Diversity in Molecular Structures and Functions of the IL-6/IL-12 Heterodimeric Cytokine Family

et al. 2016

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The interleukin (IL)-6/IL-12 family cytokines have pleiotropic functions and play critical roles in multiple immune responses. This cytokine family has very unique characteristics in that they comprise two distinct subunits forming a heterodimer and each cytokine and receptor subunit shares with each other. The members of this cytokine family are increasing; currently, there are more than six cytokines, including the tentatively named cytokines IL-Y (p28/p40), IL-12 (p35/p40), IL-23 (p19/p40), IL-27 [p28/Epstein–Barr virus-induced protein 3 (EBI3)], IL-35 (p35/EBI3), and IL-39 (p19/EBI3). This family of cytokines covers a very broad range of immune responses, including pro-inflammatory responses, such as helper T (Th)1, Th2, and Th17, to anti-inflammatory responses, such as regulatory T (Treg) cells and IL-10-producing Treg cells. IL-12 is the first member of this family, and IL-12, IL-23, and IL-27 are mainly produced by activated antigen-presenting cells, such as dendritic cells and macrophages. IL-12 plays a critical role in the promotion of Th1 immune responses by inducing interferon-γ production to combat pathogens and malignant tumors. IL-23 induces IL-17 production and is necessary to maintain pathogenic Th17 cells that cause inflammatory and autoimmune diseases. IL-27 was initially reported to play a critical role in promotion of Th1 differentiation; however, subsequent studies revealed that IL-27 has broader stimulatory and inhibitory roles by inducing IL-10-producing Treg cells. IL-35 is produced by forkhead box P3+ Treg cells and activated B cells and has immunosuppressive functions to maintain immune tolerance. The most recently identified cytokine, IL-39, is produced by activated B cells and has pro-inflammatory functions. The cytokine tentatively named IL-Y seems to have anti-inflammatory functions by inhibiting Th1 and Th17 differentiation. In addition, individual cytokine subunits were also shown to have self-standing activities. Thus, promiscuity within the IL-6/IL-12 family cytokines complicates structural and functional clarification and assignment of individual cytokines. A better understanding of the recent advances and expanding diversity in molecular structures and functions of the IL-6/IL-12 family cytokines could allow the creation of novel therapeutic strategies by using them as tools and targeted molecules.

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Section: Il-y (P28/p40)mentioning

confidence: 99%

Section: Il-y (P28/p40)mentioning

confidence: 99%

Section: Il-y (P28/p40)mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Expanding Diversity in Molecular Structures and Functions of the IL-6/IL-12 Heterodimeric Cytokine Family

et al. 2016

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“…The IL-12 family cytokines are α/β heterodimers consisting of one α subunit (IL-23p19, IL-27p28, IL-12p35) and one β chain (IL-12p40, Ebi3) [14,15]. Although there are currently four known members in the family, the predictable range of combinations is six and it is conceivable that additional pairings such as IL-23p19/Ebi3 are possible [12,[14][15][16][17]. In this study, we sought to discover additional IL-12 members that might exist in nature.…”

