ReviewThe roles of activin A and its binding protein, follistatin, in inflammation and tissue repair
Introduction
The inflammatory response represents the body’s response to injury, which can arise from a variety of causes, such as infectious organisms, toxins, alcohol, allergies, autoimmune responses, trauma, lacerations, burns, circulatory occlusions and other factors that induce tissue damage. Emerging data indicate that many pathological disorders, including congestive heart failure, atherosclerosis and even type 2 diabetes have an inflammatory basis.
The inflammatory response represents an attempt by the organism to deal with the offending agent and to restore function to normal. It is a complex response that has many components, and is highly regulated by cytokines, hormones and the nervous system. The inflammatory response encapsulates both pro-inflammatory and anti-inflammatory components, and can be a detrimental process when a balance between these components cannot be achieved, leading in many cases to chronic inflammation characterised by continued tissue damage (e.g. rheumatoid arthritis) (Yu et al., 1998).
In the process of wound healing, the inflammatory response leads to the formation of a scar, the nature of which will be dependent on the severity of the injury, such as the extensive loss of an epithelial surface or significant destruction of heart muscle following myocardial infarction. The nature of the scar is also dependent on the control of pro-fibrotic processes, with inadequate control leading to significant fibrosis/scarring, which can seriously compromise function in organs such as the heart, kidney and liver.
The activins are proteins that have both pro- and anti-inflammatory activities and have now been shown to play a major role controlling the cytokine cascade that drives the inflammatory response (Jones et al., 2000, Jones et al., 2007). Follistatin is a protein that can neutralise or inhibit all of the actions of the activins, and can therefore modulate the inflammatory process and the resolution of ensuing tissue damage. This review will provide a summary of a growing body of evidence that place the activins and follistatin as key controllers of the process of inflammation and fibrosis.
Section snippets
Activins and follistatin
The activins are members of the transforming growth factor-β (TGF-β) superfamily, which are composed of disulphide linked dimers of β-subunits (βA and βB) that can also dimerise with an α-subunit to form inhibin A (αβA) and inhibin B (αβB). Consequently, three forms of activin have been described, activin A (βAβA), activin B (βBβB) and activin AB (βAβB). The majority of the information in this review will focus on the role of activin A in the inflammatory process, but there is emerging data for
The role of activin A and follistatin in the inflammatory process
Among the earliest observations linking activin A to the regulation of inflammation, fibrosis and immunity was its capacity to inhibit the activation and proliferation of thymocytes and peripheral T cells, together with stimulation of mitosis of 3T3 fibroblasts in vitro (Hedger et al., 1989, Hedger and Clarke, 1993). Later, follistatin was shown to rise in response to surgical and anaesthetic stress as part of the acute phase reaction (Phillips et al., 1996). The demonstration that serum
The role of activin A in immunoregulation
Activin A is an inhibitor of lymphocyte activation, proliferation, differentiation and survival. Activin A inhibits activation and proliferation of thymic and peripheral T cells (Hedger et al., 1989, Hedger and Clarke, 1993, Karagiannidis et al., 2006), and has been shown to inhibit the growth and survival of normal and transformed B cells (Brosh et al., 1995, Nishihara et al., 1993, Zipori and Barda-Saad, 2001). Further, the expression of the α and β subunits of the inhibins/activins is seen
The role of the activins in the stimulation of fibrosis
It is important to recognise that fibrosis is the “repair” component of the inflammatory response and is down-stream of the early events involved in the initiation of inflammation. The latter does not always end in fibrosis as exemplified by the inflammatory component of ovulation or that associated with the implantation of the embryo. Further, the degree of fibrosis varies with the severity of the tissue damage and the ultimate result is dependent on the end result of the interaction of a
Summary
In summary, this review provides the reader with a brief outline of the rapidly expanding literature concerning the actions of the activins and follistatin in inflammation, immunoregulation and induction of fibrosis. Further studies are required to further define these roles, and their interaction with other members of the TGF-β family of proteins that have similar activities. There can be no question that elucidation of these complexities will provide novel data and new concepts that will be
References (88)
Follistatin complexes Myostatin and antagonises Myostatin-mediated inhibition of myogenesis
Developmental Biology
(2004)Activin controls skin morphogenesis and wound repair predominantly via stromal cells and in a concentration-dependent manner via keratininocytes
American Journal of Pathology
(2005)The plasmacytoma growth inhibitor restrictin-P is an antagonist of interleukin 6 and interleukin 11. Identification as a stroma-derived activin A
Journal of Biological Chemistry
(1995)Biologic basis for interleukin-1 in disease
Blood
(1996)Therapeutic potential of follistatin for colonic inflammation in mice
Gastroenterology
(2005)Interferon-γ and donor MHC class 1 control alternative macrophage activation and activin expression in rejecting kidney allografts: a shift in the TH1–Th2 paradigm
American Journal of Transplantation
(2008)Identification of tocopherol-associated protein as an activin/TGF-β-inducible gene in mast cells
Biochem. Biophys. Acta
(2006)- 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
Journal of Immunological Methods
(1993) Inhibin and activin regulate [3H]thymidine uptake by rat thymocytes and 3T3 cells in vitro
Molec. Cell. Endocrinol.
