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Title

Activin A skews macrophage polarization by promoting a proinflammatory phenotype and inhibiting the acquisition of anti-inflammatory macrophage markers

AuthorsSierra-Filardi, Elena ; Puig-Kröger, Amaya ; Blanco, Francisco J. ; Nieto, Concha ; Bragado Herrero, Rafael; Palomero, M. Isabel; Bernabéu, Carmelo ; Vega, Miguel A. ; Corbí, Angel L.
KeywordsInflammation
Macrophagic
Profile expression
Issue Date12-May-2011
PublisherAmerican Society of Hematology
CitationBlood 117:5092-5101 (2011)
AbstractM-CSF favors the generation of folate receptor β–positive (FRβ+), IL-10–producing, immunosuppressive, M2-polarized macrophages [M2 (M-CSF)], whereas GM-CSF promotes a proinflammatory, M1-polarized phenotype [M1 (GM-CSF)]. In the present study, we found that activin A was preferentially released by M1 (GM-CSF) macrophages, impaired the acquisition of FRβ and other M2 (M-CSF)–specific markers, down-modulated the LPS-induced release of IL-10, and mediated the tumor cell growth–inhibitory activity of M1 (GM-CSF) macrophages, in which Smad2/3 is constitutively phosphorylated. The contribution of activin A to M1 (GM-CSF) macrophage polarization was evidenced by the capacity of a blocking anti–activin A antibody to reduce M1 (GM-CSF) polarization markers expression while enhancing FRβ and other M2 (M-CSF) markers mRNA levels. Moreover, an inhibitor of activin receptor-like kinase 4/5/7 (ALK4/5/7 or SB431542) promoted M2 (M-CSF) marker expression but limited the acquisition of M1 (GM-CSF) polarization markers, suggesting a role for Smad2/3 activation in macrophage polarization. In agreement with these results, expression of activin A and M2 (M-CSF)–specific markers was oppositely regulated by tumor ascites. Therefore, activin A contributes to the proinflammatory macrophage polarization triggered by GM-CSF and limits the acquisition of the anti-inflammatory phenotype in a Smad2-dependent manner. Our results demonstrate that activin A–initiated Smad signaling skews macrophage polarization toward the acquisition of a proinflammatory phenotype.
Description6 Figures. The online version of this article contains a data supplement. The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked ‘‘advertisement’’ in accordance with 18 USC section 1734.
Publisher version (URL)http://bloodjournal.hematologylibrary.org/content/117/19/5092.abstract
URI10261/42552
DOIhttp://dx.doi.org/10.1182/blood-2010-09-306993
ISSN0006-4971
E-ISSN1528-0020
Appears in Collections:(CIB) Artículos
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