Redox-based control of synergy and antagonism among TLRs modulates cytokine production by monocytes
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1
IRCCS AOU San Martino-IST, Italy
In human monocytes, single stimulation of different TLRs results in induction of IL-1b and of cytokines downstream of it. The process is tightly regulated by redox signaling. Here we show that the simultaneous administration of agonists of TLR 2, 4 and 7, at doses providing optimal monocyte activation when used individually, strongly enhances IL-1b but severely impairs IL-1Ra and IL-6 secretion and induces oxidative stress. Antioxidants restore IL-1Ra and IL-6 secretion, demonstrating the functional link between generation of oxidative stress and impairment of secretion of cytokines downstream of IL-1. When TLRs are concomitantly triggered by lower doses of the three agonists, which are unable to induce monocyte activation if provided individually, oxidative stress is prevented and cytokine secretion is maintained. Thus, multiple triggering of TLRs and sustained doses of single agonists concur to the loss of redox control and the consequent block of secretion of cytokines downstream of IL-1. In conclusion, we have identify a novel redox-mediated mechanism responsible for the correct development of TLR-triggered inflammatory response. This mechanism provides a molecular basis to the unbalance between pro- and anti-inflammatory circuits occurring in pathologic conditions such as sepsis and chronic diseases, and open the way to new strategies for controlling inflammation.
Keywords:
Inflammation,
redox signaling,
TLRs (Toll-like receptors),
Interleukin-1,
citokine
Conference:
15th International Congress of Immunology (ICI), Milan, Italy, 22 Aug - 27 Aug, 2013.
Presentation Type:
Abstract
Topic:
Innate immunity
Citation:
Lavieri
R,
Piccioli
P,
Delfino
L,
Repaci
E,
Castellani
P and
Rubartelli
A
(2013). Redox-based control of synergy and antagonism among TLRs modulates cytokine production by monocytes.
Front. Immunol.
Conference Abstract:
15th International Congress of Immunology (ICI).
doi: 10.3389/conf.fimmu.2013.02.01052
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Received:
30 Jun 2013;
Published Online:
22 Aug 2013.
*
Correspondence:
Dr. Rosa Lavieri, IRCCS AOU San Martino-IST, Genova, Italy, rosalavieri@msn.com