Elsevier

Vitamins & Hormones

Volume 85, 2011, Pages 255-297
Vitamins & Hormones

Chapter Thirteen - The Regulation and Functions of Activin and Follistatin in Inflammation and Immunity

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Abstract

The activins are members of the transforming growth factor β superfamily with broad and complex effects on cell growth and differentiation. Activin A has long been known to be a critical regulator of inflammation and immunity, and similar roles are now emerging for activin B, with which it shares 65% sequence homology. These molecules and their binding protein, follistatin, are widely expressed, and their production is increased in many acute and chronic inflammatory conditions. Synthesis and release of the activins are stimulated by inflammatory cytokines, Toll-like receptor ligands, and oxidative stress. The activins interact with heterodimeric serine/threonine kinase receptor complexes to activate SMAD transcription factors and the MAP kinase signaling pathways, which mediate inflammation, stress, and immunity. Follistatin binds to the activins with high affinity, thereby obstructing the activin receptor binding site, and targets them to cell surface proteoglycans and lysosomal degradation. Studies on transgenic mice and those with gene knockouts, together with blocking studies using exogenous follistatin, have established that activin A plays critical roles in the onset of cachexia, acute and chronic inflammatory responses such as septicemia, colitis and asthma, and fibrosis. However, activin A also directs the development of monocyte/macrophages, myeloid dendritic cells, and T cell subsets to promote type 2 and regulatory immune responses. The ability of both endogenous and exogenous follistatin to block the proinflammatory and profibrotic actions of activin A has led to interest in this binding protein as a potential therapeutic for limiting the severity of disease and to improve subsequent damage associated with inflammation and fibrosis. However, the ability of activin A to sculpt the subsequent immune response as well means that the full range of effects that might arise from blocking activin bioactivity will need to be considered in any therapeutic applications.

Introduction

The activins are members of the transforming growth factor β (TGFβ) superfamily of growth and differentiation regulating factors that also includes the bone morphogenetic proteins (BMPs), growth differentiation factors (GDFs), nodal and the gonadal hormone, and inhibin. The naming of the activins, their subunits, and their genes was due to their initial identification as regulators of the pituitary hormone, follicle-stimulating hormone (FSH), in antagonism of inhibin (Ling et al., 1986). Inhibin itself comprises one of the activin β-subunits (βA or βB) dimerized to a larger homologous α-subunit (Fig. 13.1) (Stewart et al., 1986). It later became evident that (i) the effects of inhibin on FSH were derived from its ability to antagonize activin produced by the pituitary (Corrigan et al., 1991), and (ii) that activins played regulatory roles in a number of other systems, particularly the hematopoietic and immune system (Broxmeyer et al., 1988, Hedger et al., 1989). Indeed, activin A was isolated several times by several groups, on the basis of its ability to regulate, among others, erythroid differentiation (Eto et al., 1987) and B cell apoptosis (Brosh et al., 1995), resulting in early synonyms for activin such as “erythroid differentiation factor” and “restrictin-P,” respectively. Today, as outlined in this chapter, there is burgeoning interest in the activins because of their ability to regulate inflammation, fibrosis, and immunity in a broad range of systems.

Although the biology and regulation of the activins has been under investigation for more than 25 years, progress has not been rapid. This is partly related to the complexity of the activin system itself, but also because, as far as inflammation and immunity are concerned, the activins have had a tendency to be overshadowed by the TGFβs, with which they share a crucial signaling pathway (Wrana and Attisano, 2000). It is only more recently that it has become obvious, particularly from studies with knockout mice or experiments employing specific inhibitors, that the activins play critical, unique roles in inflammation and immunity that are clearly distinguishable from an ability to act as weak agonists of the TGFβs.

