title: β-defensin-3 negatively regulates TLR4-HMGB1 axis mediated HLA-G expression in IL-1β treated glioma cells.
abstract: The non-classical HLA class I antigen HLA-G contributes to immune escape mechanisms in glioblastoma multiforme (GBM). We have previously shown that IL-1β-HIF-1α axis connects inflammatory and oncogenic pathways in GBM. In this study, we investigated the role of IL-1β induced inflammation in regulating HLA-G expression. IL-1β increased HLA-G and Toll like receptor 4 (TLR4) expression in a HIF-1α dependent manner. Inhibition of TLR4 signaling abrogated IL-1β induced HLA-G. IL-1β increased HMGB1 expression and its interaction with TLR4. Inhibition of HMGB1 inhibited TLR4 and vice versa suggesting the existence of HMGB1-TLR4 axis in glioma cells. Interestingly, HMGB1 inhibition prevented IL-1β induced HLA-G expression. Elevated levels of HMGB1 and β-defensin 3 were observed in GBM tumors. Importantly, β-defensin-3 prevented IL-1β induced HLA-G, TLR4, HMGB1 expression and release of pro-inflammatory mediators. Our studies indicate that β-defensin-3 abrogates IL-1β induced HLA-G expression by negatively affecting key molecules associated with its regulation.
authors.affiliation: National Brain Research Centre, Manesar, Haryana 122 050, India.
authors.forename: Piyushi
authors.initials: P
authors.lastname: Gupta
authors.forename: Sadashib
authors.initials: S
authors.lastname: Ghosh
authors.forename: Ashwat
authors.initials: A
authors.lastname: Nagarajan
authors.forename: Veer Singh
authors.initials: VS
authors.lastname: Mehta
authors.forename: Ellora
authors.initials: E
authors.lastname: Sen
mesh_terms: D045744:Cell Line, Tumor; D005910:Glioma / Q000378:metabolism / Q000473:pathology; D059951:HLA-G Antigens / Q000378:metabolism*; D024243:HMGB1 Protein / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D007150:Immunohistochemistry; D007249:Inflammation / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism / Q000494:pharmacology*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D023083:beta-Defensins / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D059951:HLA-G Antigens; D024243:HMGB1 Protein; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D053583:Interleukin-1beta; D034741:RNA, Small Interfering; D051197:Toll-Like Receptor 4; D023083:beta-Defensins