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TGF-?3 Inhibits Antibody Production by Human B Cells.

ABSTRACT: TGF-? is a pleotropic cytokine involved in various biological processes. Of the three isoforms of TGF-?, TGF-?1 has long been recognized as an important inhibitory cytokine in the immune system and has been reported to inhibit B cell function in both mice and humans. Recently, it has been suggested that TGF-?3 may play an important role in the regulation of immune system in mice. Murine CD4+CD25-LAG3+ regulatory T cells suppress B cell function through the production of TGF-?3, and it has been reported that TGF-?3 is therapeutic in a mouse model of systemic lupus erythematosus. The effect of TGF-?3 on human B cells has not been reported, and we herein examined the effect of TGF-?3 on human B cells. TGF-?3 suppressed B cell survival, proliferation, differentiation into plasmablasts, and antibody secretion. Although the suppression of human B cells by TGF-?1 has long been recognized, the precise mechanism for the suppression of B cell function by TGF-?1 remains elusive; therefore, we examined the effect of TGF-?1 and ?3 on pathways important in B cell activation and differentiation. TGF-?1 and TGF-?3 inhibited some of the key molecules of the cell cycle, as well as transcription factors important in B cell differentiation into antibody secreting cells such as IRF4, Blimp-1, and XBP1. TGF-?1 and ?3 also inhibited B cell receptor signaling. Our results suggest that TGF-?3 modifying therapy might be therapeutic in autoimmune diseases with B cell dysregulation in humans.

SUBMITTER: Tsuchida Y

PROVIDER: S-EPMC5215424 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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TGF-β3 Inhibits Antibody Production by Human B Cells.

Tsuchida Yumi Y Sumitomo Shuji S Ishigaki Kazuyoshi K Suzuki Akari A Kochi Yuta Y Tsuchiya Haruka H Ota Mineto M Komai Toshihiko T Inoue Mariko M Morita Kaoru K Okamura Tomohisa T Yamamoto Kazuhiko K Fujio Keishi K

PloS one 20170104 1

TGF-β is a pleotropic cytokine involved in various biological processes. Of the three isoforms of TGF-β, TGF-β1 has long been recognized as an important inhibitory cytokine in the immune system and has been reported to inhibit B cell function in both mice and humans. Recently, it has been suggested that TGF-β3 may play an important role in the regulation of immune system in mice. Murine CD4+CD25-LAG3+ regulatory T cells suppress B cell function through the production of TGF-β3, and it has been r ...[more]

PMID: 28052118

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Project description:IntroductionToll-like receptor (TLR)4 promotes joint inflammation in mice. Despite that several studies report a functional link between TLR4 and interleukin-(IL-)1? in arthritis, TLR4-mediated regulation of the complicated cytokine network in arthritis is poorly understood. To address this, we investigated the mechanisms by which TLR4 regulates the cytokine network in antibody-induced arthritis.MethodsTo induce arthritis, we injected mice with K/BxN serum. TLR4-mediated pathogenesis in antibody-induced arthritis was explored by measuring joint inflammation, cytokine levels and histological alteration.ResultsCompared to wild type (WT) mice, TLR4-/- mice showed attenuated arthritis and low interferon (IFN)-?, IL-12p35 and IL-1? transcript levels in the joints, but high transforming growth factor (TGF)-? expression. Injection of lipopolysaccharide (LPS) enhanced arthritis and exaggerated joint cytokine alterations in WT, but not TLR4-/- or IL-12p35-/- mice. Moreover, STAT4 phosphorylation in joint cells and intracellular IL-12p35 expression in macrophages, mast cells and Gr-1+ cells were detected in WT mice with arthritis and enhanced by LPS injection. Therefore, IL-12p35 appears to act downstream of TLR4 in antibody-induced arthritis. TLR4-mediated IL-12 production enhanced IFN-? and IL-1? production via T-bet and pro-IL-1? production. Recombinant IL-12, IFN-? and IL-1? administration restored arthritis, but reduced joint TGF-? levels in TLR4-/- mice. Moreover, a TGF-? blockade restored arthritis in TLR4-/- mice. Adoptive transfer of TLR4-deficient macrophages and mast cells minimally altered joint inflammation and cytokine levels in macrophage- and mast cell-depleted WT mice, respectively, whereas transfer of WT macrophages or mast cells restored joint inflammation and cytokine expression. Gr-1+ cell-depleted splenocytes partially restored arthritis in TLR4-/- mice.ConclusionTLR4-mediated IL-12 production by joint macrophages, mast cells and Gr-1+ cells enhances IFN-? and IL-1? production, which suppresses TGF-? production, thereby promoting antibody-induced arthritis.

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TGF-?3 Inhibits Antibody Production by Human B Cells.

Publications

TGF-β3 Inhibits Antibody Production by Human B Cells.

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