(1989)Divergent cell-specific effects of activin-A on thymocyte proliferation stimulated by phytohemagglutinin, and interleukin 1b or interleukin 6 in vitro
Cytokine
(2000)
The regulation and functions of activin and follistatin in inflammation and immunity
Vitamins and Hormones
Strong induction of activin expression after injury suggests an important role of activin in wound repair
Develop. Biol.
Serum growth factors and proinflammatory cytokines are potent inducers of activin expression in cultured fibroblasts and keratinocytes
Experimental Cell Research
Activin A is an acute allergen-responsive cytokine and provides a link to TGF-b-mediated airway remodeling in asthma
J. Allergy Clin. Immunol.
Molecular insights into connective tissue growth factor action in rat pancreatic stellate cells
Cellular Signalling
Activin and transforming growth factor-β signalling pathways are activated after allergen challenge in mild asthma
J. Allergy Clin. Immunol.
Activin A stimulates IgA expression in mouse B cells
Biochemical and Biophysical Research Communications
Structural and biophysical coupling of heparin and activin binding to follistatin isoform functions
Journal of Biological Chemistry
Transcriptional regulation of plasminogen activator inhibitor-1 by transforming growth factor-β, activin A and microphthalmia-associated transcription factor
Cellular Signalling
Follistatin, an activin-binding protein, associates with heparan sulfate chains of proteoglycans on follicular granulosa cells
Journal of Biological Chemistry
Activin A induces apoptotic cell death
Biochemical and Biophysical Research Communications
Activin and related proteins in inflammation: not just interested bystanders
Cytokine and Growth Factor Reviews
Activin-A: a novel dendritic cell-derived cytokine that potently attenuates CD40 ligand-specific cytokine and chemokine production
Blood
Activin-A attenuates several human natural killer cell functions
Blood
Activin A regulates growth and acute phase proteins in the human liver cell line, HepG2
Mol. Cell. Endocri.
Activin Ainduces dendritic cell migration through prolonged release of CXC chemokine ligands 12 & 14
Blood
Contrasting effects of inflammatory cytokines and glucocorticoids on the production of activin A in human marrow stromal cells and their implications
Cytokine
Activin A skews macrophage polarization by promoting a proinflammatory phenotype and inhibiting the acquisition of anti-inflammatory macrophage markers
Blood
Langerhans cells are strongly reduced in the skin of transgenic mice overexpressing mice in the epidermis
European Journal of Cell Biology
Activin as an anti-inflammatory cytokine produced by microglia
Journal of Neuroimmunology
Tumor necrosis factor and interleukin-1 induce activin A gene expression in a human bone marrow stromal cell line
Biochemical and Biophysical Research Communications
The structure of the follistatin:activin complex reveals antagonism of both type I and type II receptor binding
Develop. Cell
Stimulatory effects of lipopolysaccharide on endothelial cell activin and follistatin
Mol. Cell. Endocr.
Activin A down-regulates the phagocytosis of lipopolysaccharide-activated mouse peritoneal macrophages in vitro and in vivo
Cellular Immunology
Relationship between transforming growth factor β1, myostatin and decorin: implications for skeletal muscle fibrosis
Journal of Biological Chemistry
Toll-like receptor signalling
Nature Reviews Immunology
Attenuation of bleomycin-induced pulmonary fibrosis by follistatin
Am J Resp Crit Care Med
Regulation of activin A expression in mast cells and asthma: its effect on the proliferation of human airway smooth muscle cells
Journal of Immunology
Evidence for an autocrine role of activin B within rat anterior pituitary cultures
Endocrinology
Insulin regulates macrophage activation through activin A
Shock
Analysis of activin A gene expression in human bone marrow stromal cells
Journal of Cellular Biochemistry
Large-scale culture and selective maturation of human Langerhans cells from granulocyte colony-stimulating factor-mobilized CD34+ progenitors
Journal of Immunology
Transforming growth factor beta1, in the presence of granulocyte/macrophage colony-stimulating factor and interleukin 4, induces differentiation of human peripheral blood monocytes into dendritic Langerhan cells
Journal of Experimental Medicine
Over expression of Smad2 drives house-dust mite-mediated airway remodelling and airway hyperresponsiveness via activin and IL-25
American Journal of Respiratory and Critical Care Medicine
Cited by (134)
Activin A and pathologies of pregnancy: a review
2023, PlacentaActivin-A, Growth Differentiation Factor-11 and Transforming Growth Factor-β as predictive biomarkers for platinum chemotherapy in advanced non-small cell lung cancer
2022, Cancer Treatment and Research CommunicationsComparative single-cell analysis of biopsies clarifies pathogenic mechanisms in Klinefelter syndrome
2021, American Journal of Human Genetics