Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2018 Aug 1;19(8):2261.
doi: 10.3390/ijms19082261.

Reevaluation of Pluripotent Cytokine TGF-β3 in Immunity

Toshihiko Komai  1 , Tomohisa Okamura  2   3   4 , Mariko Inoue  5 , Kazuhiko Yamamoto  6   7   8 , Keishi Fujio  9
Affiliations
Review

Reevaluation of Pluripotent Cytokine TGF-β3 in Immunity

Toshihiko Komai et al. Int J Mol Sci. .

Abstract

Transforming growth factor (TGF)-βs are pluripotent cytokines with stimulatory and inhibitory properties for multiple types of immune cells. Analyses of genetic knockouts of each isoform of TGF-β have revealed differing expression patterns and distinct roles for the three mammalian isoforms of TGF-β. Considerable effort has been focused on understanding the molecular mechanisms of TGF-β1-mediated immune regulation, given its pivotal role in prohibiting systemic autoimmune disease. In recent years, functional similarities and differences between the TGF-β isoforms have delineated their distinct roles in the development of immunopathology and immune tolerance, with increased recent attention being focused on TGF-β3. In addition to the characteristic properties of each TGF-β isoform, recent progress has identified determinants of context-dependent functionality, including various cellular targets, cytokine concentrations, tissue microenvironments, and cytokine synergy, which combine to shape the physiological and pathophysiological roles of the TGF-βs in immunity. Controlling TGF-β production and signaling is being tested as a novel therapeutic strategy in multiple clinical trials for several human diseases. This review highlights advances in the understanding of the cellular sources, activation processes, contextual determinants, and immunological roles of TGF-β3 with comparisons to other TGF-β isoforms.

Keywords: autoimmune disease; fibrosis; immune tolerance; immunometabolism; regulatory T cell; transforming growth factor-β1; transforming growth factor-β3.

PubMed Disclaimer

Conflict of interest statement

Tomohisa Okamura received financial support or fees from Chugai and Bristol-Myers Squibb (BMS). Kazuhiko Yamamoto received financial support or fees from AbbVie, Astellas, BMS, Daiichi-Sankyo, Mitsubishi Tanabe, Pfizer, Sanofi, Santen, Takeda, Teijin, Boehringer Ingelheim, Chugai, Eisai, Ono, Taisho Toyama, UCB, ImmunoFuture, Asahi Kasei, Janssen, and NIPPON KAYAKU. Keishi Fujio received financial support or fees from Astellas, BMS, Daiichi-Sankyo, Mitsubishi Tanabe, Pfizer, Ayumi, Takeda, Chugai, Eisai, Taisho Toyama, UCB, Janssen, Eli Lilly and NIPPON KAYAKU. Toshihiko Komai, Tomohisa Okamura, Mariko Inoue, Kazuhiko Yamamoto, and Keishi Fujio received patent-licensing arrangements with Chugai.

Figures

Figure 1
Figure 1
The roles of Egr in TGF-β3 production in CD4+CD25−LAG3+ regulatory T cells. Synthesized latency-associated peptide (LAP) and mature TGF-β3 binds to latent TGF-β binding protein-3 (LTBP-3), and the large latent complex is secreted from cells. Early growth response gene 2 (Egr2) and Egr3 regulate the expression of Ltbp3, which leads to efficient secretion of TGF-β3 from CD4+CD25−LAG3+ regulatory T cells (LAG3+ Tregs).
Figure 2
Figure 2
Schematic description of the “inhibitory cytokine synergy” of TGF-β3 and IL-10 in activated B cells. Phosphorylation of S6 kinase 1 (S6K1) and expression of hypoxia inducible factor 1α (HIF1α), which is a downstream signaling of mammalian target of rapamycin complex 1 (mTORC1), are suppressed by a combination of the inhibitory cytokines TGF-β3 and IL-10. ICS further suppresses B cell cellular energetic metabolism, such as glycolysis and oxidative phosphorylation. Arrows, positive regulation; T-bar, negative regulation.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Chen W., Ten Dijke P. Immunoregulation by members of the TGFβ superfamily. Nat. Rev. Immunol. 2016;16:723–740. doi: 10.1038/nri.2016.112. - DOI - PubMed
    1. Zhao M., Mishra L., Deng C.X. The role of TGF-β/SMAD4 signaling in cancer. Int. J. Biol. Sci. 2018;14:123. doi: 10.7150/ijbs.23230. - DOI - PMC - PubMed
    1. Wakefield L.M., Hill C.S. Beyond TGFβ: Roles of other TGFβ superfamily members in cancer. Nat. Rev. Cancer. 2013;13:328–341. doi: 10.1038/nrc3500. - DOI - PMC - PubMed
    1. Meng X., Nikolic-Paterson D.J., Lan H.Y. TGF-β: The master regulator of fibrosis. Nat. Rev. Nephrol. 2016;12:325–338. doi: 10.1038/nrneph.2016.48. - DOI - PubMed
    1. Li M.O., Wan Y.Y., Sanjabi S., Robertson A.K., Flavell R.A. Transforming growth factor-β regulation of immune responses. Annu. Rev. Immunol. 2006;24:99–146. doi: 10.1146/annurev.immunol.24.021605.090737. - DOI - PubMed

MeSH terms

Substances

LinkOut - more resources

-