Activin and transforming growth factor-β signaling pathways are activated after allergen challenge in mild asthma

Kariyawasam, Harsha H.; Pégorier, Sophie; Barkans, J.; Xanthou, Georgina; Aizen, Maxine; Sun, Yu; Kay, A. B.; Lloyd, Clare M.; Robinson, Douglas S.

doi:10.1016/j.jaci.2009.06.022

Cited by 69 publications

(83 citation statements)

References 33 publications

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“…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). We believe that the discordance between the results presented in the latter study and ours may be due to the differences in the experimental set up employed (i.e., distinct species and cell types, stimulation protocol, and time point of Articles Petrakou et al…”

Section: Discussionmentioning

confidence: 99%

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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: 99%

“…The optimal doses of LPS, PHA, and r-activin-A were determined by dose-response studies (data not shown). A similar dose (50 ng/ml) of activin-A has been used in several studies for the examination of responses mediated by immune cells (35,41,42).…”

Section: In Vitro Stimulation Of Neonatal Peripheral Blood Leukocytesmentioning

confidence: 99%

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

et al. 2013

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“…Our previous studies, using an ovalbumin-induced mouse model of allergic airway inflammation, have revealed that activin-A protects against experimental asthma partly through the generation of Foxp3 − IL-10 + Treg cells (18). Moreover, we and others have shown that activin-A and its signaling components are induced in T cells infiltrating the lungs of asthmatics and become further up-regulated following in vivo inhalational allergen challenge (19,20). Still, the effects of activin-A on the generation of human Treg cells suppressive against allergic responses, and the molecular mechanisms involved, remain unexplored.…”

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confidence: 93%

Activin-A co-opts IRF4 and AhR signaling to induce human regulatory T cells that restrain asthmatic responses

Tousa

Semitekolou

Morianos

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Type 1 regulatory T (Tr1) cells play a pivotal role in restraining human T-cell responses toward environmental allergens and protecting against allergic diseases. Still, the precise molecular cues that underlie their transcriptional and functional specification remain elusive. Here, we show that the cytokine activin-A instructs the generation of CD4 + T cells that express the Tr1-cell-associated molecules IL-10, inducible T-Cell costimulator (ICOS), lymphocyte activation gene 3 protein (LAG-3), and CD49b, and exert strongly suppressive functions toward allergic responses induced by naive and in vivo-primed human T helper 2 cells. Moreover, mechanistic studies reveal that activin-A signaling induces the activation of the transcription factor interferon regulatory factor (IRF4), which, along with the environmental sensor aryl hydrocarbon receptor, forms a multipartite transcriptional complex that binds in IL-10 and ICOS promoter elements and controls gene expression in human CD4 + T cells. In fact, IRF4 silencing abrogates activin-A-driven IL10 and ICOS up-regulation and impairs the suppressive functions of human activin-A-induced Tr1-like (act-A-iTr1) cells. Importantly, using a humanized mouse model of allergic asthma, we demonstrate that adoptive transfer of human act-A-iTr1 cells, both in preventive and therapeutic protocols, confers significant protection against cardinal asthma manifestations, including pulmonary inflammation. Overall, our findings uncover an activin-A-induced IRF4-aryl hydrocarbon receptor (AhR)-dependent transcriptional network, which generates suppressive human Tr1 cells that may be harnessed for the control of allergic diseases.cytokines | allergic inflammation | immune regulation | activin-A | human T regulatory cells

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“…In fact, activin A has been involved in different clinical inflammatory conditions such as rheumatoid arthritis, inflammatory bowel disease, allergic airway inflammation and clinical sepsis condition. [18][19][20][21][22] This review examines the recent findings about the role of activin signaling on immune cells, including the crosstalk with the Toll-like receptor (TLR) pathway, the impact in hematopoiesis and lymphocyte development, the effects on dendritic cell (DC) maturation, its emergence as a novel T helper cell type 2 (Th2) cytokine and its recent role in the induction of regulatory T-cell subsets. Collectively, these data support the role of activins/inhibins as key orchestrators of the immune system in homeostasis and inflammation.…”

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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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Activin and transforming growth factor-β signaling pathways are activated after allergen challenge in mild asthma

Abstract: Background-Both transforming growth factor (TGF)-β 1 and activin-A have been implicated in airway remodelling in asthma but the modulation of their specific signalling pathways after disease activation remains undefined.

Cited by 69 publications

References 33 publications

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

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

Activin-A co-opts IRF4 and AhR signaling to induce human regulatory T cells that restrain asthmatic responses

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

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