Activin A and follistatin: their role in the acute phase reaction and inflammation.

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The activins are a family of proteins which consist of disulphide-linked homodimers and heterodimers of the â subunits of inhibin termed âA and âB. These three proteins, called activin A (âA-âA), activin B (âB-âB) and activin AB (âA-âB), are members of the transforming growth factor â (TGFâ) super-family of proteins (de Kretser & Robertson 1989). Recently, three additional members of this family have been identified, called âC, âD and âE, but as yet their actions remain to be defined (see Fang et al. 1996 for review). The physiological roles of this family of proteins are largely based on the established properties of activin A, as sufficient supplies of this protein have been made available in recombinant form. Although the activins were originally isolated for their ability to stimulate follicle-stimulating hormone secretion, they have been shown to influence many biological processes, including parenchymal haemopoiesis, embryogenesis, neurotransmission, hepatic parenchymal cell division, prostate biology and angiogenesis. Some of the actions of activin A are antagonised by inhibin A, which is a dimer of the âA subunit with its a subunit, and inhibin B, an a-âB dimer. The actions of activin A are expressed through a system of specific transmembrane serine-threonine kinase receptors which exist in two subgroups, type I and type II, both of which are essential for activin to act (ten Dijke et al. 1996). Further regulation of the actions of the activins is achieved through follistatin, a protein which binds activin A and B with high affinity and neutralises its biological activity (Nakamura et al. 1990, Phillips & de Kretser 1998 for review). It is not known whether follistatin binds âC, âD and âE. Additionally, the factors which regulate the balance of production between the inhibins and activins also represent a mechanism modulating activin A levels and thus its biological activity. The involvement of activin and follistatin in the response to trauma and inflammation emerged from the capacity of activin, like TGFâ, to suppress T cell activation (Hedger et al. 1989) and from the rise in follistatin induced in response to surgical stress (Klein et al. 1993). In the intervening years, a considerable body of evidence has accumulated to support the involvement of both activin and follistatin in inflammation and the acute phase reaction. Tissue injury and inflammation are accompanied by the release of the cytokines interleukin (IL)-1, IL-6 and tumour necrosis factor a (TNFa) from macrophages and stromal cells at the site of injury (Steel & Whitehead 1994). These cytokines, in turn, act at systemic sites, in particular the liver, to activate gene expression and the febrile response to injury, collectively known as the acute phase response (APR). The APR is a response to injury which induces numerous changes designed to protect the host and, in turn, to limit the potentially widespread actions of the cytokines and acute phase proteins released (Steel & Whitehead 1994). The acute phase proteins (APP) that are up-regulated include agents which limit the inflammatory process, minimise tissue damage and facilitate the repair process. Included in this group are metal binding proteins, coagulation proteins, complement proteins, proteinase inhibitors and others such as serum amyloid A, serum amyloid P component and C-reactive protein. In addition, IL-1 and IL-6 act on the pituitary–adrenal axis to induce glucocorticoid secretion, which facilitates APP secretion and inhibits cytokine gene expression by monocytes and macrophages. Several observations have linked the activin A/follistatin system to the modulation of the APR. While our studies established that the pattern of follistatin secretion was similar to that of an APP (Klein et al. 1993, Phillips et al. 1996), its role in this process remained unclear, since no data were available to demonstrate a role for activin A in this process, partly due to difficulties in assaying this protein. However, recently Brosh et al. (1995) showed that activin A was an IL-6 antagonist at a number of sites, and established that this action was probably mediated by interference with the signal transduction mechanism of IL-6. Further, activin A decreases IL-1â production and 195