Chapter Thirteen - The Regulation and Functions of Activin and Follistatin in Inflammation and Immunity
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)
- et al.
Follistatin complexes Myostatin and antagonises Myostatin-mediated inhibition of myogenesis
Dev. Biol.
(2004) - et al.
Activin controls skin morphogenesis and wound repair predominantly via stromal cells and in a concentration-dependent manner via keratinocytes
Am. J. Pathol.
(2005) - et al.
Endoglin is an accessory protein that interacts with the signaling receptor complex of multiple members of the transforming growth factor-β superfamily
J. Biol. Chem.
(1999) - et al.
Acute inhibition of myostatin-family proteins preserves skeletal muscle in mouse models of cancer cachexia
Biochem. Biophys. Res. Commun.
(2010) - et al.
A Smad-binding element in intron 1 participates in activin-dependent regulation of the follistatin gene
J. Biol. Chem.
(2008) - et al.
The plasmacytoma growth inhibitor restrictin-P is an antagonist of interleukin 6 and interleukin 11. Identification as a stroma-derived activin A
J. Biol. Chem.
(1995) - et al.
The p38 MAPK pathway is required for cell growth inhibition of human breast cancer cells in response to activin
J. Biol. Chem.
(2001) - et al.
Wounds increase activin in skin and a vasoactive neuropeptide in sensory ganglia
Dev. Biol.
(2004) - et al.
Localization and cellular sources of activins in normal and fibrotic rat liver
Hepatology
(1997) The transforming growth factor-β superfamily of receptors
Cytokine Growth Factor Rev.
(2004)
Competitive protein binding assay for activin A/EDF using follistatin determination of activin levels in human plasma
Biochem. Biophys. Res. Commun.
Biologic basis for interleukin-1 in disease
Blood
Therapeutic potential of follistatin for colonic inflammation in mice
Gastroenterology
Activin A concentrations in human cerebrospinal fluid are age-dependent and elevated in meningitis
J. Neurol. Sci.
Microglial cells and peritoneal macrophages release activin A upon stimulation with Toll-like receptor agonists
Neurosci. Lett.
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.
Purification and characterization of erythroid differentiation factor (EDF) isolated from human leukemia cell line THP-1
Biochem. Biophys. Res. Commun.
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.
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.
Molecular cloning of the mouse activin βE subunit gene
Biochem. Biophys. Res. Commun.
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.
Calcium-regulated expression of activin A in RBL-2H3 mast cells
Cell. Signal.
Identification of tocopherol-associated protein as an activin/TGF-β-inducible gene in mast cells
Biochim. Biophys. Acta
Cell-specific expression of βC-activin in the rat reproductive tract, adrenal and liver
Mol. Cell. Endocrinol.
Activin C antagonizes activin A in vitro and overexpression leads to pathologies in vivo
Am. J. Pathol.
A flexible activin explains the membrane-dependent cooperative assembly of TGF-beta family receptors
Mol. Cell
Expression of activin A in inflammatory arthropathies
Mol. Cell. Endocrinol.
Enzyme immunoassays for inhibins, activins and follistatins
Mol. Cell. Endocrinol.
LPS induction of gene expression in human monocytes
Cell. Signal.
Antagonists of activin signaling: Mechanisms and potential biological applications
Trends Endocrinol. Metab.
Follistatin is a developmentally regulated cytokine in neural differentiation
J. Biol. Chem.
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.
Impaired growth of pancreatic exocrine cells in transgenic mice expressing human activin βE subunit
Biochem. Biophys. Res. Commun.
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
Inhibin and activin regulate [3H]thymidine uptake by rat thymocytes and 3T3 cells in vitro
Mol. Cell. Endocrinol.
Divergent cell-specific effects of activin-A on thymocyte proliferation stimulated by phytohemagglutinin, and interleukin 1β or interleukin 6 in vitro
Cytokine
The interferon in TLR signaling: More than just antiviral
Trends Immunol.
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.
Cloning of a new member of the TGF-β family: A putative new activin βC chain
Biochem. Biophys. Res. Commun.
Serum growth factors and proinflammatory cytokines are potent inducers of activin expression in cultured fibroblasts and keratinocytes
Exp. Cell Res.
Strong induction of activin expression after injury suggests an important role of activin in wound repair
Dev. Biol.
Activity and injury-dependent expression of inducible transcription factors, growth factors and apoptosis-related genes within the central nervous system
Prog. Neurobiol.
Monomeric activin A retains high receptor binding affinity but exhibits low biological activity
J. Biol. Chem.
Site-specific mutagenesis of human follistatin
Biochem. Biophys. Res. Commun.
TIR-containing adaptors in Toll-like receptor signalling
Cytokine
Activin A is an acute allergen-responsive cytokine and provides a link to TGF-β-mediated airway remodeling in asthma
J. Allergy Clin. Immunol.
Molecular insights into connective tissue growth factor action in rat pancreatic stellate cells
Cell. Signal.
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.
Potent induction of activin A secretion from monocytes and bone marrow stromal fibroblasts by cognate interaction with activated T cells
J. Leukoc. Biol.
Expression of myostatin and follistatin in Mdx mice, an animal model for muscular dystrophy
Zool. Sci.
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Current address: Research Services, La Trobe University, Bundoora, Victoria, Australia
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Current address: Governor of Victoria, Government House, Melbourne, Victoria, Australia