Evidence for activin A and follistatin involvement in the systemic inflammatory response
Introduction
Inflammation is a multifaceted process at the cellular, tissue and systemic level, and is co-ordinated through a complex network of cytokine pathways. These networks are activated to restore the body to normal homeostasis, but at other times the hyperactivation of immunoregulatory molecules may prove deleterious to the host.
Although many of the key cytokines involved in inflammatory processes have been identified and their function determined, there is continuing interest in the intracellular signalling pathways that are activated and how immunoregulatory factors interact with other cytokine and growth factor systems. One of these is for transforming growth factor-β (TGF-β), the prototype member of a large superfamily comprising more than 40 members. A role for TGF-β in inflammation is clearly established (Letterio and Roberts, 1998). However, another TGF-β family member, activin A, has also been implicated in several immune processes, and is the subject of this article. Activin A is a homodimer of activin βA subunits that has pleiotrophic actions in the body (Woodruff, 1998). Its biological activity is controlled at many levels, including through interaction with a high affinity binding protein, follistatin (Phillips, 2000). It should also be pointed out that the activin βB subunit (forming activin B or activin AB), which has close structural homology to the βA subunit, or indeed the inhibins, consisting of an α–β dimer, do not seem to possess significant immunomodulatory activities.
While more recent studies on activin A have shed considerable light on its characterization as an immunomodulatory factor, it has been known for some time that it was implicated in several aspects of immune function. Indeed, one of the original properties attributed to activin A was as an erythroid differentiation factor isolated from THP-1 leukemic cells (Eto et al., 1987). A classic study by Broxmeyer et al. (1988) showed that activin A enhanced the colony formation of multipotential and erythroid progenitor cells, but had little effect on granulocyte-macrophage progenitor cells. Subsequent studies also established that activin A induced the accumulation of hemoglobin in erythroleukemic cell lines (Yu et al., 1987). While stimulating the differentiation of erythroid lineages, activin A is also a powerful inhibitor of proliferation and an apoptotic agent for a number of immune cells, particularly B and T cells (Hedger et al., 1989, Hedger and Clarke, 1993, Brosh et al., 1995). Implicitly the role of follistatin in inflammatory processes is thought to be part of a short-loop feedback system to modulate and contain the effects of activin A. While this is the most straightforward explanation, as mentioned below there are several lines of evidence to show that follistatin may respond to inflammatory stimuli directly, potentially to facilitate other roles beyond that of neutralizing activin's bioactivity.
Section snippets
Activin versus TGF-β effects on inflammatory pathways
Activin and TGF-β signal through separate serine threonine kinase receptor subunits, yet the intracellular signalling pathways are intimately linked through the common activation of Smad proteins, Smads 2, 3 and 4, and the inhibitory Smads 6 and 7. These are discussed in thorough detail in some of the other articles in this special issue and are beyond the scope of the present review. Mice in which the TGF-β1 gene has been knocked out develop gross inflammatory conditions which lead to
Studies of systemic inflammation in a sheep model
Much of the work defining the circulatory response of activin A and follistatin during systemic inflammation has arisen from work carried out in a sheep model. There are a number of reasons why we feel that this is a useful system. First, the response of sheep to inflammatory stimuli such as lipopolysaccharide (LPS) or interleukin (IL)-1β mimics very closely that of the human, in terms of the pyrogenic response and cytokines released. This has advantages compared with rodent models where
Clinical studies
The number of clinical studies that address activin or follistatin's role in inflammatory processes are limited. In serum, it is known that follistatin is elevated in patients with sepsis (Michel et al., 1998). The peak response varied greatly with patient but generally paralleled that of C-reactive protein. Nevertheless, follistatin concentrations were not correlated with leucocyte counts or patient outcome. More recently this group has reported elevated follistatin concentrations in the
Source of release
Nearly every cell type in the body is capable of synthesizing and secreting activin A and follistatin. Clearly, the release of these proteins into the circulation during systemic inflammation is the result of a tightly coordinated process. Yet the source or sources of this release have not been absolutely determined. Various in vitro studies have given indications of the leading candidate cell types. For instance, it has been known for some years that activated circulating monocytes and tissue
Pro- versus anti-inflammatory actions of activin A
An intriguing aspect of activin's role in inflammatory processes is the dichotomy between pro- and anti-inflammatory actions. It should be pointed out that this behavior is consistent with that of TGF-β, which although mainly anti-inflammatory, does exhibit some pro-inflammatory aspects (Letterio and Roberts, 1998).
A role for activin A in stimulating inflammatory pathways comes from several studies in diverse cell types. In bone marrow-derived macrophages, activin A profoundly stimulated the
Interaction with other cytokine signalling pathways
With the definition of the Smad signalling pathway for the TGF-β superfamily has come an understanding of how activin A and follistatin might intersect with other cytokine and growth factor pathways. A simplified schematic of some of these points of interaction are depicted in Fig. 3. At the present time, the majority of studies have delineated the manner in which other pathways modulate Smad expression or action. For instance, in some contexts activin A is known to potentiate the stimulatory
Concluding remarks
The last 5 years have established activin A as a true cytokine. This can be envisioned both in terms of the biological properties that are now being unveiled, and using a common definition of a cytokine (Vilcek, 1998): (i) a (simple) polypeptide of 30 kDa or less, (ii) constitutive production is usually low or absent, (iii) production under stimulatory conditions is transient, (iv) it acts through high-affinity receptors, and (v) its actions can be broad and diverse, but some actions are
Acknowledgements
This work was supported as part of a Program Grant (973218) from the National Health and Medical Research Council of Australia.
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