Viral and bacterial patterns induce TLR-mediated sustained inflammation and calcification in aortic valve interstitial cells

López, Javier; Fernández‐Pisonero, Isabel; Dueñas, Antonio; Maeso, Patricia; Román, José Alberto San; Crespo, Mariano Sánchez; García-Rodríguez, Carmen

doi:10.1016/j.ijcard.2010.12.089

Cited by 44 publications

(67 citation statements)

References 30 publications

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“…that observed in the early stages of atherosclerosis) [114]. In addition, in 2012 the group of Garcia-Rodrigues [115] investigated TLR-mediated inflammation and osteogenesis in interstitial human cells, isolated from stenotic and non-stenotic aortic valves and stimulated with viral and Gram-negative bacteria molecular patterns. TLR-expression and signaling were evaluated by several assays, including quantitative-PCR and flow cytometry, to Western blot analysis, ELISA, and cytokine arrays.…”

Section: Role Of Tlr-4 Pathway In Aneurysms (Sporadic Taa)?mentioning

confidence: 99%

“…Moreover, they showed that TLR3 and TLR-4 agonists induced alkaline phosphatase expression and activity. Thus, they concluded that exposure of aortic valve interstitial cells to viral and Gramnegative bacteria molecular patterns induces distinct and long-term TLR-mediated pro-inflammatory and pro-osteogenic responses, likely relevant in the pathogenesis of degenerative aortic stenosis [115].…”

Section: Role Of Tlr-4 Pathway In Aneurysms (Sporadic Taa)?mentioning

confidence: 99%

“…A considerable number of them are listed in Table 5, together with their effects [136,137]. With regard to the latter, some have been reported in the studies described [115,[120][121][122][123][124][125] in the previous paragraph. Their action has shown that both the TLR-4 activation and inhibition may have beneficial effects in various conditions, reducing tissue immune inflammatory responses [115, 120-125,136,and 137].…”

Section: Therapeutic Role Of Tlr-4 Pathway: From Experimental Data Tomentioning

confidence: 99%

See 2 more Smart Citations

Toll-like receptor-4 signaling pathway in aorta aging and diseases: “its double nature”

Balistreri

Ruvolo

Lio

et al. 2017

Journal of Molecular and Cellular Cardiology

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Section: Role Of Tlr-4 Pathway In Aneurysms (Sporadic Taa)?mentioning

confidence: 99%

Section: Role Of Tlr-4 Pathway In Aneurysms (Sporadic Taa)?mentioning

confidence: 99%

Section: Therapeutic Role Of Tlr-4 Pathway: From Experimental Data Tomentioning

confidence: 99%

See 1 more Smart Citation

Toll-like receptor-4 signaling pathway in aorta aging and diseases: “its double nature”

Balistreri

Ruvolo

Lio

et al. 2017

Journal of Molecular and Cellular Cardiology

View full text Add to dashboard Cite

“…In this regard, proinflammatory mediators, such as tumor necrosis factor-α, have been shown to up-regulate the expression of osteogenic factor bone morphogenetic protein-2 (BMP-2) and early osteoblastic differentiation biomarker alkaline phosphatase (ALP) in AVICs (6, 7). We and others have observed that stimulation of either Toll-like receptor (TLR) 2 or TLR4 induces the osteogenic responses characterized by the expression of BMP-2 and ALP, among several other osteogenic biomarkers, in human AVICs (8)(9)(10)(11)(12), leading to the formation of calcification deposits in vitro (11)(12)(13). Moreover, bacteria associated with chronic periodontal infection and bacterial agents have been detected in diseased human aortic valves (14,15), and inoculation of rabbits with oral bacteria induces aortic valve lesions (16).…”

mentioning

confidence: 99%

Interleukin-37 suppresses the osteogenic responses of human aortic valve interstitial cells in vitro and alleviates valve lesions in mice

