Microglial cells and peritoneal macrophages release activin A upon stimulation with Toll-like receptor agonists

Ebert, Sandra; Zeretzke, Moritz; Nau, Roland; Michel, Uwe

doi:10.1016/j.neulet.2006.11.065

Cited by 47 publications

(31 citation statements)

References 34 publications

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“…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.…”

Section: Discussionmentioning

confidence: 92%

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

et al. 2013

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Background: Activin-A is a cytokine with a critical role in infections and associated inflammation in experimental models and humans. Still, the effects of activin-A on neonatal infections remain elusive. Here, we investigated the expression of activin-A in the serum of septicemic preterm and term neonates and in peripheral blood leukocytes stimulated with inflammatory agents in vitro. The role of activin-A in the regulation of inflammatory responses by neonatal leukocytes was delineated. Methods: Peripheral blood was obtained from 37 septicemic neonates between the first and fifth days postinfection and from 35 healthy controls. Isolated monocytes and lymphocytes were stimulated with lipopolysaccharide (LPS) or phytohemagglutinin (PHA) in vitro in the presence of activin-A. Cell proliferation, cytokine, and chemokine release were investigated. results: Activin-A was significantly increased in the serum of preterm septicemic neonates. Neonatal leukocytes secreted copious amounts of activin-A following stimulation, pointing to these cells as an essential source of activin-A in the circulation. Of note, treatment of neonatal leukocytes with activin-A during PHA and LPS stimulation resulted in significantly decreased interleukin (IL)-1β, IL-6, and CXCL8 production, concomitant with a striking increase in the anti-inflammatory mediator, IL-10. conclusion: Our findings uncover activin-A as a novel immunomodulatory agent critical for the control of inflammatory responses in septicemic neonates.

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Section: Discussionmentioning

confidence: 92%

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

et al. 2013

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“…Peritoneal macrophages TLR2 (Pam3cys), -4 (LPS) and -9 (CpG) mactivin A secretion 35 Bone marrow-derived macrophages, peritoneal macrophages and cell line RAW264.7…”

Section: In Vitromentioning

confidence: 99%

“…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. 22,40 Furthermore, treatment with FS increased the survival of mice that were lethally challenged with LPS, 22 supporting the role of activin A as an early proinflammatory mediator in these models.…”

Section: Monocytesmentioning

confidence: 99%

“…As described for conventional macrophages, TLR2, TLR4 and TLR9 signaling also increases activin A levels in microglial cells. 35,50 In addition, activin A modulates microglial activation induced by LPS, reducing the production of IL-6, IL-18 and inducible nitric oxide synthase. However, in contrast to what was described for conventional macrophages, activin A also acts as antiinflammatory factor in microglial cells under steady-state conditions.…”

Section: Microglial Cellsmentioning

confidence: 99%

“…86 However, activin A is not able to directly induce IgE production by B cells, but rather may influence the activation of other immune cells (Figure 3b). 30,35,58 In addition, in vitro studies suggest that activin A acts on resting B cells, but not on activated B cells to stimulate IgG production. Preincubation of B cells with activin A and subsequent stimulation with LPS promote an enhanced B-cell proliferation and upregulation of IgG1, IgG2a, IgG2b and IgG3 (Figure 3b).…”

