1,720,977 research outputs found
How Can Interleukin-1 Receptor Antagonist Modulate Distinct Cell Death Pathways?
No full textMultiple mechanisms of cell death exist (apoptosis, necroptosis, pyroptosis) and the subtle balance of several distinct proteins and inhibitors tightly regulates the cell fate toward one or the other pathway. Here, by combining coimmunoprecipitation, enzyme assays, and molecular simulations, we ascribe a new role, within this entangled regulatory network, to the interleukin-1 receptor antagonist (IL-1Ra). Our study enlightens that IL-1Ra, which usually inhibits the inflammatory effects of IL-1α/β by binding to IL-1 receptor, under advanced pathological states prevents apoptosis and/or necroptosis by noncompetitively inhibiting the activity of caspase-8 and -9. Consensus docking, followed by cumulative 10 μs of molecular dynamics simulations unprecedentedly reveal that IL-1Ra binds both caspases at their dimeric interface, preventing, in this manner, the formation of their catalytically/signaling active form. The resulting IL-1Ra/caspase-8(9) adducts are stabilized by hydrophobic and by few key hydrogen bonding interactions, formed by residues fully conserved across distinct caspases (-3, -6, -7, -8, and -9), and closely resemble the binding mode of the caspases inhibitors XIAP (X-linked inhibitor of apoptosis) and c-FLIP (cellular FLICE-like inhibitory protein). Tight regulation of the different forms of cell death has a major impact on distinct human illnesses (i.e., cancer, neurodegeneration, ischemic injury, atherosclerosis, viral/bacterial infections, and immune reaction). Hence, our study, pinpointing IL-1Ra as new actor of the intricate cell death regulatory network and gaining an atomic-scale understanding of its mechanism may open new avenues toward innovative therapeutic strategies to tackle major human diseases
Soluble interleukin-2 receptor: is there a role in ischaemic cardiomyopathy?
No full textWe believe that sIL-2R levels should be regarded as markers of LV dysfunction independently from its cause. Moreover, we believe that in the current effort to understand and appraise fully the role of inflammatory mechanism in cardiac remodelling and failure, sIL-2R levels should be determined in the active phases of the disease when LV dysfunction ensues, rather than in its advanced phase
Leptospira interrogans and Leptospira peptidoglycans induce the release of tumor necrosis factor alpha from human monocytes.
No full textLeptospira icterohemorrhagiae and leptospire peptidoglycans induce endothelial cell adhesiveness for polymorphonuclear leukocytes
No full textINFECT IMMU
Decellularization and in vivo and in vitro repopulation with endothelial cells of porcine heart valve leaflets
No full textBioprostheses are widely used to replace cardiac valves. Besides favorable hemodynamic properties, however, these prostheses suffer from the major disadvantage of limited duration linked to sclerosis and dystrophic calcification events. These are linked, at least in part, to defective extracellular matrix (ECM) preservation and incomplete removal of native cells in currently glutaraldehyde-treated scaffolds. In addition, the absence of the endothelial coat may represent a relevant pathogenetic factor of the graft sclerotic process. As previously reported in Spina et al. (2003), we achieved complete cell extraction from porcine valve leaflets with concurrent preservation of their extracellular matrix. Moreover, as reported by Bertipaglia et al. (2003), these acellular scaffolds allowed in vitro repopulation with homologous valve interstitial cells, which also redifferentiated into all four cell phenotypes existing in heart valves. Porcine pulmonary valvulated segments (PVCs) were decellularized using combined nondenaturating neutral detergents Triton X-100 and cholate, followed by Benzonase® digestion. Acellular PVCs were othotopically implanted in recipient pigs for 1-2 months, or in vivo seeded with endothelial cells derived from human umbilical cord (HUVEC), and incubated for 2 weeks. Histological and TEM-SEM ultrastructural analysis was performed, also after histochemical reactions for glycosaminoglycan (GAG) localization, laminin immunolocalization, immune reactions for endothelial cell inflammatory or thrombotic