INTRODUCTION: Sarcoidosis is an inflammatory disease of unknown etiology. However, an infectious cause has been proposed suggesting a role for pattern-recognition receptors, such as Toll-like receptors (TLRs) and nucleotide-binding domain, leucin-rich repeat containing family proteins (NLRs), in the pathogenesis. OBJECTIVE: Our aim was to investigate whether differences in TLR2 and TLR4 expression, and the response to TLR2, TLR4, and NOD2 stimulation, are associated with sarcoidosis. MATERIALS AND METHODS: Blood mononuclear cells from sarcoidosis patients (n=24) and healthy subjects (n=19) were incubated with the TLR2 ligands PGN and Pam3CSK4, the TLR4 ligand LPS, the NOD2 ligand MDP, or medium alone. After 16 h, monocyte TLR2 and TLR4 expression and cyto-kine secretion, including TNFα, IL-1β, IL-6, IL-8, IL-10, and IL-12p70, were measured using flow cytometry and cytometric bead array. RESULTS: TLR2 and TLR4 expression at baseline was significantly higher in patients. Combined TLR2 and NOD2 stimulation induced a four-fold higher secretion of TNFα and a 13-fold higher secretion of IL-1 β in patients. Additionally, there was a synergistic effect of TLR2 with NOD2 stimulation on induction of IL-1 β in patients, whereas IL-10 was synergistically induced in healthy subjects. CONCLUSION: Increased TLR expression and enhanced secretion of pro-inflammatory cytokines after combined TLR2 and NOD2 stimulation may be related to the pathogenesis of sarcoidosis.