Inflammatory imbalance between IL‐10 and TNFα in unstable angina potential plaque stabilizing effects of IL‐10

Wæhre, Torgun; Halvorsen, Bente; Damås, Jan Kristian; Yndestad, Arne; Brosstad, Frank; Gullestad, Lars; Kjekshus, John; Frøland, Stig S.; Aukrust, Pål

doi:10.1046/j.1365-2362.2002.01069.x

Cited by 101 publications

(70 citation statements)

References 30 publications

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“…Thus, it has been shown that the marked rise in inflammatory cytokines during ACS is not accompanied by elevation of the anti-inflammatory cytokine IL-10. 16,17 In the present study, we show a similar pattern in the balance between IL-1 and the naturally occurring antagonist IL-1Ra, with markedly increased mRNA levels of IL-1␣ and IL-1␤ in circulating mononuclear leukocytes in both stable and particularly in unstable angina, accompanied by only modestly increased IL-1Ra levels in the unstable patients. Hence, although IL-1 is highly inflammatory and potentially plaque-destabilizing, for example by inducing adhesion molecules, clotting factors, chemokines, and matrix metalloproteinases, IL1Ra may protect against those deleterious IL-1 effects.…”

Section: Discussionsupporting

confidence: 76%

Increased Expression of Interleukin-1 in Coronary Artery Disease With Downregulatory Effects of HMG-CoA Reductase Inhibitors

et al. 2004

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Background-Inflammation is important in atherogenesis. Interleukin (IL)-1 is the prototypic inflammatory cytokine. We hypothesized a dysbalance between inflammatory and anti-inflammatory mediators in the IL-1 family in coronary artery disease (CAD) and a possible modulation of these mediators by HMG-CoA inhibitors (statins). Methods and Results-In a microarray screening experiment examining peripheral blood mononuclear cells (PBMCs) from 6 CAD patients and 4 healthy control subjects, IL-1␤ was identified as 1 of 25 genes whose expression were upregulated in CAD and downregulated by statins. In the following, we studied the role of IL-1␤ and related mediators in CAD. Our major findings were as follows. (1) Although mRNA levels of IL-1␣ and IL-1␤ were markedly reduced in PBMCs from CAD patients after 6 months of simvastatin (20 mg/d, nϭ15) and atorvastatin (80 mg/d, nϭ15) therapy, the reduction in IL-1 receptor antagonist (IL-1Ra) was more modest. Statins also reduced the spontaneous release of IL-1␤ and IL-1Ra from PBMCs in CAD patients. (2) mRNA levels of IL-1␣, IL-1␤, and IL-1Ra were increased in PBMCs from patients with stable (nϭ20) and unstable (nϭ20) angina compared with healthy control subjects (nϭ15). Although the unstable patients had particularly high levels of IL-1␤ and IL-1␣, IL-1Ra was not correspondingly increased. (3) IL-1␤ induced release of proatherogenic cytokines from PBMCs, whereas atorvastatin partly abolished this effect. Conclusions-Our findings suggest that cytokines in the IL-1 family may represent therapeutic targets in CAD. The ability of statins to modulate these cytokines in an anti-inflammatory direction underscores their immunomodulatory potential.

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Section: Discussionsupporting

confidence: 76%

Increased Expression of Interleukin-1 in Coronary Artery Disease With Downregulatory Effects of HMG-CoA Reductase Inhibitors

et al. 2004

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“…Second, previous studies of human atherosclerotic plaques have revealed an inverse association between the presence of IL-10 and TUNEL staining, supporting a link between IL-10 and decreased apoptosis (34), and such an association has also recently been demonstrated in LDL-receptor mice overexpressing IL-10 (35). Finally, although several studies have shown increased levels of inflammatory cytokines such as TNF␣ in ACS, we and others have recently reported normal IL-10 levels in these patients, suggesting an inflammatory imbalance (6,(36)(37)(38). However, the clinical consequences of the IL-10-mediated enhancement of foam cell formation is far from clear and will need to be further elucidated before any firm conclusion can be drawn.…”