Section: Role Of Activins/inhibins On Adaptive Immune Cells B Cellsmentioning

confidence: 99%

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

Alemán-Muench

Soldevila

2011

Immunol Cell Biol

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Activins and inhibins are members of the transforming growth factor-b superfamily that have been considered crucial regulators of cell processes, such as differentiation, proliferation and apoptosis, in different cell types. Initial studies about the function of activin A in the immune system focused on the regulation of hematopoiesis in the bone marrow under homeostatic and inflammatory conditions. Recent data provide a more comprehensive understanding about the role of activins/inhibins in the immune system. Novel findings included in this review point out the important requirement of activin/inhibin signaling to maintain the balance between homeostatic and inflammatory signals that are required for the optimal development and function of immune cells. The purpose of this review is to highlight the versatile nature of activins/inhibins as key regulators of both the innate and adaptive immune responses. Keywords: activin; inhibin; inflammation; immune cells; immunity; tolerance Activins and inhibins are members of the transforming growth factor-b (TGF-b) superfamily that were initially described as regulators of reproductive processes in mammals, and were first named after their positive and negative effect in the release of follicle-stimulating hormone from the pituitary gland, respectively. 1 These dimeric ligands have been shown to modulate a variety of cellular functions such as apoptosis, proliferation, differentiation, cellular migration, among others. 2,3 Activin A (bA/bA) is the best-characterized ligand of this subfamily, although there are other bioactive forms, activin B (bB/bB) and activin AB (bA/bB), which differ in their potency and cellular function. 4 Activin A is a molecule with pleiotropic functions, which shares with TGF-b the SMAD2/3 canonical signaling pathway (reviewed by Shi and Massague 5 ) but uses distinct type II (ActRIIs) and type I (ALK2, ALK4 and ALK7) receptors. [6][7][8][9] The biological function of activins can be blocked by follistatin (FS), a glycoprotein that binds activin A with high affinity, functioning as a ligand trap. 10 On the other hand, inhibins are heterodimers formed by uncommon a-and b-subunits and exist in two isoforms, inhibin A (a/bA) and B (a/bB). Inhibins have been shown to antagonize activinmediated functions by a mechanism that involves binding to b-glycan (TGFbRIII) and formation of a ternary complex with ActRIIs. As a consequence, activin type I receptors (ALK4 and ALK2) are excluded from the receptor complex, leading to the inhibition of SMADmediated signaling. 3,[11][12][13][14] Despite the fact that inhibins have been classically considered as activin antagonists, there is evidence showing that they do not always antagonize activin-mediated functions in several cell types, suggesting the existence of an independent inhibinmediated signaling pathway. 3 Compelling evidence has shown that activins also regulate various non-reproductive processes, such as mesoderm induction, liver proliferation, skin morphogenesis, erythropoiesis, bone formation, neu...

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Gene expression profiling of peripheral blood from patients with untreated new‐onset systemic juvenile idiopathic arthritis reveals molecular heterogeneity that may predict macrophage activation syndrome

Fall

Barnes

Thornton

et al. 2007

Arthritis & Rheumatism

229

233

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Objective. Systemic juvenile idiopathic arthritis (JIA) is frequently associated with the development of macrophage activation syndrome. This study was undertaken to better understand the relationship between systemic JIA and macrophage activation syndrome.Methods. Gene expression profiles were examined in 17 patients with untreated new-onset systemic JIA, 5 of whom showed evidence of subclinical macrophage activation syndrome (of whom 2 eventually developed overt macrophage activation syndrome). Peripheral blood mononuclear cells (PBMCs) were separated on Ficoll gradients, and purified RNA was analyzed using Affymetrix GeneChip expression arrays. A fraction of the PBMCs were used for flow cytometry to define the cellular composition of the samples.Results. Two hundred twenty-five differentially expressed genes (P < 0.05) that distinguished patients with systemic JIA from healthy controls (n ‫؍‬ 30) were identified. Clustering analysis indicated that expression patterns correlated with serum ferritin levels. Three main clusters distinguished systemic JIA patients with highly elevated ferritin levels (including those with subclinical macrophage activation syndrome) from those with normal or only moderately elevated ferritin levels. The first cluster comprised genes involved in the synthesis of hemoglobins and structural proteins of erythrocytes. This transcriptional profile was consistent with immature nucleated red blood cells, likely reflective of high red blood cell turnover. Also included were transcripts indicating immature granulocytes. The second cluster was enriched for genes involved in cell cycle regulation. The third cluster was enriched for genes involved in innate immune responses, including those involved in the negative regulation of Toll-like receptor/ interleukin-1 receptor-triggered inflammatory cascades and markers of the alternative pathway of macrophage differentiation. Additional differentially expressed genes of interest were those involved in the cytolytic pathway, including SH2D1A and Rab27a. Conclusion. These data indicate that gene expression profiling can be a useful tool for identifying early macrophage activation syndrome in patients with systemic JIA.At onset, systemic juvenile idiopathic arthritis (JIA), which constitutes ϳ10% of all cases of JIA, is distinguished from other forms of JIA by the prominence of extraarticular features, such as spiking fevers,

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Microglial cells and peritoneal macrophages release activin A upon stimulation with Toll-like receptor agonists

Cited by 47 publications

References 34 publications

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

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

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

Gene expression profiling of peripheral blood from patients with untreated new‐onset systemic juvenile idiopathic arthritis reveals molecular heterogeneity that may predict macrophage activation syndrome

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