Activin A is a critical component of the inflammatory response, and its binding protein, follistatin, reduces mortality in endotoxemia

Abstract

Activin A is a member of the transforming growth factor-␤ superfamily, which we have identified as having a role in inflammatory responses. We show that circulating levels of activin increase rapidly after LPS-induced challenge through activation of Toll-like receptor 4 and the key adaptor protein, MyD88. Treatment with the activin-binding protein, follistatin, alters the profiles of TNF, IL-1␤, and IL-6 after LPS stimulation, indicating that activin modulates the release of several key proinflammatory cytokines. Further, mice administered one 10-g dose of follistatin to block activin effects have increased survival after a lethal dose of LPS, and the circulating levels of activin correlate with survival outcome. These findings demonstrate activin A's crucial role in the inflammatory response and show that blocking its actions by the use of follistatin has significant therapeutic potential to reduce the severity of inflammatory diseases.lipopolysaccharide ͉ cytokines ͉ Toll-like receptor ͉ MyD88 ͉ innate immunity

Activin-A exerts a crucial anti-inflammatory role in neonatal infections

“…Of note, activin-A induces the generation of mouse regulatory T cells suppressive against responses by other T cells in vitro and in vivo (5,35). By contrast, certain studies point to proinflammatory effects of activin-A as shown by enhanced survival during systemic administration of follistatin following a lethal dose of LPS in vivo (8). Moreover, increased TNF-α and IL-1β release was observed upon stimulation of rat macrophages with activin-A in vitro (42).…”

“…Although previous studies have demonstrated induction of activin-A during infections in animal models and in adults (6)(7)(8)22,23), as far as we know, this is the first study that investigated activin-A expression in neonates. We demonstrate that activin-A is significantly increased in the serum of neonates during infections.…”

“…For example, administration of bacterial endotoxin (LPS) in vivo induces a rapid (within 40 min) release of activin-A in the circulation (7). Of note, activin-A expression is observed at an earlier time point as compared with that of tumor necrosis factor (TNF)-α and well ahead the release of IL-6 (7,8). In addition, activin-A levels are significantly increased following in vitro stimulation with toll-like receptor ligands (including viruses and bacteria) or proinflammatory cytokines (i.e., TNF-α and IFN-γ) in a wide array of cells, such as monocytes, dendritic cells (DCs), lymphocytes, epithelial, and endothelial cells (4,5).…”

“…Growing evidence suggests that activin-A is also induced during inflammatory processes and, more specifically, during infections (6)(7)(8). For example, administration of bacterial endotoxin (LPS) in vivo induces a rapid (within 40 min) release of activin-A in the circulation (7).…”

Candidate genes for colour and vision exhibit signals of selection across the pied flycatcher (Ficedula hypoleuca) breeding range

“…A closer examination of these pathways revealed 2 of the 14 connections could bear relevance in the context of feather generation. The first of these is a pathway that connects follistatin with the localization of the tumor necrosis factor-a protein (Jones et al, 2007), which in turn decreases the activation of Collagen-a-2(I) in human dermal fibroblasts (Yamane et al, 2003). The second putatively relevant pathway was one that showed follistatin Figure 3 The relationship between pairwise F ST values for SNP markers and microsatellites with the same population pairs (see Lehtonen et al, 2009a).…”