TLR8-mediated activation of human monocytes inhibits TL1A expression

Abstract

TLR play important roles in inflammation and innate immune response to pathogens. TLR8 recognizes ssRNA and induces NF-κB via MyD88 signaling. TL1A is a member of the TNF superfamily that markedly enhances IFN-γ production by IL-12/IL-18-stimulated peripheral and mucosal CD4+ T cells. TL1A expression is increased in the mucosa of patients with inflammatory bowel disease and is considered a key mediator of Crohn's disease (CD). We have previously shown that TL1A is strongly induced by immune complexes (IC) but not TLR ligands in antigen-presenting cells. However, a potential interaction between these pro-inflammatory signaling pathways has not been investigated. IC-induced TL1A expression of monocytes was potently inhibited by a TLR8 or TLR7/8 ligand (R848) in a dose-dependent manner. Furthermore, when co-cultured with CD4+ T cells, TLR8 ligands inhibited TL1A production, resulting in almost complete inhibition of IFN-γ production by the CD4+ T cells. Furthermore, we demonstrate that IFN-α is not required for this suppressive effect by TLR8 signaling. Our data demonstrate for the first time a direct interaction between TLR and TL1A signaling pathways. TLR8 activation may be an important, novel pathway for targeted treatment of Th1-mediated diseases, such as CD. © 2009 Wiley-VCH Verlag GmbH & Co. KGaA.