mentioning

confidence: 99%

A novel IL‐23p19/Ebi3 (IL‐39) cytokine mediates inflammation in Lupus‐like mice

et al. 2016

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Interleukin-12 family cytokines have emerged as critical regulators of immunity with some members (IL-12, IL-23) associated with disease pathogenesis while others (IL-27sue injury by promoting the expansion of regulatory B and T-cell subsets [2,3].Discovery of IL-23 in 2000 [4] led to the reevaluation of IL-12 and IL-23 in autoimmune diseases. For example, therapeutic targeting of IL-12p40 decreases pathology in many mouse models of autoimmune diseases [5], while disease is exacerbated in IL-12p35-deficient mice [6,7]. Thus, IL-23 rather than IL-12 was * These authors contributed equally to this work as first authors.* * These authors contributed equally to this work as senior authors. Eur. J. Immunol. 2016. 46: 1343-1350 found to be the critical cytokine for autoimmune inflammation including experimental immune-mediated disease [6][7][8][9][10]. Currently, at least ten therapeutic agents targeting IL-23 are being tested in the clinic for more than 17 human immune-mediated diseases [11]. Both IL-27 and IL-35 have immune-suppressive activities and are also cytokines with strikingly diverse influences on the immune response so that viable therapeutic targets may also be exploited for treatment of human inflammatory diseases [12,13]. Thus, understanding immunobiology of IL-12 family cytokines would undoubtedly provide valuable knowledge that can be exploited therapeutically. The IL-12 family cytokines are α/β heterodimers consisting of one α subunit (IL-23p19, IL-27p28, IL-12p35) and one β chain (IL-12p40, Ebi3) [14,15]. Although there are currently four known members in the family, the predictable range of combinations is six and it is conceivable that additional pairings such as IL-23p19/Ebi3 are possible [12,[14][15][16][17]. In this study, we sought to discover additional IL-12 members that might exist in nature. By combining different alpha and beta IL-12 subunit proteins in vitro we detected a novel stable p19/Ebi3 heterodimeric complex by immunoprecipitation. We have characterized the p19/Ebi3 cytokine (IL-39) and demonstrated that it possesses biological activities in vitro and in vivo. Results IL-23p19 (p19) and Ebi3 form a composite factor (IL-39)To examine whether p19 can form a stable complex with Ebi3, we mixed equal amounts of the two proteins and immunoprecipitation (IP)/Western blot analyses revealed formation of a stable human p19/Ebi3 complex (Fig. 1A). We could not detect the p19/Ebi3 following IP with isotype IgG or anti-c-Jun antibody, providing suggestive evidence for potential bona fide p19/Ebi3 cytokine. To confirm our finding in another animal species, we genetically engineered and expressed mouse p19 and Ebi3 subunits in CHO cells (Fig. 1B). IP of supernatants derived from transfectants with anti-p19 mAb and followed by Western blot analysis using anti-Ebi3 mAb confirmed coexpression p19 and Ebi3 and formation of a stable p19/Ebi3 heterodimer (Fig. 1C). We further confirmed this observation by reciprocal IP with anti-Ebi3 mAb and Western blotting with anti-p19 mAb and the p19/Ebi3 comple...

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Engineered Cytokines for Cancer and Autoimmune Disease Immunotherapy

Uricoli

Birnbaum

et al. 2021

Adv Healthcare Materials

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Cytokine signaling is critical to a range of biological processes including cell development, tissue repair, aging, and immunity. In addition to acting as key signal mediators of the immune system, cytokines can also serve as potent immunotherapies with more than 20 recombinant products currently Food and Drug Administration (FDA)‐approved to treat conditions including hepatitis, multiple sclerosis, arthritis, and various cancers. Yet despite their biological importance and clinical utility, cytokine immunotherapies suffer from intrinsic challenges that limit their therapeutic potential including poor circulation, systemic toxicity, and low tissue‐ or cell‐specificity. In the past decade in particular, methods have been devised to engineer cytokines in order to overcome such challenges and here, the myriad strategies are reviewed that may be employed in order to improve the therapeutic potential of cytokine and chemokine immunotherapies with applications in cancer and autoimmune disease therapy, as well as tissue engineering and regenerative medicine. For clarity, these strategies are collected and presented as they vary across size scales, ranging from single amino acid substitutions, to larger protein‐polymer conjugates, nano/micrometer‐scale particles, and macroscale implants. Together, this work aims to provide readers with a timely view of the field of cytokine engineering with an emphasis on early‐stage therapeutic approaches.

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IL‐Y, a synthetic member of the IL‐12 cytokine family, suppresses the development of type 1 diabetes in NOD mice

Cited by 27 publications

References 52 publications

Expanding Diversity in Molecular Structures and Functions of the IL-6/IL-12 Heterodimeric Cytokine Family

Expanding Diversity in Molecular Structures and Functions of the IL-6/IL-12 Heterodimeric Cytokine Family

A novel IL‐23p19/Ebi3 (IL‐39) cytokine mediates inflammation in Lupus‐like mice

Engineered Cytokines for Cancer and Autoimmune Disease Immunotherapy

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