Dataset Information

Transforming Growth Factor-? and Interleukin-10 Synergistically Regulate Humoral Immunity via Modulating Metabolic Signals.

ABSTRACT: Inhibitory cytokines, such as transforming growth factor-? (TGF-?) 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-? 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-? 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-? 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-? 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-? 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.

SUBMITTER: Komai T

PROVIDER: S-EPMC6010538 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Transforming Growth Factor-β and Interleukin-10 Synergistically Regulate Humoral Immunity <i>via</i> Modulating Metabolic Signals.

Komai Toshihiko T Inoue Mariko M Okamura Tomohisa T Morita Kaoru K Iwasaki Yukiko Y Sumitomo Shuji S Shoda Hirofumi H Yamamoto Kazuhiko K Fujio Keishi K

Frontiers in immunology 20180614

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 cyto ...[more]

PMID: 29963056

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Dataset Information

Transforming Growth Factor-? and Interleukin-10 Synergistically Regulate Humoral Immunity via Modulating Metabolic Signals.

Publications

Transforming Growth Factor-β and Interleukin-10 Synergistically Regulate Humoral Immunity <i>via</i> Modulating Metabolic Signals.

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