Section snippets

Nomenclature, synthesis, and measurement

The canonical representative of the activin family is activin A. Like most members of the TGFβ superfamily, activin A is a disulfide-linked dimer of two identical subunits, with additional intra-strand disulfide bonds that form a cysteine knot folding motif (Fig. 13.2) (Greenwald et al., 2004, Harrington et al., 2006, Lin et al., 2006). Activin A is highly conserved across a broad range of species, with 100% conservation between the human, monkey, rat, mouse, bovine, and porcine molecules at

Sites of production and measurement issues

Both activins A and B are measurable in the serum (Demura et al., 1992, Knight et al., 1996, Ludlow et al., 2009, McFarlane et al., 1996), but it has proven difficult to identify the main source of these circulating proteins for a number of reasons. First, their genes are very widely expressed. Based on studies in the rat, mouse, pig, and human, the highest levels of βA mRNA expression are found in the ovary, uterus, placenta, male reproductive tract, the CNS, liver, bone marrow, heart, adrenal

Activin roles in inflammation, cachexia, and fibrosis

Early studies using an α-subunit knockout mouse model discovered that the resulting increase in systemic activin A levels (and presumably activin B) was accompanied by gonadal tumor development and cachexia, characterized by anemia, weight loss, focal necrosis and inflammation of the liver, and atrophy of the stomach (Matzuk et al., 1994). Simultaneously knocking out the ActRII receptor reversed the cachexia and liver pathology in these mice, but not the tumors, indicating that activin

Conclusions

In the context of inflammation and immunity, activin A bioactivity is regulated by multiple mechanisms at several different levels. Gene expression, synthesis, and release are induced by bacterial and viral molecular products through activation of TLR, and possibly other pattern recognition receptors, signaling, by various proinflammatory cytokines and other growth factors, and by oxidative stress. Unlike the TGFβs, which are secreted as latent prohormone forms, there is no evidence that

References (275)

  • R. Demura et al.

    Competitive protein binding assay for activin A/EDF using follistatin determination of activin levels in human plasma

    Biochem. Biophys. Res. Commun.

    (1992)
  • C.A. Dinarello

    Biologic basis for interleukin-1 in disease

    Blood

    (1996)
  • T. Dohi et al.

    Therapeutic potential of follistatin for colonic inflammation in mice

    Gastroenterology

    (2005)
  • S. Ebert et al.

    Activin A concentrations in human cerebrospinal fluid are age-dependent and elevated in meningitis

    J. Neurol. Sci.

    (2006)
  • S. Ebert et al.

    Microglial cells and peritoneal macrophages release activin A upon stimulation with Toll-like receptor agonists

    Neurosci. Lett.

    (2007)
  • M. Erämaa et al.

    Transforming growth factor-beta 1 and -beta 2 induce inhibin and activin beta B-subunit messenger ribonucleic acid levels in cultured human granulosa-luteal cells

    Fertil. Steril.

    (1996)
  • Y. Eto et al.

    Purification and characterization of erythroid differentiation factor (EDF) isolated from human leukemia cell line THP-1

    Biochem. Biophys. Res. Commun.

    (1987)
  • S. Evron et al.

    Activin βA in term placenta and its correlation with placental inflammation in parturients having epidural or systemic meperidine analgesia: A randomized study

    J. Clin. Anesth.

    (2007)
  • K.S. Famulski et al.

    Interferon-γ and donor MHC class I control alternative macrophage activation and activin expression in rejecting kidney allografts: A shift in the Th1–Th2 paradigm

    Am. J. Transplant.

    (2008)
  • J. Fang et al.

    Molecular cloning of the mouse activin βE subunit gene

    Biochem. Biophys. Res. Commun.

    (1996)
  • J. Fang et al.

    Genes coding for mouse activin βC and βE are closely linked and exhibit a liver-specific expression pattern in adult tissues

    Biochem. Biophys. Res. Commun.

    (1997)
  • M. Funaba et al.

    Calcium-regulated expression of activin A in RBL-2H3 mast cells

    Cell. Signal.

    (2003)
  • M. Funaba et al.

    Identification of tocopherol-associated protein as an activin/TGF-β-inducible gene in mast cells

    Biochim. Biophys. Acta

    (2006)
  • E.J. Gold et al.

    Cell-specific expression of βC-activin in the rat reproductive tract, adrenal and liver

    Mol. Cell. Endocrinol.

    (2004)
  • E. Gold et al.

    Activin C antagonizes activin A in vitro and overexpression leads to pathologies in vivo

    Am. J. Pathol.

    (2009)
  • J. Greenwald et al.

    A flexible activin explains the membrane-dependent cooperative assembly of TGF-beta family receptors

    Mol. Cell

    (2004)
  • R. Gribi et al.

    Expression of activin A in inflammatory arthropathies

    Mol. Cell. Endocrinol.

    (2001)
  • N.P. Groome et al.

