Transforming Growth Factor-β and Interleukin-10 Synergistically Regulate Humoral Immunity via Modulating Metabolic Signals
Inhibitory cytokines, such as transforming growth factor-β (TGF-β) and interleukin-10 (IL-10), are humoral factors involved in the suppressive function of regulatory T cells and play critical roles in maintaining immune homeostasis. However, TGF-β and IL-10 also have pleiotropic effects and induce h...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2018-06-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fimmu.2018.01364/full |
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| author | Toshihiko Komai Mariko Inoue Tomohisa Okamura Tomohisa Okamura Tomohisa Okamura Kaoru Morita Yukiko Iwasaki Shuji Sumitomo Hirofumi Shoda Kazuhiko Yamamoto Kazuhiko Yamamoto Kazuhiko Yamamoto Keishi Fujio |
| author_facet | Toshihiko Komai Mariko Inoue Tomohisa Okamura Tomohisa Okamura Tomohisa Okamura Kaoru Morita Yukiko Iwasaki Shuji Sumitomo Hirofumi Shoda Kazuhiko Yamamoto Kazuhiko Yamamoto Kazuhiko Yamamoto Keishi Fujio |
| author_sort | Toshihiko Komai |
| collection | DOAJ |
| description | Inhibitory cytokines, such as transforming growth factor-β (TGF-β) and interleukin-10 (IL-10), are humoral factors involved in the suppressive function of regulatory T cells and play critical roles in maintaining immune homeostasis. However, TGF-β and IL-10 also have pleiotropic effects and induce humoral immune responses depending on conditions, and thus their therapeutic application to autoimmune diseases remains limited. Here, we show that a combination of TGF-β and IL-10, but not single cytokine, is required to suppress B cell activation induced by toll-like receptor (TLR) stimulation. In in vivo analyses, the simultaneous presence of TGF-β and IL-10 effectively suppressed TLR-mediated antigen-specific immune responses and ameliorated pathologies in imiquimod (TLR7 agonist)-induced lupus model and lupus-prone MRL/lpr mice. Intriguingly, TGF-β and IL-10 synergistically modulated transcriptional programs and suppressed cellular energetics of both glycolysis and oxidative phosphorylation via inhibition of the mammalian target of rapamycin complex 1 (mTORC1)/S6 kinase 1 (S6K1) pathway in TLR-stimulated B cells. On the other hand, enhancement of mTOR signaling and mitochondrial biosynthesis in TLR-stimulated B cells counteracted the synergistic inhibitory effects. The inhibitory cytokine synergy of TGF-β and IL-10 via suppression of energy metabolism was also observed in human TLR-stimulated B cells. There is increasing evidence supporting the importance of adequate metabolic signals in various immune cells to exert their immune function. In this study, we have shown that a previously unrecognized synergy of inhibitory cytokines regulates systemic humoral immune responses via modulating immunometabolism in B cells. Our findings indicate that inhibition of B cell metabolism mediated by two synergistic cytokines contributes to the induction of immune tolerance and could be a new therapeutic strategy for autoimmune diseases such as systemic lupus erythematosus. |
| first_indexed | 2024-12-12T01:33:09Z |
| format | Article |
| id | doaj.art-5c6d586da84646909b16f84ed1dcb2ce |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-12T01:33:09Z |
| publishDate | 2018-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-5c6d586da84646909b16f84ed1dcb2ce2022-12-22T00:42:55ZengFrontiers Media S.A.Frontiers in Immunology1664-32242018-06-01910.3389/fimmu.2018.01364373187Transforming Growth Factor-β and Interleukin-10 Synergistically Regulate Humoral Immunity via Modulating Metabolic SignalsToshihiko Komai0Mariko Inoue1Tomohisa Okamura2Tomohisa Okamura3Tomohisa Okamura4Kaoru Morita5Yukiko Iwasaki6Shuji Sumitomo7Hirofumi Shoda8Kazuhiko Yamamoto9Kazuhiko Yamamoto10Kazuhiko Yamamoto11Keishi Fujio12Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Tokyo, JapanDepartment of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Tokyo, JapanDepartment of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Tokyo, JapanDepartment of Functional Genomics and Immunological Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, JapanMax Planck-The University of Tokyo Center for Integrative Inflammology, The University of Tokyo, Tokyo, JapanDepartment of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Tokyo, JapanDepartment