title: Endothelin-1 induces interleukin-18 expression in human osteoblasts.
abstract: OBJECTIVE
  Both endothelin-1 (ET-1) and interleukin (IL)-18 induce osteoblast proliferation under normal and pathophysiological conditions. In the present study, we explored the interaction between the two proteins by examining the effect of ET-1 on IL-18 expression in cultured human osteoblasts.
  
  
  METHODS
  Human osteoblasts were treated with ET-1 in different concentrations (1, 10, 20, 40, or 50 nM) for different length of time (1, 6, 12, 18, or 24 h) in the presence or absence of ET A receptor (ETAR) blocker BQ123, ET B receptor (ETBR) blocker BQ788, p38 mitogen-activated protein kinase (MAPK) siRNA, or different kinase inhibitors.
  
  
  RESULTS
  ET-1 increased the IL-18 mRNA level in a statistically significant dose- and time-dependent manner within 18 h, which was reflected in dose-dependent induction of the human IL-18 gene promoter activity and IL-18 protein/secreted protein expression. BQ123 (1μ M) and p38 MAPK siRNA and inhibitor PD169316 (25 μM) completely abolished the promoting effect of ET-1 on IL-18 expression. [(3)H]thymidine incorporation assays showed that ET-1 lost a major part (57%) of its promoting effect on osteoblast proliferation when the endogenous IL-18 expression in osteoblasts was knocked down by 75%.
  
  
  CONCLUSIONS
  ET-1 induces IL-18 expression in human osteoblasts at the gene promoter/transcription level via ETAR by a p38 MAPK-dependent mechanism, and that IL-18 mediates a major part of ET-1 induced osteoblast proliferation. This study provides the first evidence of interaction between ET-1 and IL-18 in osteoblast and adds new insights into bone physiology and pathophysiology.
authors.affiliation: Department of Stomatology, Xiangya Hospital, Central South University, Changsha 410008, Hunan, PR China.
authors.forename: Xiaohuan
authors.initials: X
authors.lastname: Zhong
authors.affiliation: Department of Stomatology, Xiangya Hospital, Central South University, Changsha 410008, Hunan, PR China.
authors.forename: Huixin
authors.initials: H
authors.lastname: Wang
authors.affiliation: Dental Center, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan, PR China. Electronic address: huangsg1964@126.com.
authors.forename: Shenggao
authors.initials: S
authors.lastname: Huang
mesh_terms: D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D019332:Endothelin-1 / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D020382:Interleukin-18 / Q000378:metabolism*; D008301:Maleimides / Q000494:pharmacology; D009025:Morpholines / Q000494:pharmacology; D010006:Osteoblasts / Q000378:metabolism*; D010456:Peptides, Cyclic / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D017466:Receptors, Endothelin / Q000187:drug effects*; D013997:Time Factors; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
chemical_list: C465664:2-(1-(3-dimethylaminopropyl)-5-methoxyindol-3-yl)-3-(1H-indol-3-yl)maleimide; D002867:Chromones; D019332:Endothelin-1; D007093:Imidazoles; D007211:Indoles; D020382:Interleukin-18; D008301:Maleimides; D009025:Morpholines; D010456:Peptides, Cyclic; D034741:RNA, Small Interfering; D017466:Receptors, Endothelin; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D048051:p38 Mitogen-Activated Protein Kinases; C408604:2-(4-nitrophenyl)-4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-imidazole; C072247:cyclo(Trp-Asp-Pro-Val-Leu)
keywords: Cell proliferation; Endothelin A receptor; Endothelin-1; Interleukin-18; Osteoblast; p38 mitogen-activated protein kinase