%0 Journal Article
%T T-cell activation is enhanced by targeting IL-10 cytokine production in toll-like receptor- stimulated macrophages
%A Walk RM
%A Elliot ST
%A Blanco FC
%A Snyder JA
%A Jacobi AM
%A Rose SD
%A Behlke MA
%A Salem AK
%A Vukmanovic S
%A Sandler AD
%J ImmunoTargets and Therapy
%D 2012
%I 
%R http://dx.doi.org/10.2147/ITT.S32615
%X ell activation is enhanced by targeting IL-10 cytokine production in toll-like receptor- stimulated macrophages Original Research (737) Total Article Views Authors: Walk RM, Elliot ST, Blanco FC, Snyder JA, Jacobi AM, Rose SD, Behlke MA, Salem AK, Vukmanovic S, Sandler AD Published Date November 2012 Volume 2012:1 Pages 13 - 23 DOI: http://dx.doi.org/10.2147/ITT.S32615 Received: 08 August 2012 Accepted: 02 October 2012 Published: 27 November 2012 Ryan M Walk,1,2 Steven T Elliott,2 Felix C Blanco,2 Jason A Snyder,2 Ashley M Jacobi,3 Scott D Rose,3 Mark A Behlke,3 Aliasger K Salem,4 Stanislav Vukmanovic,2 Anthony D Sandler2 1Department of Surgery, Walter Reed Army Medical Center, Washington, DC, USA; 2Sheikh Zayed Institute for Pediatric Surgical Innovation, Children's National Medical Center, Washington, DC, USA; 3Integrated DNA Technologies, Coralville, IA, USA; 4Division of Pharmaceutics, University of Iowa, Iowa City, IA, USA Abstract: Toll-like receptor (TLR) agonists represent potentially useful cancer vaccine adjuvants in their ability to stimulate antigen-presenting cells (APCs) and subsequently amplify the cytotoxic T-cell response. The purpose of this study was to characterize APC responses to TLR activation and to determine the subsequent effect on lymphocyte activation. We exposed murine primary bone marrow-derived macrophages to increasing concentrations of agonists to TLRs 2, 3, 4, and 9. This resulted in a dose-dependent increase in production of not only tumor necrosis factor¨Calpha (TNF-¦Á), a surrogate marker of the proinflammatory response, but also interleukin 10 (IL-10), a well-described inhibitory cytokine. Importantly, IL-10 secretion was not induced by low concentrations of TLR agonists that readily produced TNF-¦Á. We subsequently stimulated lymphocytes with anti-CD3 antibody in the presence of media from macrophages activated with higher doses of TLR agonists and observed suppression of interferon gamma release. Use of both IL-10 knockout macrophages and IL-10 small-interfering RNA (siRNA) ablated this suppressive effect. Finally, IL-10 siRNA was successfully used to suppress CpG-induced IL-10 production in vivo. We conclude that TLR-mediated APC stimulation can induce a paradoxical inhibitory effect on T-cell activation mediated by IL-10.
%K toll-like receptors
%K innate immunity
%K IL-10
%U https://www.dovepress.com/t-cell-activation-is-enhanced-by-targeting-il-10-cytokine-production-i-peer-reviewed-article-ITT