Zeng

Song

Fullerton

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Calcific aortic valve disease is a chronic inflammatory process, and aortic valve interstitial cells (AVICs) from diseased aortic valves express greater levels of osteogenic factors in response to proinflammatory stimulation. Here, we report that lower cellular levels of IL-37 in AVICs of diseased human aortic valves likely account for augmented expression of bone morphogenetic protein-2 (BMP-2) and alkaline phosphatase (ALP) following stimulation of Toll-like receptor (TLR) 2 or 4. Treatment of diseased AVICs with recombinant human IL-37 suppresses the levels of BMP-2 and ALP as well as calcium deposit formation. In mice, aortic valve thickening is observed when exposed to a TLR4 agonist or a high fat diet for a prolonged period; however, mice expressing human IL-37 exhibit significantly lower BMP-2 levels and less aortic valve thickening when subjected to the same regimens. A high fat diet in mice results in oxidized low-density lipoprotein (oxLDL) deposition in aortic valve leaflets. Moreover, the osteogenic responses in human AVICs induced by oxLDL are suppressed by recombinant IL-37. Mechanistically, reduced osteogenic responses to oxLDL in human AVICs are associated with the ability of IL-37 to inhibit NF-κB and ERK1/2. These findings suggest that augmented expression of osteogenic factors in AVICs of diseased aortic valves from humans is at least partly due to a relative IL-37 deficiency. Because recombinant IL-37 suppresses the osteogenic responses in human AVICs and alleviates aortic valve lesions in mice exposed to high fat diet or a proinflammatory stimulus, IL-37 has therapeutic potential for progressive calcific aortic valve disease.Toll-like receptors | inflammation | oxidized low-density lipoprotein | calcification | signal transduction

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“…Previous work demonstrated that TLR3 stimulation also activates NF-κB in human AVICs (41,42). However, we recently found that the TLR3-TRIF cascade activates noncanonical NF-κB in human AVICs, whereas LPS activates canonical NF-κB in this cell type (43).…”

Section: Disclosurementioning

confidence: 72%

IL-37 Suppresses MyD88-mediated Inflammatory Responses in Human Aortic Valve Interstitial Cells

Zhan¹,

Zeng²,

Song³

et al. 2017

Mol Med

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Calcific aortic valve disease (CAVD) is common among the elderly, and aortic valve interstitial cells (AVICs) exhibit unique inflammatory and osteogenic responses to proinflammatory stimulation, which plays an important role in valvular fibrosis and calcification. Thus, suppression of AVIC proinflammatory response may have therapeutic utility for the prevention of CAVD progression. Interleukin (IL)-37, an antiinflammatory cytokine, reduces tissue inflammation. This study aimed to test the hypothesis that IL-37 suppresses human AVIC inflammatory responses to Toll-like receptor (TLR) agonists. Human AVICs were exposed to Pam3CSK4, poly(I:C) and lipopolysaccharide in the presence and absence of recombinant human IL-37. Stimulation of TLR4 increased the production of intercellular adhesion molecule-1, IL-6, IL-8 and monocyte chemoattractant protein-1. Knockdown of myeloid differentiation factor 88 (MyD88) or TIR-domain-containing adaptor-inducing interferon-β differentially affected inflammatory mediator production following TLR4 stimulation. IL-37 reduced production of these inflammatory mediators induced by TLR4. Moreover, knockdown of IL-37 enhanced induction of these mediators by TLR4. IL-37 also suppressed inflammatory mediator production induced by the MyD88-dependent TLR2, but had no effect on the inflammatory responses to the TRIF-dependent TLR3. Furthermore, IL-37 inhibited NF-κB activation induced by TLR2 or TLR4 through a mechanism dependent of IL-18 receptor α-chain. Activation of TLR2, TLR3 or TLR4 upregulates the production of inflammatory mediators in human AVICs. IL-37 suppresses MyD88-mediated responses to reduce inflammatory mediator production following stimulation of TLR2 and TLR4. This antiinflammatory cytokine may be useful for suppression of aortic valve inflammation elicited by MyD88-dependent TLR signaling.

show abstract

Viral and bacterial patterns induce TLR-mediated sustained inflammation and calcification in aortic valve interstitial cells

Abstract: Exposure of aortic valve interstitial cells to viral and Gram-negative bacteria molecular patterns induces distinct and long-term TLR-mediated pro-inflammatory and pro-osteogenic responses that might be relevant to the pathogenesis of degenerative aortic stenosis.

Cited by 44 publications

References 30 publications

Toll-like receptor-4 signaling pathway in aorta aging and diseases: “its double nature”

Toll-like receptor-4 signaling pathway in aorta aging and diseases: “its double nature”

Interleukin-37 suppresses the osteogenic responses of human aortic valve interstitial cells in vitro and alleviates valve lesions in mice

IL-37 Suppresses MyD88-mediated Inflammatory Responses in Human Aortic Valve Interstitial Cells

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