Soluble biglycan induces the production of ICAM-1 and MCP-1 in human aortic valve interstitial cells through TLR2/4 and the ERK1/2 pathway
- 438 Downloads
Mononuclear cell infiltration in valvular tissue is one of the characteristics in calcific aortic valve disease. The inflammatory responses of aortic valve interstitial cells (AVICs) play an important role in valvular inflammation. However, it remains unclear what may evoke AVIC inflammatory responses. Accumulation of biglycan has been found in diseased aortic valve leaflets. Soluble biglycan can function as a danger-associated molecular pattern to induce the production of proinflammatory mediators in cultured macrophages. We tested the hypothesis that soluble biglycan induces AVIC production of proinflammatory mediators involved in mononuclear cell infiltration through Toll-like receptor (TLR)-dependent signaling pathways.
Human AVICs isolated from normal aortic valve leaflets were treated with specific siRNA and neutralizing antibody against TLR2 or TLR4 before biglycan stimulation. The production of ICAM-1 and MCP-1 was assessed. To determine the signaling pathway involved, phosphorylation of ERK1/2 and p38 MAPK was analyzed, and specific inhibitors of ERK1/2 and p38 MAPK were applied.
Soluble biglycan induced ICAM-1 expression and MCP-1 release in human AVICs, but had no effect on IL-6 release. TLR4 blockade and knockdown reduced ICAM-1 and MCP-1 production induced by biglycan, while knockdown and neutralization of TLR2 resulted in greater suppression of the inflammatory responses. Biglycan induced the phosphorylation of ERK1/2 and p38 MAPK, but ICAM-1 and MCP-1 production was reduced only by inhibition of the ERK1/2 pathway. Further, inhibition of ERK1/2 attenuated NF-κB activation following biglycan treatment.
Soluble biglycan induces the expression of ICAM-1 and MCP-1 in human AVICs through TLR2 and TLR4 and requires activation of the ERK1/2 pathway. AVIC inflammatory responses induced by soluble biglycan may contribute to the mechanism of chronic inflammation associated with calcific aortic valve disease.
KeywordsBiglycan AVIC Cytokines TLR2 TLR4
This study was supported in part by National Institutes of Heart, Lung and Blood Grant HL106582.
Conflict of interest
- 9.Zeng Q, Jin C, Ao L, Cleveland JC Jr, Song R, Xu D, et al. Cross-talk between the toll-like receptor 4 and notch1 pathways augments the inflammatory response in the interstitial cells of stenotic human aortic valves. Circulation. 2012;126(11 Suppl 1):S222–30.PubMedCentralPubMedCrossRefGoogle Scholar
- 12.Popovic ZV, Wang S, Papatriantafyllou M, Kaya Z, Porubsky S, Meisner M, et al. The proteoglycan biglycan enhances antigen-specific T cell activation potentially via MyD88 and TRIF pathways and triggers autoimmune perimyocarditis. J Immunol. 2011;187(12):6217–26.PubMedCentralPubMedCrossRefGoogle Scholar
- 22.Yang X, Fullerton DA, Su X, Ao L, Cleveland JC, Meng X. Pro-osteogenic phenotype of human aortic valve interstitial cells is associated with higher levels of Toll-like receptors 2 and 4 and enhanced expression of bone morphogenetic protein 2. J Am Coll Cardiol. 2009;53:491–500.PubMedCrossRefGoogle Scholar
- 26.Schaefer L, Macakova K, Raslik I, Micegova M, Grone HJ, Schonherr E, et al. Absence of decorin adversely influences tubulointerstitial fibrosis of the obstructed kidney by enhanced apoptosis and increased inflammatory reaction. Am J Pathol. 2002;160(3):1181–91.PubMedCentralPubMedCrossRefGoogle Scholar
- 34.Dillon S, Agrawal A, Van Dyke T, Landreth G, McCauley L, Koh A, et al. A Toll-like receptor 2 ligand stimulates Th2 responses in vivo, via induction of extracellular signal-regulated kinase mitogen-activated protein kinase and c-Fos in dendritic cells. J Immunol. 2004;172(8):4733–43.PubMedCrossRefGoogle Scholar