Interleukin-10 Regulates the Tissue Factor Activity of Monocytes in an In Vitro Model of Bacterial Endocarditis

Abstract

Monocytes are important effector cells in the pathogenesis of bacterial endocarditis since they provide the tissue factor that activates the coagulation system and maintains established vegetations. Monocytes secrete cytokines that can modulate monocyte tissue factor activity (TFA), thereby affecting the formation and maintenance of vegetations. In this study, we show that monocytes cultured for 4 h on a Streptococcus sanguis-infected fibrin matrix mimicking the in vivo vegetational surface express high levels of TFA. This was accompanied by secretion of the proinflammatory cytokines tumor necrosis factor alpha (TNF-␣), interleukin-1␣ (IL-1␣), and IL-1␤. After a 24-h incubation period the anti-inflammatory cytokine IL-10 could also be detected. Our data show that, whereas TNF-␣ and IL-1 have a minor role in the induction of TFA by monocytes cultured on a fibrin matrix, TNF-␣ but not IL-1 plays an important role in the induction of IL-10 by these cells. In turn, our data show that IL-10 is an important factor in the downregulation of monocyte TFA. In summary, we conclude that IL-10 is an important factor in the control of monocyte TFA in endocardial vegetations.Tissue factor (TF), a transmembrane glycoprotein, is the most important factor in the initiation of the extrinsic coagulation pathway (25). Monocytes can be stimulated by various agents, such as endotoxin, phorbol ester, lipoteichoic acid, and C-reactive protein, to express TF molecules on their membranes, thereby generating TF activity (TFA) (9,25,26,30,31). We have shown that monocytes also express TFA when they adhere in vitro to fibrin matrixes containing bacteria, in particular bacteria that are known to cause the endovascular disease bacterial endocarditis (BE) (1-4, 38). With respect to the pathogenesis of BE, Drake and coworkers (13) have shown that in vivo TF is a crucial factor in the formation of an endocardial fibrin clot, called endocardial vegetation, in which the infecting microorganisms and blood cells are embedded (33). In a rabbit model of BE it was found that the TF needed to maintain the endocardial vegetation is generated by monocytes that settle from the circulation onto the infected endocardial lesion (2,3,6,38).Monocyte TFA can be regulated by cytokines. Proinflammatory cytokines, such as tumor necrosis factor alpha (TNF-␣) and interleukin-1 (IL-1), induce TFA on monocytes (15,17,18,22,24,25). Monocytes isolated from patients with atherosclerosis, a disease in which TNF-␣ and IL-1 play a significant role, express TF on their membranes (24). Furthermore, macrophages in atherosclerotic plaques express TF (32). Anti-inflammatory cytokines, such as IL-10 and transforming growth factor beta, inhibit or suppress monocyte TFA (14,18,20,24,29,30).It is well known that pro-and anti-inflammatory cytokines each control the other's production (5, 33). TNF-␣ and IL-1, which are examples of the earliest cytokines produced by monocytes upon appropriate stimulation (15, 28), are able to stimulate monocyte IL-10 production (15,27,28,40). In turn, IL...

Monocytes Maintain Tissue Factor Activity after Cytolysis of Bacteria‐Infected Endothelial Cells in an In Vitro Model of Bacterial Endocarditis

“…The present results, together with those of our previous studies [13][14][15][16][17][18][19]56] and considering some clinical observations [2][3][4][5][6], have led us to propose the following sequence of events that may explain how, during the initial phase of BE, when the EC lining is still intact and monocytes are not yet involved, fibrin formation may start. Depending on the strain and/or their virulence, bloodborne bacteria will attach to and invade ECs.…”

“…Apparently, specific molecules that constitute the ECM and are lacking at the membrane of intact ECs generate appropriate costimulatory signals for the induction of TFA in monocytes in the presence of bacteria. In line with this, it was shown that monocytes adherent to a fibrincoated surface express TFA and do so to a much higher degree in the context of S. sanguis [18,56], S. aureus [17], or S. epidermidis [16]. Second, the observed differences in TFA levels of ECM-bound monocytes are not explained by differences in the number of ECM-adherent bacteria, because the degree of infection of S. aureus-, S. sanguis-, or S. epidermidis-infected ECMs is similar.…”

Systemic inflammatory response and local cytokine expression in porcine models of endocarditis

“…The in vivo expression of IL‐1β in human heart valves with S. aureus IE remains to be elucidated. Nevertheless, considering the results from the in vitro study of human monocytes , and the increasing evidence of IL‐1β as an important contributor in the pathogenesis of different cardiovascular diseases in humans , the results from this study suggests IL‐1β as an important component in the local inflammatory response in S. aureus endocarditis, which likely parallels the disease in man.…”

Interleukin-10 microsatellite variants and the risk of acute coronary syndrome among Tunisians

“…, 2009). Third, IL‐10 inhibits TF expression and modulates thrombin generation kinetics (Veltrop et al. , 2001; Kamimura et al.…”