Section: The Effect Of Il-10 On Foam Cells In Human Atherosclerotic Dmentioning

confidence: 64%

“…Thus, studies in IL-10-transgenic and IL-10-deficient mice models suggest an important protective role for this cytokine in both the formation and the stabilization of atherosclerotic lesions (2,4,5). Moreover, we have recently shown that IL-10 inhibits the release of inflammatory cytokines, tissue factor, and matrix metalloproteinases from periph-eral blood mononuclear cells (PBMCs) in patients with ACS, potentially promoting plaque stabilization (6). However, the exact mechanisms of action of IL-10 in atherogenesis have not been fully clarified and its role in plaque stabilization is far from clear.…”

mentioning

confidence: 99%

Interleukin-10 enhances the oxidized LDL-induced foam cell formation of macrophages by antiapoptotic mechanisms

Halvorsen

Wæhre

Scholz

et al. 2005

Journal of Lipid Research

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“…8A, which is published as supporting information on the PNAS web site). TNF concentrations of this level (Ϸ5 ng͞ml) have been reported in animal models of inflammation and atherosclerosis and also in clinical studies (23,24). The synergistic effect was observed over a range of TNF concentrations, up to 20 ng͞ml, that have been reported to be effective in the activation of endothelial cells (Fig.…”

Section: Tf Induction By Proinflammatory Cytokines Tnf Il-1␤ and Cmentioning

confidence: 68%

Synergistic induction of tissue factor by coagulation factor Xa and TNF: Evidence for involvement of negative regulatory signaling cascades

Hezi-Yamit

Wong

Bien-Ly

et al. 2005

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

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Enzymes of the blood coagulation pathway enhance the inflammatory response leading to endothelial dysfunction, accounting, in part, for the vascular complications occurring in sepsis and cardiovascular disease. The responses of endothelial cell activation include induction of the expression of tissue factor (TF), a membrane glycoprotein that promotes thrombosis, and of E-selectin, a cell adhesion molecule that promotes inflammation. In this report, we demonstrate synergistic interactions between the coagulation factor Xa (fXa) and the proinflammatory cytokines TNF, IL-1␤, and CD40L, leading to enhanced expression of TF and E-selectin in endothelial cells. A detailed analysis of the molecular pathways that could account for this activity of fXa showed that fXa inhibited the cytokine-induced expression of dual specificity phosphatases, MAP kinase phosphatase-L, -4, -5, and -7, blocking a negative regulatory effect on c-Jun N-terminal kinase. The synergistic interaction between fXa and TNF was also involved in the inhibition of A20 and I B␣ expression in the I B kinase-NF-B pathway. The data indicate that inhibition of negative regulatory signaling accounts for the amplification of cytokine-induced endothelial cell activation by fXa.cytokines ͉ endothelial cells ͉ factor Xa ͉ inflammation

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Inflammatory imbalance between IL‐10 and TNFα in unstable angina potential plaque stabilizing effects of IL‐10

Abstract: Patients with unstable angina appear to have an imbalance between TNFalpha and IL-10, possibly favouring inflammatory net effects. IL-10 may have beneficial effects on mechanisms that are important in plaque rupture and thrombus formation.

Cited by 101 publications

References 30 publications

Increased Expression of Interleukin-1 in Coronary Artery Disease With Downregulatory Effects of HMG-CoA Reductase Inhibitors

Increased Expression of Interleukin-1 in Coronary Artery Disease With Downregulatory Effects of HMG-CoA Reductase Inhibitors

Interleukin-10 enhances the oxidized LDL-induced foam cell formation of macrophages by antiapoptotic mechanisms

Synergistic induction of tissue factor by coagulation factor Xa and TNF: Evidence for involvement of negative regulatory signaling cascades

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