Toll-like receptors (TLRs) play key roles in detecting pathogens and initiating inflammatory responses that, subsequently, prime specific adaptive responses. Several mechanisms control TLR activity to avoid excessive inflammation and consequent immunopathology, including the anti-inflammatory cytokine IL-10. Recently, several TLR-responsive microRNAs (miRs) have also been proposed as potential regulators of this signaling pathway, but their functional role during the inflammatory response still is incompletely understood. In this study, we report that, after LPS engagement, monocytes up-regulate miR- 146b via an IL-10-mediated STAT3-dependent loop. We show evidence thatmiR-146b modulates the TLR4 signaling pathway by direct targeting of multiple elements, including the LPS receptor TLR4 and the key adaptor/signaling proteinsmyeloid differentiation primary response (MyD88), interleukin-1 receptor-associated kinase 1 (IRAK-1), and TNF receptor-associated factor 6 (TRAF6). Furthermore, we demonstrate that the enforced expression of miR-146b in human monocytes led to a significant reduction in the LPS-dependent production of several proinflammatory cytokines and chemokines, including IL-6, TNF-α, IL-8, CCL3, CCL2, CCL7, and CXCL10. Our results thus identify miR-146b as an IL-10-responsive miR with an anti-inflammatory activity based on multiple targeting of components of the TLR4 pathway in monocytes and candidate miR-146b as a molecular effector of the IL-10 anti-inflammatory activity.

Negative regulation of Toll-like receptor 4 signaling by IL-10-dependent microRNA-146b / G. Curtale, M. Mirolo, T.A. Renzi, M. Rossato, F. Bazzoni, M. Locati. - In: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA. - ISSN 0027-8424. - 110:28(2013), pp. 11499-11504.

Negative regulation of Toll-like receptor 4 signaling by IL-10-dependent microRNA-146b

G. Curtale
Primo
;
M. Mirolo
Secondo
;
T.A. Renzi;M. Locati
Ultimo
2013

Abstract

Toll-like receptors (TLRs) play key roles in detecting pathogens and initiating inflammatory responses that, subsequently, prime specific adaptive responses. Several mechanisms control TLR activity to avoid excessive inflammation and consequent immunopathology, including the anti-inflammatory cytokine IL-10. Recently, several TLR-responsive microRNAs (miRs) have also been proposed as potential regulators of this signaling pathway, but their functional role during the inflammatory response still is incompletely understood. In this study, we report that, after LPS engagement, monocytes up-regulate miR- 146b via an IL-10-mediated STAT3-dependent loop. We show evidence thatmiR-146b modulates the TLR4 signaling pathway by direct targeting of multiple elements, including the LPS receptor TLR4 and the key adaptor/signaling proteinsmyeloid differentiation primary response (MyD88), interleukin-1 receptor-associated kinase 1 (IRAK-1), and TNF receptor-associated factor 6 (TRAF6). Furthermore, we demonstrate that the enforced expression of miR-146b in human monocytes led to a significant reduction in the LPS-dependent production of several proinflammatory cytokines and chemokines, including IL-6, TNF-α, IL-8, CCL3, CCL2, CCL7, and CXCL10. Our results thus identify miR-146b as an IL-10-responsive miR with an anti-inflammatory activity based on multiple targeting of components of the TLR4 pathway in monocytes and candidate miR-146b as a molecular effector of the IL-10 anti-inflammatory activity.
Cells, Cultured; Cytokines; Humans; Inflammation Mediators; Interleukin-10; MicroRNAs; Monocytes; Signal Transduction; Toll-Like Receptor 4; Multidisciplinary
Settore MED/04 - Patologia Generale
Article (author)
File in questo prodotto:
File Dimensione Formato  
PNAS-2013-Curtale-11499-504.pdf

accesso aperto

Tipologia: Publisher's version/PDF
Dimensione 694.23 kB
Formato Adobe PDF
694.23 kB Adobe PDF Visualizza/Apri
Pubblicazioni consigliate

Caricamento pubblicazioni consigliate

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/252122
Citazioni
  • ???jsp.display-item.citation.pmc??? 112
  • Scopus 198
  • ???jsp.display-item.citation.isi??? 197
social impact