3-S23-1
ILC2 からのIL-4 はB1 細胞の低親和性IgE 産生を誘導する
ILC2 induce innate IgE secretion by B1 cells via IL-4 production
〇茂呂和世1,2,3
KazuyoMoro1,2,3
1Laboratory for Innate Immune Systems, RIKEN-IMS、2Department of Medical Life Science, Yokohama City University、3Laboratory for Innate Immune Systems, Department of Microbiology and Immunology, Graduate School of Medicine, Osaka University
1Laboratory for Innate Immune Systems, RIKEN-IMS
, 2Department of Medical Life Science, Yokohama City University
, 3Laboratory for Innate Immune Systems, Department of Microbiology and Immunology, Graduate School of Medicine, Osaka University
Group 2 innate lymphoid cells (ILC2s), a new type of innate lymphocyte that we originally reported as natural helper cells in 2010, are known to regulate type 2 immune responses in an antigen-independent manner. In contrast to Th2 cells, ILC2s lack rearranged antigen receptors and are directly stimulated by epithelial cell-derived cytokines such as IL-33 and IL-25. Activated ILC2s are capable of producing a variety of cytokines, chemokines, and peptides including IL-5, IL-6, IL-9, IL-13, GM-CSF, amphiregulin, eotaxin, and methionine-enkephalin. ILC2s play a vital role in protection against parasite infections and induction of eosinophilic inflammation, which is involved in asthma, atopic dermatitis, eosinophilic esophagitis, allergic rhinitis, and chronic rhinosinusitis with nasal polyps. ILC2s are now considered to be associated with a wide range of diseases including allergic diseases, infection, obesity, cancer, and fibrosis.
IL-4, a key type 2 cytokine, is involved in multiple immune reactions including Th2 cell development, IgG1 and IgE production by B cells and M2 macrophage differentiation. While Th2 cells produce IL-4 together with IL-5 and IL-13 under antigen-induced TCR stimulation, ILC2s fail to produce IL-4 under IL-33 stimulation, which induces a large amount of IL-5 and IL-13. Based on this fact, ILC2s are not thought to contribute to IL-4-mediated immune responses, even though they express high levels of the IL-4 gene.
Recently, we identified the physiological condition that induces IL-4 production from ILC2. The mechanisms for IL-4 production from ILC2 were more intricate than that in Th2 cells and differ widely from those in IL-5 and IL-13 production. Furthermore, IL-4 from ILC2s elevates polyclonal IgE levels in steady state, helminth infection and allergy, and supports survival and expansion of FcεR+ cells such as basophils and mast cells. These findings provide evidence for factors involved in susceptibility to allergic diseases, which is still not understood, but is an important issue in the treatment or prevention of allergic disorders.
3-S23-2
炎症性サイトカインの肺動脈性肺高血圧症病態における役割
The role of inflammatory cytokines in the pathogenesis of pulmonary arterial hypertension
〇中岡良和1
YoshikazuNakaoka1
1国立循環器病研究センター研究所血管生理学部
1National Cerebral and Cardiovascular Center
Pulmonary arterial hypertension (PAH) is a serious disease characterized by arteriopathy in the small to medium-sized distal pulmonary arteries, that is associated with arterial muscularization, concentric intimal thickening, and the formation of plexiform lesions. Inflammation and autoimmunity are currently thought of as critical factors to the pathogenesis of PAH. Interleukin-6 (IL-6), a multifunctional pro-inflammatory cytokine, is elevated in the serum of pulmonary arterial hypertension (PAH) patients and can predict the survival of idiopathic (I)PAH patients. Previous animal experiments and clinical human studies indicate that IL-6 is important in the pathogenesis of PAH. We recently found that IL-6/IL-21 signaling axis plays a critical role in the pathogenesis of PAH (PNAS. 112(20): E2677, 2015). First, we found that IL-6 blockade by the monoclonal anti-IL-6 receptor antibody, MR16-1, ameliorated hypoxia-induced pulmonary hypertension (HPH) and prevented the hypoxia-induced accumulation of Th17 cells and M2 macrophages in the lungs. Furthermore, the hypoxia-induced upregulation of IL-17 and IL-21, which are primarily produced by Th17 cells, was also ameliorated by IL-6 blockade in mice. Whereas IL-17 blockade with an anti-IL-17 neutralizing antibody had no effect on HPH, IL-21 receptor-deficient mice were resistant to HPH and exhibited no significant accumulation of M2 macrophages in the lungs. Consistently, IL-21 indeed promoted the polarization of primary alveolar macrophages toward the M2 phenotype. Moreover, significantly enhanced expressions of IL-21 and M2 macrophage markers were detected in the lungs of IPAH patients who underwent lung transplantation. We are currently examining the effect of IL-21-blockade on the pathogenesis of severe PAH rat model (namely Sugen5416(Su)/hypoxia (Hx) PAH model). IL-21 receptor deletion significantly ameliorated the pathologies of Su/Hx PAH in rats. Taken together, these findings indicate that IL-21blockade might be a promising therapeutic option for refractory PAH. We would like to validate the therapeutic effect of IL-21 blockade for refractory patients with PAH in the near future.