    Enzyme immunoassays for inhibins, activins and follistatins

    Mol. Cell. Endocrinol.

    (2001)
  • M. Guha et al.

    LPS induction of gene expression in human monocytes

    Cell. Signal.

    (2001)
  • C.A. Harrison et al.

    Antagonists of activin signaling: Mechanisms and potential biological applications

    Trends Endocrinol. Metab.

    (2005)
  • M. Hashimoto et al.

    Follistatin is a developmentally regulated cytokine in neural differentiation

    J. Biol. Chem.

    (1992)
  • O. Hashimoto et al.

    A novel role of follistatin, an activin-binding protein, in the inhibition of activin action in rat pituitary cells. Endocytotic degradation of activin and its acceleration by follistatin associated with cell-surface heparan sulfate

    J. Biol. Chem.

    (1997)
  • O. Hashimoto et al.

    Impaired growth of pancreatic exocrine cells in transgenic mice expressing human activin βE subunit

    Biochem. Biophys. Res. Commun.

    (2006)
  • M.P. Hedger et al.

    Isolation of rat blood lymphocytes using a two-step Percoll density gradient. Effect of activin (erythroid differentiation factor) on peripheral T lymphocyte proliferation in vitro

    J. Immunol. Methods

    (1993)
  • M.P. Hedger et al.

    Inhibin and activin regulate [3H]thymidine uptake by rat thymocytes and 3T3 cells in vitro

    Mol. Cell. Endocrinol.

    (1989)
  • M.P. Hedger et al.

    Divergent cell-specific effects of activin-A on thymocyte proliferation stimulated by phytohemagglutinin, and interleukin 1β or interleukin 6 in vitro

    Cytokine

    (2000)
  • P.J. Hertzog et al.

    The interferon in TLR signaling: More than just antiviral

    Trends Immunol.

    (2003)
  • K. Hildén et al.

    Co-ordinate expression of activin A and its type I receptor mRNAs during phorbol ester-induced differentiation of human K562 erythroleukemia cells

    Mol. Cell. Endocrinol.

    (1999)
  • G. Hötten et al.

    Cloning of a new member of the TGF-β family: A putative new activin βC chain

    Biochem. Biophys. Res. Commun.

    (1995)
  • G. Hübner et al.

    Serum growth factors and proinflammatory cytokines are potent inducers of activin expression in cultured fibroblasts and keratinocytes

    Exp. Cell Res.

    (1996)
  • G. Hübner et al.

    Strong induction of activin expression after injury suggests an important role of activin in wound repair

    Dev. Biol.

    (1996)
  • P.E. Hughes et al.

    Activity and injury-dependent expression of inducible transcription factors, growth factors and apoptosis-related genes within the central nervous system

    Prog. Neurobiol.

    (1999)
  • P. Hüsken-Hindi et al.

    Monomeric activin A retains high receptor binding affinity but exhibits low biological activity

    J. Biol. Chem.

    (1994)
  • S. Inouye et al.

    Site-specific mutagenesis of human follistatin

    Biochem. Biophys. Res. Commun.

    (1991)
  • K.A. Jenkins et al.

    TIR-containing adaptors in Toll-like receptor signalling

    Cytokine

    (2010)
  • C. Karagiannidis et al.

    Activin A is an acute allergen-responsive cytokine and provides a link to TGF-β-mediated airway remodeling in asthma

    J. Allergy Clin. Immunol.

    (2006)
  • A. Karger et al.

    Molecular insights into connective tissue growth factor action in rat pancreatic stellate cells

    Cell. Signal.

    (2008)
  • M. Abe et al.

    Interleukin-1 β enhances and interferon-gamma suppresses activin A actions by reciprocally regulating activin A and follistatin secretion from bone marrow stromal fibroblasts

    Clin. Exp. Immunol.

    (2001)
  • M. Abe et al.

    Potent induction of activin A secretion from monocytes and bone marrow stromal fibroblasts by cognate interaction with activated T cells

    J. Leukoc. Biol.

    (2002)
  • S. Abe et al.

    Expression of myostatin and follistatin in Mdx mice, an animal model for muscular dystrophy

    Zool. Sci.

    (2009)
  • Cited by (0)

    1

    Current address: Research Services, La Trobe University, Bundoora, Victoria, Australia

    2

    Current address: Governor of Victoria, Government House, Melbourne, Victoria, Australia

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