title: Signaling mechanism for Aspergillus fumigatus tolerance in corneal fibroblasts induced by LPS pretreatment.
abstract: 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-independent Toll-IL-1 receptor domain-containing adaptor inducing IFN-β pathway was increased in THSFs pretreated with LPS. These results indicated that TLR4 mediates attenuated cytokine production induced by LPS pretreatment, and regulation of MyD88-dependent and MyD88-independent pathways may contribute to the development of A. fumigatus hyphae tolerance in LPS-pretreated THSFs.
authors.affiliation: Department of Ophthalmology, Qilu Hospital of Shandong University, Jinan, Shandong, PR China.
authors.forename: Leyi
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Ophthalmology, Qilu Hospital of Shandong University, Jinan, Shandong, PR China.
authors.forename: Hongling
authors.initials: H
authors.lastname: Yang
authors.affiliation: Department of Ophthalmology, Qilu Hospital of Shandong University, Jinan, Shandong, PR China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Ophthalmology, Qilu Hospital of Shandong University, Jinan, Shandong, PR China.
authors.forename: Fu-Shin X
authors.initials: FS
authors.lastname: Yu
authors.affiliation: Department of Ophthalmology, Qilu Hospital of Shandong University, Jinan, Shandong, PR China xywu8868@163.com.
authors.forename: Xinyi
authors.initials: X
authors.lastname: Wu
mesh_terms: D001228:Aspergillosis / Q000276:immunology* / Q000382:microbiology; D001232:Aspergillus fumigatus / Q000276:immunology*; D002460:Cell Line; D003315:Cornea / Q000473:pathology*; D016207:Cytokines / Q000378:metabolism; D005347:Fibroblasts / Q000473:pathology*; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects*; D007634:Keratitis / Q000188:drug therapy / Q000382:microbiology; D008070:Lipopolysaccharides / Q000494:pharmacology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects*; D051195:Toll-Like Receptor 2 / Q000235:genetics; D051197:Toll-Like Receptor 4 / Q000235:genetics
chemical_list: D016207:Cytokines; D008070:Lipopolysaccharides; C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; C495342:TLR2 protein, human; C495345:TLR4 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D020928:Mitogen-Activated Protein Kinases
keywords: Aspergillus fumigatus; MyD88-dependent pathways; MyD88-independent pathway; Toll-like receptors; lipopolysaccharide
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