title: IGF-1 induced HIF-1α-TLR9 cross talk regulates inflammatory responses in glioma.
abstract: The insulin-like growth factor (IGF-1) induces hypoxia inducible factor (HIF-1α) regulated genes in glioblastoma multiforme (GBM). As HIF-1α links inflammatory and oncogenic pathways in GBM, we investigated whether IGF-1 affects HIF-1α to regulate inflammatory response in glioma cells under normoxia. IGF-1 induced Ras and Calmodulin-dependent kinase II (CaMKII) regulated HIF-1α transcriptional activity in glioma cells. Increase in HIF-1α was concurrent with decreased Toll-like receptor (TLR9) and CXCR4 expression and elevated suppressor of cytokine signaling (SOCS3) levels. Interestingly, while synthetic CpG containing oligodeoxynucleotide TLR9 agonist (CpG DNA) decreased IGF-1 mediated increase in HIF-1α activity, siRNA mediated knockdown of HIF-1α decreased TLR9 levels. This suggested that IGF-1 induced HIF-1α-TLR9 axis is regulated by both positive and negative feedback loops. Importantly, TLR9 agonist reversed the effect of IGF-1 on CXCR4 and SOCS3 expression. While knockdown of HIF-1α abrogated IGF-1 mediated increase in SOCS3 it elevated IGF-1 induced decrease in CXCR4 levels. Thus HIF-1α positively and negatively regulates SOCS3 and CXCR4 expression respectively, in glioma cells. Though TLR9 agonist had no additive effect on IGF-1 mediated increase in pro-inflammatory cytokines IL-1β, IL-6 and IL-8, treatment with TLR9 agonist alone elevated expression of these pro-inflammatory cytokines. Our studies indicate that a complex HIF-1α-TLR9 cross-talk sustains a self-regulating cycle of inflammatory response through intrinsic negative and positive feedback mechanisms.
authors.affiliation: National Brain Research Centre, Manesar, Haryana 122 050, India. sancharisinha79@gmail.com
authors.forename: Sanchari
authors.initials: S
authors.lastname: Sinha
authors.forename: Nitin
authors.initials: N
authors.lastname: Koul
authors.forename: Deobrat
authors.initials: D
authors.lastname: Dixit
authors.forename: Vivek
authors.initials: V
authors.lastname: Sharma
authors.forename: Ellora
authors.initials: E
authors.lastname: Sen
mesh_terms: D015153:Blotting, Western; D045744:Cell Line, Tumor; D016207:Cytokines / Q000032:analysis / Q000096:biosynthesis; D025461:Feedback, Physiological; D005260:Female; D015870:Gene Expression; D020868:Gene Silencing / Q000187:drug effects; D017930:Genes, Reporter; D005909:Glioblastoma / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D007334:Insulin-Like Growth Factor I / Q000378:metabolism* / Q000494:pharmacology; D008156:Luciferases / Q000032:analysis; D010100:Oxygen; D040081:Protein Array Analysis; D034741:RNA, Small Interfering / Q000494:pharmacology; D015398:Signal Transduction / Q000235:genetics* / Q000276:immunology; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism; D051217:Toll-Like Receptor 9 / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D016207:Cytokines; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D034741:RNA, Small Interfering; C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; C495371:TLR9 protein, human; D051217:Toll-Like Receptor 9; D007334:Insulin-Like Growth Factor I; D008156:Luciferases; D018631:ras Proteins; D010100:Oxygen