Ligation of metabotropic glutamate receptor 3 (Grm3) ameliorates lupus-like disease by reducing B cells

Ma, Ning; Liu, Xiaoling; Chen, Xing; Wang, Xiaoqian; Wei, Yinxiang; Han, Gencheng; Chen, Guojiang; Hou, Chunmei; Shen, Beifen; Li, Yan; Xiao, He; Wang, Renxi

doi:10.1016/j.clim.2015.05.016

Cited by 19 publications

(27 citation statements)

References 57 publications

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“…However, in view of our data (Supporting Information Fig. 3D-F) showing that adoptive transfer of activated B cells depleted of p28, p35, or p40 also had minimal effects on pathogenic B cells and proteinuria, both of which are the hallmark features of SLE [21,22,[35][36][37][38], it is still justifiable to conclude that the IL-39 subunits impact disease much more so than other cytokine components. Taken together, our data suggest that IL-39, secreted by activated B cells, may be an important proinflammatory cytokine and the potential therapeutic target in lupus diseases.…”

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confidence: 77%

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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confidence: 77%

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

et al. 2016

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“…These studies suggest that the mechanisms underlying defect of B-cell apoptosis and therapeutic target are similar in autoimmune diseases such as SLE and B-cell lymphoma. We further found that metabotropic glutamate receptor 3 (Grm3) may be involved in autoreactive B-cell apoptosis in atacicept-treated lupus-like mice and ligation of Grm3 ameliorates lupus-like disease by reducing B-cell numbers (24). Because both autoimmune diseases and B-cell lymphoma including multiple myeloma share similar abnormal apoptosis of B cells, we proposed that Grm3 may be involved in apoptosis of B-cell lymphoma including multiple myeloma.…”

Section: Metabotropic Glutamate Receptor 3 Is Involved In B-cell-relamentioning

confidence: 94%

Metabotropic glutamate receptor 3 is involved in B-cell-related tumor apoptosis

Liu¹,

Zhang²,

Wang³

et al. 2016

International Journal of Oncology

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Cell apoptosis plays a critical role in initiation and progression of tumor and autoimmune diseases, resistance and susceptibility to various therapeutic agents. Our previous study showed that metabotropic glutamate receptor 3 (Grm3) may be involved in autoreactive B-cell apoptosis in a B-cell-depleted agent atacicept-treated lupus-like mice. In the present study, we explore whether Grm3 is involved in the apoptosis in B-cell-related tumor including multiple myeloma and B-cell leukemia. We found that human B-cell leukemia cell line Nalm-6 cells and mouse myeloma cell line SP 2/0 cells could express Grm3. In addition, Grm3 expression emerged mainly in the middle stage of Nalm-6 and SP 2/0 cell apoptosis. Furthermore, apoptosis-induced agents effectively upregulated Grm3 expression in SP 2/0 cells. Critically, Grm3 deficiency promoted tumor progression in an SP 2/0 xenograft mouse model by suppressing cell apoptosis, whereas Grm3 overexpression effectively upregulates SP 2/0 cell apoptosis. Finally, we showed that Grm3 mediated cell apoptosis by Foxo1. Together, our data suggest that Grm3 effectively suppresses the mouse myeloma cell line SP 2/0 cell growth by mediating apoptosis. Thus, Grm3 may be used as an indicator in apoptosis of B-cell-related tumor and a potential target for the treatment of B-cell-related tumor including multiple myeloma and B-cell leukemia.

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“…4a,b). SLE and its murine model including MRL/lpr mice are characterized by B cell over-activation [23][24][25][26][27][28][29]. Our previous study has shown that GL7 1 B cells induces inflammation by secreting IL-39 in lupus-prone mice [6].…”

Section: Il-39 Deficiency Reduced the Capacity Of Gl7 1 B Cells In Upmentioning

confidence: 99%

Interleukin (IL)-39 [IL-23p19/Epstein–Barr virus-induced 3 (Ebi3)] induces differentiation/expansion of neutrophils in lupus-prone mice

Wang¹,

Liu

Zhang

et al. 2016

Clinical and Experimental Immunology

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Interleukin (IL)-12 family cytokines play critical roles in autoimmune diseases. Our previous study has shown that IL-23p19 and Epstein-Barr virus-induced 3 (Ebi3) form a new IL-12 family heterodimer, IL-23p19/Ebi3, termed IL-39, and knock-down of p19 or Ebi3 reduced diseases by transferred GL7 B cells in lupus-prone mice. In the present study, we explore further the possible effect of IL-39 on murine lupus. We found that IL-39 in vitro and in vivo induces differentiation and/or expansion of neutrophils. GL7 B cells up-regulated neutrophils by secreting IL-39, whereas IL-39-deficient GL7 B cells lost the capacity to up-regulate neutrophils in lupus-prone mice and homozygous CD19 (CD19-deficient) mice. Finally, we found that IL-39-induced neutrophils had a positive feedback on IL-39 expression in activated B cells by secreting B cell activation factor (BAFF). Taken together, our results suggest that IL-39 induces differentiation and/or expansion of neutrophils in lupus-prone mice.

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Ligation of metabotropic glutamate receptor 3 (Grm3) ameliorates lupus-like disease by reducing B cells

Cited by 19 publications

References 57 publications

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

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

Metabotropic glutamate receptor 3 is involved in B-cell-related tumor apoptosis

Interleukin (IL)-39 [IL-23p19/Epstein–Barr virus-induced 3 (Ebi3)] induces differentiation/expansion of neutrophils in lupus-prone mice

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