3-S23-3
EicosapentaenoicacidはチロシンキナーゼFYNの抑制を介して肺動脈高血圧の改善効果を示す
Tyrosine kinase FYN inhibitionmediates thetherapeutic effects of Eicosapentaenoic acid on pulmonary hypertension
〇倉原(海)琳1、平石敬三1、山村彩2、張影3、塩井成留美4、井上隆司1
Hai LinKurahara1, KeizoHiraishi1, AyaYamamura2, YingZhang3, NarumiShioi4, RyujiInoue1
1福岡大・医・生理、2愛知医科大・医・生理、3山口大・院医・分子細胞生理、4福岡大学理学部化学科
1Dept. Physio. Sch. Med., Fukuoka Univ., 2Dept. Physio. Grad., Aichi Medical University, 3Dept Mol. and Cell. Physiol., Grad. Sch. Med., Yamaguchi Univ., 4Dept. Chem., Faculty of Science, Fukuoka Univ.
Background and Purpose: Pulmonary arterial hypertension (PAH) is a multifactorial disease characterized by pulmonary arterial remodeling in which the Src family non-receptor tyrosine kinases including Fyn play non-trivial roles. In this study, we explored the therapeutic potential of eicosapentaenoic acid (EPA) and its metabolite resolvin E1 (RvE1) for PAH through inhibition of Fynin vitroandin vivo.
Method: Cardiodynamic parameters of rat hearts were measured by the echocardiography. Contractile responses of isolated pulmonary arteries were examined by the isometric tension measurement. Proliferation of human pulmonary artery smooth muscle cells (HPASMCs) derived from PAH patients were evaluated by the MTT assay. Stress fiber formation and STAT3 phosphorylation in HPAECs and HPASMCs were examined by immunohistochemical and western blot analyses, respectively.
Results: Administration of EPA to MCT-treated rats significantly improved the pathological changes characteristic for PAH, i.e.pulmonary arterial thickening, right ventricle dysfunction and cardiovascular fibrosis. Pulmonary arteries from MCT-treated rats showed exaggerated contractile responses compared with those from vehicle-treated rats, which were greatly normalized by EPA treatment. Administration ofEPA or RvE1 decelerated the enhanced proliferation of PAH patient-derived PASMCs. Immunocytochemical and western blot analyses showed that a dominant negative form of Fyn prevented TGF-β2-induced stress fiber formation and IL-6-induced STAT3 phosphorylation. EPA and RvE1 suppressed Src family activity by modulating it's autophosphorylation level.
Summary: EPA significantly improved PAH-associated pathophysiology and cardiac dysfunction, which is likely mediated at least in part via Fyn inhibition. These results also point to the therapeutic significance of targeting this molecule in PAH treatment.
3-S23-4
心疾患関連線維化におけるTRPM7の役割
The role of TRPM7 in fibrosis associated heart diseases
YueZhichao1、YuAlbert S.1、SunSun1、FengJianlin1、YueLixia1
ZhichaoYue1, Albert S.Yu1, BaonanSun1, JianlinFeng1, LixiaYue1
1University of Connecticut Health CenterCardiology/Cell Biology
1Cardiology/Cell Biology, University of Connecticut Health Center
Cardiac fibrosis is a hallmark of various heart diseases including hypertrophy, heart failure, and arrhythmia. Cardiac fibroblasts play an important role in fibrogenesis because they differentiate to myofibroblasts under various pathological conditions. Thus, targeting cardiac fibroblast differentiation to attenuate fibrosis represents a new therapeutic strategy for fibrosis associated heart diseases. We have previously used fibroblasts from atrial fibrillation (AF) patients and demonstrated that the Transient Receptor Potential Melastatin 7 (TRPM7) plays an essential role in fibroblast differentiation to myofibroblasts. Here we propose that TRPM7 plays a key role in fibrosis-associated arrhythmia. We used transverse aortic restriction (TAC) inducedhypertrophy/heart failure mouse model to generate fibrosis in the hearts. We found that deletion ofTrpm7(TRPM7-KO) significantly increased survival rate after TAC, and improved heart performance. Moreover, TRPM7 deletion drastically reduced fibrosis in both atria and ventricles. The reduced fibrosis in TRPM7-KO-TAC mice significantly decreased the vulnerability of AF and the duration of induced AF. Thus, TRPM7 plays an important role in fibrosis associated AF, and may serve as a therapeutic target for fibrosis associated arrhythmia.