Signaling mechanism for Aspergillus fumigatus tolerance in corneal fibroblasts induced by LPS pretreatment.

TLRs, particularly TLR2 and TLR4, play primary roles in inflammatory responses triggered by Aspergillus fumigatus and lead to the activation of signaling pathways that initiate host defense responses. We previously demonstrated that LPS, a ligand of TLR4, can induce tolerance of A. fumigatus hyphae in telomerase-immortalized human stroma fibroblasts (THSFs). In the present study we investigated the role of TLR4, TLR2 and their downstream signaling pathways in this activity. The THSFs were pretreated with low-dose LPS and then exposed to A. fumigatus hyphae. It was demonstrated that enhanced expression of TLR4, but not of TLR2, was associated with LPS pretreatment. Inhibition of TLR4 with monoclonal Ab prevented reduction of pro-inflammatory cytokine secretion in LPS-pretreated THSFs. Pretreatment of THSFs with low-dose LPS caused an impaired response of the MyD88-dependent classical and MAPK signaling pathway upon subsequent A. fumigatus challenge, while expression of signaling molecules in the MyD88-inde...