phenotype. The treated PVCs exhibited complete cell remotion, good ECM preservation, and surface reactivity for laminin. After 2-month implantation, in vivo cell colonization spontaneously occurred by two distinct cell populations: endothelial-like cells, adhering to PVC luminal areas, and mesenchymal-like cells, migrating through PVC interstitium. After cell seeding and 2-week incubation, monolayers of antiinflammatory and anti-thrombogenic human endothelial cells completely covered PVC luminal surfaces. Cell adhesion to the retained basal lamina and cell junction formation also were observed. In addition, valve interstitium was enriched by newly secreted GAGs. After cell seeding and 2-week incubation, micropinocytotic activity by endothelium and increased GAG-reactivity were observed. The decellularized PVCs are propensive for both in vivo homologous cell repopulation and in vitro heterologous endothelization with HUVEC. In addition, PVC stroma acquired more and more hybrid character because human-endothelium-generated GAGs were added to the native ECM macromolecules retained within the treated porcine PVCs. Thus, these engineered PVCs appear as promising autologous-like, glutaraldehyde-free, and antithrombogenic bioprostheses
Interleukin-1 receptor antagonist myocardial synthesis in ischemic cardiomyopathy
No full textPlasma levels of systemic markers of inflammation have been used to monitor the risk of coronary artery disease (CAD). Interleukin-1 receptor antagonist (IL-1Ra) modulates the production and the activity of IL-1, a cytokine associated with inflammatory response. In order to ascertain whether detection of increased levels of IL-1Ra may be useful in the characterization of ischemic syndromes, we investigated IL-1ra levels in a first series of 117 consecutive patients undergoing coronary angiography with a clinical diagnosis of Braunwald's unstable or chronic stable angina, or atypical chest pain (lesion-free coronary arteries at coronary angiography). Characteristics of the patients were similar in the three groups. Clinical and laboratory assessment excluded active immune diseases. A statistically significant (p<0.001) increase of IL-1ra was found in unstable angina, compared to stable chronic angina and normal control group patients. In contrast, there were not significant differences between normal controls and chronic stable angina patients. On the other hand, C-reactive protein (CRP) levels were significantly higher in pts with stable and unstable angina as compared to subjects without corornary disease (P=0.034), but they did not discriminate between stable and unstable pts (P=0.7). IL-1Ra plasma levels were then measured upon Emergency Department (ED) admission in 44 consecutive pts with ST-segment elevation acute myocardial infarction (aMI). A comparison between IL-1Ra and common indicators of myocardial necrosis [creatin-kinase (CK), CK-MB, Troponin I and Myoglobin] or systemic inflammation [CRP] was also performed. On admission to ED, 82% of pts had elevated IL-1Ra levels vs 41% of pts with raised CK (P=0.001), CK-MB (45%, P=0.002), Troponin I ( 57%, P=0.027), Myoglobin (48%, P=0.004) and CRP (57%, P= 0.019) levels. Sensitivity of IL-1Ra determination to identify in the Emergency Department pts with aMI raised to 86% if pre-coronary time was <3 hours and to 91% if heralded infarction occurred. We then investigated the actual source of IL-1Ra in subjects with myocardial ischemic disease. Myocardial samples were taken in the peri-infarct and remote regions at time of explant for heart transplant in 4 subjects with ischemic cardiomyopathy and previous AMI. IL-1Ra production was evaluated using in situ hybridization for IL-1Ra mRNA and immunostaining with anti-IL-1Ra-protein specific antibodies. Myocardial IL-1Ra expression was found in all cases, particularly in the peri-infarct regions, with cardiomyocytes being the prevalent source for IL-1Ra. Conclusions. IL-1Ra, a cytokine with potential anti-inflammatory properties, is produced by the ischemic myocardium. Elevation of serum IL-1ra may identify pts with unstable angina with greater sensitivity than CRP and precedes the release of markers of necrosis in pts with aMI
Endothelial cell E- and P-selectin and vascular cell adhesion molecule-1 function as signaling receptors.
