title: Hypoxia attenuates inflammatory mediators production induced by Acanthamoeba via Toll-like receptor 4 signaling in human corneal epithelial cells.
abstract: Acanthamoeba keratitis (AK) is a vision-threatening corneal infection that is intimately associated with contact lens use which leads to hypoxic conditions on the corneal surface. However, the effect of hypoxia on the Acanthamoeba-induced host inflammatory response of corneal epithelial cells has not been studied. In the present study, we investigated the effect of hypoxia on the Acanthamoeba-induced production of inflammatory mediators interleukin-8 (IL-8) and interferon-β (IFN-β) in human corneal epithelial cells and then evaluated its effects on the Toll-like receptor 4 (TLR4) signaling, including TLR4 and myeloid differentiation primary response gene (88) (MyD88) expression as well as the activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and extracellular signal-regulated kinases 1/2 (ERK1/2). We then studied the effect of hypoxia on a TLR4-specific inflammatory response triggered by the TLR4 ligand lipopolysaccharide (LPS). Our data showed that hypoxia significantly decreased the production of IL-8 and IFN-β. Furthermore, hypoxia attenuated Acanthamoeba-triggered TLR4 expression as well as the activation of NF-κB and ERK1/2, indicating that hypoxia abated Acanthamoeba-induced inflammatory responses by affecting TLR4 signaling. Hypoxia also inhibited LPS-induced IL-6 and IL-8 secretion, myeloid differentiation primary response gene (88) MyD88 expression and NF-κB activation, confirming that hypoxia suppressed the LPS-induced inflammatory response by affecting TLR4 signaling. In conclusion, our results demonstrated that hypoxia attenuated the host immune and inflammatory response against Acanthamoeba infection by suppressing TLR4 signaling, indicating that hypoxia might impair the host cell's ability to eliminate the Acanthamoeba invasion and that hypoxia could enhance cell susceptibility to Acanthamoeba infection. These results may explain why contact lens use is one of the most prominent risk factors for AK.
authors.affiliation: Department of Ophthalmology, Qilu Hospital, Shandong University, 107#, Wenhua Xi Road, Jinan 250012, PR China.
authors.forename: Hong
authors.initials: H
authors.lastname: Pan
authors.forename: Xinyi
authors.initials: X
authors.lastname: Wu
mesh_terms: D000048:Acanthamoeba; D015823:Acanthamoeba Keratitis / Q000276:immunology*; D015687:Cell Hypoxia; D002478:Cells, Cultured; D003261:Contact Lenses / Q000009:adverse effects; D015536:Down-Regulation; D006801:Humans; D000860:Hypoxia / Q000276:immunology* / Q000469:parasitology*; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000378:metabolism; D016899:Interferon-beta / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D016209:Interleukin-8 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D020935:MAP Kinase Signaling System; D053594:Myeloid Differentiation Factor 88 / Q000096:biosynthesis; D016328:NF-kappa B / Q000378:metabolism; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*; D000093242:Interleukin-6 Inhibitors
chemical_list: D018836:Inflammation Mediators; D016899:Interferon-beta; D015850:Interleukin-6; D016209:Interleukin-8; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D051197:Toll-Like Receptor 4; D000093242:Interleukin-6 Inhibitors; C507779:MYD88 protein, human; C495345:TLR4 protein, human