of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Tokyo, JapanDepartment of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Tokyo, JapanDepartment of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Tokyo, JapanDepartment of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Tokyo, JapanMax Planck-The University of Tokyo Center for Integrative Inflammology, The University of Tokyo, Tokyo, JapanLaboratory for Autoimmune Diseases, Center for Integrative Medical Sciences, RIKEN, Kanagawa, JapanDepartment of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Tokyo, JapanInhibitory cytokines, such as transforming growth factor-β (TGF-β) and interleukin-10 (IL-10), are humoral factors involved in the suppressive function of regulatory T cells and play critical roles in maintaining immune homeostasis. However, TGF-β and IL-10 also have pleiotropic effects and induce humoral immune responses depending on conditions, and thus their therapeutic application to autoimmune diseases remains limited. Here, we show that a combination of TGF-β and IL-10, but not single cytokine, is required to suppress B cell activation induced by toll-like receptor (TLR) stimulation. In in vivo analyses, the simultaneous presence of TGF-β and IL-10 effectively suppressed TLR-mediated antigen-specific immune responses and ameliorated pathologies in imiquimod (TLR7 agonist)-induced lupus model and lupus-prone MRL/lpr mice. Intriguingly, TGF-β and IL-10 synergistically modulated transcriptional programs and suppressed cellular energetics of both glycolysis and oxidative phosphorylation via inhibition of the mammalian target of rapamycin complex 1 (mTORC1)/S6 kinase 1 (S6K1) pathway in TLR-stimulated B cells. On the other hand, enhancement of mTOR signaling and mitochondrial biosynthesis in TLR-stimulated B cells counteracted the synergistic inhibitory effects. The inhibitory cytokine synergy of TGF-β and IL-10 via suppression of energy metabolism was also observed in human TLR-stimulated B cells. There is increasing evidence supporting the importance of adequate metabolic signals in various immune cells to exert their immune function. In this study, we have shown that a previously unrecognized synergy of inhibitory cytokines regulates systemic humoral immune responses via modulating immunometabolism in B cells. Our findings indicate that inhibition of B cell metabolism mediated by two synergistic cytokines contributes to the induction of immune tolerance and could be a new therapeutic strategy for autoimmune diseases such as systemic lupus erythematosus.https://www.frontiersin.org/article/10.3389/fimmu.2018.01364/fullhumoral immunitysystemic lupus erythematosuscytokine synergytransforming growth factor-βinterleukin-10B cells |
| spellingShingle | Toshihiko Komai Mariko Inoue Tomohisa Okamura Tomohisa Okamura Tomohisa Okamura Kaoru Morita Yukiko Iwasaki Shuji Sumitomo Hirofumi Shoda Kazuhiko Yamamoto Kazuhiko Yamamoto Kazuhiko Yamamoto Keishi Fujio Transforming Growth Factor-β and Interleukin-10 Synergistically Regulate Humoral Immunity via Modulating Metabolic Signals Frontiers in Immunology humoral immunity systemic lupus erythematosus cytokine synergy transforming growth factor-β interleukin-10 B cells |
| title | Transforming Growth Factor-β and Interleukin-10 Synergistically Regulate Humoral Immunity via Modulating Metabolic Signals |
| title_full | Transforming Growth Factor-β and Interleukin-10 Synergistically Regulate Humoral Immunity via Modulating Metabolic Signals |
| title_fullStr | Transforming Growth Factor-β and Interleukin-10 Synergistically Regulate Humoral Immunity via Modulating Metabolic Signals |
| title_full_unstemmed | Transforming Growth Factor-β and Interleukin-10 Synergistically Regulate Humoral Immunity via Modulating Metabolic Signals |
| title_short | Transforming Growth Factor-β and Interleukin-10 Synergistically Regulate Humoral Immunity via Modulating Metabolic Signals |
| title_sort | transforming growth factor β and interleukin 10 synergistically regulate humoral immunity via modulating metabolic signals |
| topic | humoral immunity systemic lupus erythematosus cytokine synergy transforming growth factor-β interleukin-10 B cells |
| url | https://www.frontiersin.org/article/10.3389/fimmu.2018.01364/full |
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