No full textJ.CELL BIOL
Cytolytically inactive terminal complement complex causes transendothelial migration of polymorphonuclear leukocytes in vitro and in vivo
No full textIntravital microscopy was used to monitor leukocyte traffic across rat mesenteric postcapillary venules induced by the inactive terminal complement (C) complex (iTCC) topically applied to ileal mesentery. Leukocytes started rolling within 15 minutes from the administration of iTCC, and by 1 hour they adhered almost completely to the endothelium emigrating from the vessels in the next 3 hours. C5a caused a similar, though less marked, effect, whereas boiled iTCC was inactive, excluding the contribution of contaminating lipopolysaccharide. The complex stimulated the migration of polymorphonuclear neutrophils (PMNs) across endothelial cells (ECs) in a transwell system after a 4-hour incubation of ECs with iTCC added to the lower chamber of the transwell, whereas a 30-minute incubation was sufficient for C5a and interleukin (IL)-8 to induce the passage of PMNs. C5a was not responsible for the effect of iTCC because this complex had no chemotactic activity and contained too small an amount of C5a to account for the transendothelial migration of PMNs. Similarly, the effect of iTCC was not mediated by IL-8 released by stimulated ECs because anti-IL-8 failed to inhibit the migration of PMNs induced by the complex. Unlike tumor necrosis factor-alpha, iTCC did not cause the redistribution of platelet-endothelial cell adhesion molecule-1 (PECAM-1), and PMN mobilization was partially blocked by anti-PECAM-1 antibodies
Plasma concentrations of interleukin-2 soluble receptor in mild ischaemic left ventricular dysfunction.
No full textIn the present study, we evaluated plasma levels of the prototypical acute phase protein CRP, Interleukin-1 receptor antagonist (IL-1Ra) which is synthesized and released by activated monocyte-macrophages at sites of tissue damageyinflammation and Interleukin-2 soluble receptor (sIL-2R), a specific marker of T-lymphocyte activation, in patients with mild ischaemic LVD
Humanization of porcine pulmonary valvulated conduits after decellularization and repopulation with human endothelial cells
No full textIntroduction. In heart valve surgical replacement, the most suitable hemodynamic properties and mechanical performances depend on the preservation of cusp anatomical shape and stromal structure. In addition, post-operatory valve calcification can be avoided only after removing all native cells from bioprostheses. Previously, complete cell extraction was achieved from porcine valve leaflets with concurrent preservation of their extracellular matrix (ECM) (1). These acellular scaffolds allowed "in vitro" repopulation with homologous valve interstitial cells, which also re-differentiated into all four cell phenotypes existing in heart valves (2). Methods. Porcine pulmonary valvulated segments (PVCs) were decellularized using combined non -denaturating neutral detergents Triton X-100 and Cholate, followed by Benzonase® digestion. Acellular PVCs were (i) orthotopically implanted in recipient pigs for 1-2 months, or (ii) "in vitro" seeded with endothelial cells derived from human umbilical cord (HUVEC), and incubated for 1-2 weeks. Histological and TEM-SEM ultrastructural analysis was performed, also after histochemical reactions for glycosaminoglycan (GAG) localization and laminin immuno-localization. Results. The treated PVCs exhibited complete cell remotion, good ECM preservation and surface reactivity for laminin. (i) After 2-month implantation, "in vivo" cell colonization spontaneously occurred by two distinct cell populations: endothelial-like cells, adhering to PVC luminal areas, and mesenchimal-like cells, migrating through PVC interstitium. (ii) After cell seeding and 1-week incubation, monolayers of human endothelial cells completely covered PVC luminal surfaces. Cell adhesion to the retained basal "lamina" and cell junction formation were also observed. In addition, valve interstitium was enriched by newly secreted GAGs at the subendothelial aspects. After cell seeding and 2-week incubation, micropinocytotic activity by endothelium and increased GAG-reactivity were observed. Conclusions. The decellularized PVCs are propensive for both (i) "in vivo" homologous cell repopulation, and (ii) "in vitro" heterologous endothelization with HUVEC. In addition, PVC stroma acquired more and more hybrid character because human-endothelium-generated GAGs were added to the native ECM macromolecules retained within the treated porcine PVCs. Thus these engineered PVCs appear as promising autologous-like, glutaraldehyde-free, and anti-thrombogenic bioprostheses. 1. Spina M., Ortolani F., El Messlemani A., Gandaglia A., Bujan J., Garcia-Honduvilla N., Vesely I., Gerosa G., Casarotto D., Petrelli L., Marchini M.: Isolation of intact aortic valve scaffolds for heart valve bioprostheses: extracellular matrix structure, prevention from calcification and cell repopulation features. J. Biomed. Mater. Res., 67, 1338-1350, 2003. 2. Bertipaglia B., Ortolani F., Petrelli L., Gerosa G., Spina M.,, Pauletto P., Casarotto D., Marchini M., Sartore S.: Cell characterization of porcine aortic valve and decellularized leaflets repopulated with aortic valve interstitial cells. Ann. Thorac. Surg., 75, 1274-1282, 2003
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