title: Elevated toll-like receptor 3 inhibits pancreatic β-cell proliferation through G1 phase cell cycle arrest.
abstract: Activation of the innate and acquired immune systems plays an important role in chronic inflammatory diseases and conditions such as obesity, insulin resistance, type 2 diabetes mellitus and atherosclerosis, with additional roles in regulation of cell proliferation and survival. Here, we provide evidence that TLR3 can respond to nutrient signals and induce loss of β-cell mass through induction of G1 cycle arrest. Activation of TLR3 by polyinosinic-polycytidylic acid [poly (I:C)] was shown to trigger the decline of cyclin D1/2 protein levels in pancreatic β-cell lines, which could be reversed by the proteasome inhibitor MG132. P38 was also found to interfere with this degradation which may be associated with G1 cycle arrest. Moreover, inhibitory effects of TLR3 on β-cell growth were supported by gene silencing of TRIF, which could inhibit p38 activity in response to poly (I:C) stimuli. These results support a role for TLR3 in β-cell mass loss in metabolic surplus and raise the possibility that TRIF/p38 signaling may be involved in G1 phase cycle arrest through ubiquitin/proteasome-dependent degradation of cyclin D.
authors.affiliation: Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing 210029, PR China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Wang
authors.forename: HuiWen
authors.initials: H
authors.lastname: Wu
authors.forename: LiLi
authors.initials: L
authors.lastname: Gao
authors.forename: ShanShan
authors.initials: S
authors.lastname: Chen
authors.forename: LiZe
authors.initials: L
authors.lastname: Gu
authors.forename: ZhengZheng
authors.initials: Z
authors.lastname: Ding
authors.forename: Jun
authors.initials: J
authors.lastname: Guo
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019938:Cyclin D1 / Q000378:metabolism; D056742:Cyclin D2 / Q000378:metabolism; D004195:Disease Models, Animal; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D005947:Glucose / Q000633:toxicity; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D008055:Lipids / Q000633:toxicity; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D008954:Models, Biological; D019308:Palmitic Acid / Q000494:pharmacology; D011070:Poly I-C / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D014176:Protein Biosynthesis / Q000187:drug effects; D059748:Proteolysis / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D051196:Toll-Like Receptor 3 / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D019938:Cyclin D1; D056742:Cyclin D2; D005947:Glucose; D008055:Lipids; D019308:Palmitic Acid; D011070:Poly I-C; D046988:Proteasome Endopeptidase Complex; D051196:Toll-Like Receptor 3; D048051:p38 Mitogen-Activated Protein Kinases; C476286:Ticam1 protein, mouse; C519703:TLR3 protein, mouse
keywords: Arrest; Glucolipotoxicity; Proliferation; TLR3; β-cell