The TLR7 Ligand 9-Benzyl-2-Butoxy-8-Hydroxy Adenine Inhibits IL-17 Response by Eliciting IL-10 and IL-10-Inducing Cytokines

This study evaluates the ability of a novel TLR7 ligand (9-benzyl-2-butoxy-8-hydroxy adenine, called SA-2) to affect IL-17 response. The SA-2 activity on the expression of IL-17A and IL-17-related molecules was evaluated in acute and chronic models of asthma as well as in in vivo and in vitro alpha-galactosyl ceramide (alpha-GalCer)-driven systems. SA-2 prepriming reduced neutrophils in bronchoalveolar lavage fluid and decreased methacoline-induced airway hyperresponsiveness in murine asthma models. These results were associated with the reduction of IL-17A (and type 2 cytokines) as well as of molecules favoring Th17 (and Th2) development in lung tissue. The IL-17A production in response to alpha-GalCer by spleen mononuclear cells was inhibited in vitro by the presence of SA-2. Reduced IL-17A (as well as IFN-gamma and IL-13) serum levels in mice treated with alpha-GalCer plus SA-2 were also observed. The in vitro results indicated that IL-10 produced by B cells and IL-10-promoting molecules such as IFN-alpha and IL-27 by dendritic cells are the major player for SA-2-driven IL-17A (and also IFN-gamma and IL-13) inhibition. The in vivo experiments with anti-cytokine receptor Abs provided evidence of an early IL-17A inhibition essentially due to IL-10 produced by resident peritoneal cells and of a delayed IL-17A inhibition sustained by IFN-alpha and IL-27, which in turn drive effector T cells to IL-10 production. These findings suggest that such TLR7 agonist downregulating Th17 (as well as Th2) response has to be considered a valid candidate for novel vaccine formulations in allergy. The Journal of Immunology, 2011, 186: 4707-4715.