title: Expression of functional Toll-like receptors 2 and 4 in human aortic valve interstitial cells: potential roles in aortic valve inflammation and stenosis.
abstract: Calcific aortic valve stenosis is the most common indication for surgical valve replacement. Inflammation appears to be one of the mechanisms involved in aortic valve calcification, and valve interstitial cells seem to contribute to that process. Although Toll-like receptors (TLRs) play an important role in the cellular inflammatory response, it is unknown whether human aortic valve interstitial cells (HAVICs) express functional TLRs. We examined the expression of TLR2 and TLR4 in human aortic valve leaflets and in isolated HAVICs and analyzed the response of cultured HAVICs to the TLR2 and TLR4 agonists peptidoglycan (PGN) and LPS. Abundant TLR2 and TLR4 proteins were found in human aortic valve leaflets and in isolated HAVICs, and both receptors were detected in the membrane and cytoplasm of cultured HAVICs. Stimulation by either PGN or LPS resulted in the activation of the NF-kappaB signaling pathway and the production of multiple proinflammatory mediators, including IL-6, IL-8, and ICAM-1. In addition, stimulation by either PGN or LPS upregulated the expression of bone morphogenetic protein-2 (BMP-2) and Runx2, factors associated with osteogenesis. This study demonstrates for the first time that HAVICs express TLR2 and TLR4 and that stimulation of HAVICs by PGN or LPS induces the expression of proinflammatory mediators and the upregulation of osteogenesis-associated factors. These results suggest that TLR2 and TLR4 may play a role in aortic valve inflammation and stenosis.
authors.affiliation: Department of Surgery, University of Colorado Health Sciences Center, Denver, Colorado, USA. Xianzhong.meng@uchsc.edu
authors.forename: Xianzhong
authors.initials: X
authors.lastname: Meng
authors.forename: Lihua
authors.initials: L
authors.lastname: Ao
authors.forename: Yong
authors.initials: Y
authors.lastname: Song
authors.forename: Ashok
authors.initials: A
authors.lastname: Babu
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Yang
authors.forename: Maorong
authors.initials: M
authors.lastname: Wang
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Weyant
authors.forename: Charles A
authors.initials: CA
authors.lastname: Dinarello
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Cleveland
authors.forename: David A
authors.initials: DA
authors.lastname: Fullerton
mesh_terms: D001021:Aortic Valve / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D001024:Aortic Valve Stenosis / Q000276:immunology* / Q000473:pathology; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D002114:Calcinosis / Q000276:immunology*; D002478:Cells, Cultured; D050659:Core Binding Factor Alpha 1 Subunit / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate; D007249:Inflammation / Q000276:immunology* / Q000473:pathology; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D016328:NF-kappa B / Q000378:metabolism; D010457:Peptidoglycan / Q000494:pharmacology; D015398:Signal Transduction / Q000276:immunology; D051195:Toll-Like Receptor 2 / Q000819:agonists / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000819:agonists / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D015854:Up-Regulation
chemical_list: C525718:BMP2 protein, human; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins; D050659:Core Binding Factor Alpha 1 Subunit; C508600:IL6 protein, human; D015850:Interleukin-6; D016209:Interleukin-8; D008070:Lipopolysaccharides; D016328:NF-kappa B; D010457:Peptidoglycan; C493709:RUNX2 protein, human; C495342:TLR2 protein, human; C495345:TLR4 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D016212:Transforming Growth Factor beta; C440499:lipopolysaccharide, Escherichia coli O111 B4; D018799:Intercellular Adhesion Molecule-1