Characterisation of the rapid release of activin A following acute lipopolysaccharide challenge in the ewe

Abstract

A series of experiments were conducted in adult ewes to delineate the release profile of activin A and its relationship to other cytokines following an i.v. injection of the bacterial cell wall component, lipopolysaccharide (LPS). Following this challenge, plasma activin A increased rapidly and appeared to be released in a biphasic manner, slightly preceding the release of tumour necrosis factor-(TNF ) and before elevation of interleukin (IL)-6 and follistatin levels. The concentration of activin A was correlated with body temperature during the response to LPS. A second experiment compared cytokine concentrations in matched blood and cerebrospinal fluid (CSF) samples. This revealed that activin A was not released centrally in the CSF following a peripheral LPS injection, nor was TNF or the activin binding protein, follistatin, but IL-6 showed a robust elevation. In a third experiment, the stimulus for activin A release was examined by blocking prostaglandin synthesis. Flurbiprofen, a prostaglandin synthesis inhibitor, effectively attenuated the fever response to LPS and partly inhibited cortisol release, but the cytokine profiles were unaffected. Finally, the bioactivity of TNF and/or IL-1 was blocked using soluble receptor antagonists. These treatments did not affect the initial release of activin A, but blockade of TNF depressed the second activin peak. These studies define more rigorously the release of activin A into the circulation following acute inflammatory challenge. The response is rapid and probably biphasic, independent of prostaglandinmediated pathways and does not depend upon stimulation by TNF or IL-1. The data suggest that activin A release is an early event in the inflammatory cascade following the interaction of LPS with its cellular receptor.

When versatility matters: activins/inhibins as key regulators of immunity

“…In this context, treatment with exogenous FS has confirmed the important requirement of the early release of activin A to regulate IL-1b, TNF-a and IL-6 secretion induced by LPS. 22,[32][33][34] Moreover, recent evidence has shown that macrophages are able to secrete activin A in response to the activation of TLR2, TLR4 and TLR9 (Figure 1 (1), right panel). [35][36][37][38][39] Accordingly, elevated activin A levels have been observed in a mouse model of endotoxemia and in patients with clinical sepsis condition.…”

Direct Effects of Activin A on the Activation of Mouse Macrophage RAW264.7 Cells

“…However, activin A is also a pro-inflammatory factor and increases dramatically in inflammatory situations. Lots of experiments have demonstrated that activin A is involved in the pathogenesis of fibrotic human diseases and induction of extracellular matrix expression in hepatocytes (8)(9)(10). Our previous studies have found that activin A can increase the production of inflammatory mediator, nitric oxide (NO) in mouse peritoneal macrophages (3).…”

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

“…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).…”

“…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). 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).…”

“…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).…”