title: Cross talk between vascular smooth muscle cells and monocytes through interleukin-1β/interleukin-18 signaling promotes vein graft thickening.
abstract: OBJECTIVE
  Interleukin (IL)-1β and IL-18 are key proinflammatory cytokines that play important roles in the pathophysiology of vein graft remodeling. However, the mechanism of IL-1β/IL-18 production and its role in the development of graft remodeling remain unclear.
  
  
  RESULTS
  IL-1β/IL-18 were rapidly expressed in venous interposition grafts. Vascular smooth muscle cell (VSMC) death and monocytic inflammasome activation occurred in grafted veins. Necrotic VSMCs induced the expression of IL-1β, IL-18, and other inflammasome-associated proteins in monocytes, which was partially inhibited by their antagonist, recombinant IL-1ra-Fc-IL-18bp. Activated monocytes stimulated proliferation of VSMCs by activating cell growth-related signaling molecules (AKT, STAT3, ERK1/2, and mTOR [AKT/protein kinase B, signal transducer and activator of transcription 3, extracellular signal-regulated kinase 1/2, mammalian target of rapamycin]) and increasing production of platelet-derived growth factor-bb; these effects were suppressed by IL-1ra-Fc-IL-18bp. Activated monocytes also promoted migration of VSMCs, which was independent of IL-1β/IL-18 signaling. Importantly, administration of IL-1ra-Fc-IL-18bp inhibited activation of cell growth-related signaling molecules, VSMC proliferation, and vein graft thickening in vivo.
  
  
  CONCLUSIONS
  Our work identified an interaction among necrotic VSMCs, monocytes, and viable VSMCs through IL-1β/IL-18 signaling, which might be exploited as a therapeutic target in vein graft remodeling.
authors.affiliation: From the Beijing An Zhen Hospital Affiliated the Capital Medical University, Department of Vascular Biology, Institute of Heart Lung and Blood Vessel Diseases, Beijing, China (P.L., Y.-l.L., Y.-n.W., C.-c.Z., X.A., C.-x.W., H.-t.S., J.D.); National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China (Z.-y.L.), National Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, China (M.-z.H., B.X.); and Department of Medicine, Baylor College of Medicine, Houston, TX (M.A.).
authors.forename: Ping
authors.initials: P
authors.lastname: Li
authors.affiliation: From the Beijing An Zhen Hospital Affiliated the Capital Medical University, Department of Vascular Biology, Institute of Heart Lung and Blood Vessel Diseases, Beijing, China (P.L., Y.-l.L., Y.-n.W., C.-c.Z., X.A., C.-x.W., H.-t.S., J.D.); National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China (Z.-y.L.), National Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, China (M.-z.H., B.X.); and Department of Medicine, Baylor College of Medicine, Houston, TX (M.A.).
authors.forename: Yu-lin
authors.initials: YL
authors.lastname: Li
authors.affiliation: From the Beijing An Zhen Hospital Affiliated the Capital Medical University, Department of Vascular Biology, Institute of Heart Lung and Blood Vessel Diseases, Beijing, China (P.L., Y.-l.L., Y.-n.W., C.-c.Z., X.A., C.-x.W., H.-t.S., J.D.); National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China (Z.-y.L.), National Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, China (M.-z.H., B.X.); and Department of Medicine, Baylor College of Medicine, Houston, TX (M.A.).
authors.forename: Zhen-ya
authors.initials: ZY
authors.lastname: Li
authors.affiliation: From the Beijing An Zhen Hospital Affiliated the Capital Medical University, Department of Vascular Biology, Institute of Heart Lung and Blood Vessel Diseases, Beijing, China (P.L., Y.-l.L., Y.-n.W., C.-c.Z., X.A., C.-x.W., H.-t.S., J.D.); National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China (Z.-y.L.), National Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, China (M.-z.H., B.X.); and Department of Medicine, Baylor College of Medicine, Houston, TX (M.A.).
authors.forename: Yi-na
authors.initials: YN
authors.lastname: Wu
authors.affiliation: From the Beijing An Zhen Hospital Affiliated the Capital Medical University, Department of Vascular Biology, Institute of Heart Lung and Blood Vessel Diseases, Beijing, China (P.L., Y.-l.L., Y.-n.W., C.-c.Z., X.A., C.-x.W., H.-t.S., J.D.); National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China (Z.-y.L.), National Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, China (M.-z.H., B.X.); and Department of Medicine, Baylor College of Medicine, Houston, TX (M.A.).
authors.forename: Cong-cong
authors.initials: CC
authors.lastname: Zhang
authors.affiliation: From the Beijing An Zhen Hospital Affiliated the Capital Medical University, Department of Vascular Biology, Institute of Heart Lung and Blood Vessel Diseases, Beijing, China (P.L., Y.-l.L., Y.-n.W., C.-c.Z., X.A., C.-x.W., H.-t.S., J.D.); National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China (Z.-y.L.), National Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, China (M.-z.H., B.X.); and Department of Medicine, Baylor College of Medicine, Houston, TX (M.A.).
