The roles of activin A and its binding protein, follistatin, in inflammation and tissue repair

Abstract

Activin A, a member of the transforming growth factor-β superfamily of cytokines, is a critical controller of inflammation, immunity and fibrosis. It is rapidly released into the blood following a lipopolysaccharide challenge in experimental animals, through activation of the Toll-like receptor 4 signalling pathway. Blocking activin action by pre-treatment with its binding protein, follistatin, modifies the inflammatory cytokine cascade, and reduces the severity of the subsequent inflammatory response and mortality. Likewise, high serum levels of activin A are predictive of death in patients with septicaemia. However, activin A has complex immunomodulatory actions. It is produced by inflammatory macrophages, but can regulate either pro- or anti-inflammatory responses in these cells, depending on their prior activation status. Activin A is also produced by Th2 cells, and stimulates antibody production by B cells and the development of regulatory T cells. Production of activin A during inflammatory responses stimulates fibrosis and tissue remodelling, and follistatin inhibits these actions of activin A. The modulation of activin by follistatin may represent an important therapeutic target for the modulation and amelioration of inflammatory and fibrotic disorders.

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.