TLR8-mediated activation of human monocytes inhibits TL1A expression.
TLR play important roles in inflammation and innate immune response to pathogens. TLR8 recognizes ssRNA and induces NF-kappaB via MyD88 signaling. TL1A is a member of the TNF superfamily that markedly enhances IFN-gamma 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-gamma production by the CD4(+) T cells. Furthermore, we demonstrate that IFN-alpha 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.
Saruta
Masayuki
M
Inflammatory Bowel Disease Research Center, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
Michelsen
Kathrin S
KS
Thomas
Lisa S
LS
Yu
Qi T
QT
Landers
Carol J
CJ
Targan
Stephan R
SR
D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D018920:Coculture Techniques; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D009000:Monocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D017452:Receptors, IgG / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D051200:Toll-Like Receptor 8 / Q000819:agonists / Q000235:genetics*; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15 / Q000235:genetics* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D007093:Imidazoles; D015850:Interleukin-6; D017452:Receptors, IgG; C495349:TLR8 protein, human; C117026:TNFSF15 protein, human; D051200:Toll-Like Receptor 8; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D007371:Interferon-gamma; C402365:resiquimod