authors.forename: Xi
authors.initials: X
authors.lastname: A
authors.affiliation: From the Beijing An Zhen Hospital Affiliated the Capital Medical University, Department of Vascular Biology, Institute of Heart Lung and Blood Vessel Diseases, Beijing, China (P.L., Y.-l.L., Y.-n.W., C.-c.Z., X.A., C.-x.W., H.-t.S., J.D.); National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China (Z.-y.L.), National Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, China (M.-z.H., B.X.); and Department of Medicine, Baylor College of Medicine, Houston, TX (M.A.).
authors.forename: Chun-xiao
authors.initials: CX
authors.lastname: Wang
authors.affiliation: From the Beijing An Zhen Hospital Affiliated the Capital Medical University, Department of Vascular Biology, Institute of Heart Lung and Blood Vessel Diseases, Beijing, China (P.L., Y.-l.L., Y.-n.W., C.-c.Z., X.A., C.-x.W., H.-t.S., J.D.); National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China (Z.-y.L.), National Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, China (M.-z.H., B.X.); and Department of Medicine, Baylor College of Medicine, Houston, TX (M.A.).
authors.forename: Hong-tao
authors.initials: HT
authors.lastname: Shi
authors.affiliation: From the Beijing An Zhen Hospital Affiliated the Capital Medical University, Department of Vascular Biology, Institute of Heart Lung and Blood Vessel Diseases, Beijing, China (P.L., Y.-l.L., Y.-n.W., C.-c.Z., X.A., C.-x.W., H.-t.S., J.D.); National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China (Z.-y.L.), National Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, China (M.-z.H., B.X.); and Department of Medicine, Baylor College of Medicine, Houston, TX (M.A.).
authors.forename: Mi-zhou
authors.initials: MZ
authors.lastname: Hui
authors.affiliation: From the Beijing An Zhen Hospital Affiliated the Capital Medical University, Department of Vascular Biology, Institute of Heart Lung and Blood Vessel Diseases, Beijing, China (P.L., Y.-l.L., Y.-n.W., C.-c.Z., X.A., C.-x.W., H.-t.S., J.D.); National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China (Z.-y.L.), National Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, China (M.-z.H., B.X.); and Department of Medicine, Baylor College of Medicine, Houston, TX (M.A.).
authors.forename: Bo
authors.initials: B
authors.lastname: Xie
authors.affiliation: From the Beijing An Zhen Hospital Affiliated the Capital Medical University, Department of Vascular Biology, Institute of Heart Lung and Blood Vessel Diseases, Beijing, China (P.L., Y.-l.L., Y.-n.W., C.-c.Z., X.A., C.-x.W., H.-t.S., J.D.); National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China (Z.-y.L.), National Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, China (M.-z.H., B.X.); and Department of Medicine, Baylor College of Medicine, Houston, TX (M.A.).
authors.forename: Mohammed
authors.initials: M
authors.lastname: Ahmed
authors.affiliation: From the Beijing An Zhen Hospital Affiliated the Capital Medical University, Department of Vascular Biology, Institute of Heart Lung and Blood Vessel Diseases, Beijing, China (P.L., Y.-l.L., Y.-n.W., C.-c.Z., X.A., C.-x.W., H.-t.S., J.D.); National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China (Z.-y.L.), National Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, China (M.-z.H., B.X.); and Department of Medicine, Baylor College of Medicine, Houston, TX (M.A.). jdu@bcm.edu.
authors.forename: Jie
authors.initials: J
authors.lastname: Du
mesh_terms: D000818:Animals; D017209:Apoptosis; D019917:Blood Vessel Prosthesis Implantation; D002339:Carotid Arteries / Q000601:surgery*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000494:pharmacology; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology* / Q000627:therapeutic use; D053590:Interleukin 1 Receptor Antagonist Protein / Q000494:pharmacology* / Q000627:therapeutic use; D020382:Interleukin-18 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D053583:Interleukin-1beta / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000166:cytology* / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D032389:Myocytes, Smooth Muscle / Q000166:cytology* / Q000378:metabolism; D009336:Necrosis; D058426:Neointima; D012333:RNA, Messenger / Q000096:biosynthesis; D011993:Recombinant Fusion Proteins / Q000494:pharmacology* / Q000627:therapeutic use; D012501:Saphenous Vein / Q000166:cytology; D015398:Signal Transduction / Q000502:physiology*; D013047:Specific Pathogen-Free Organisms; D014683:Vena Cava, Superior / Q000378:metabolism / Q000637:transplantation*
chemical_list: D017077:Culture Media, Conditioned; C000592496:IL-1ra-Fc-IL-18bp fusion protein; C000589760:IL18 protein, human; C587672:IL1B protein, mouse; D058847:Inflammasomes; D036341:Intercellular Signaling Peptides and Proteins; D053590:Interleukin 1 Receptor Antagonist Protein; D020382:Interleukin-18; D053583:Interleukin-1beta; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins
keywords: inflammasomes; interleukins