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Background The cysteine protease legumain is increased in patients with atherosclerosis, but its causal role in atherogenesis and cardiovascular disease is still unclear. The aim of the study was to investigate the association of legumain with clinical outcome in a large cohort of patients with acute coronary syndrome. Methods and Results Serum levels of legumain were analyzed in 4883 patients with acute coronary syndrome from a substudy of the PLATO (Platelet Inhibition and Patient Outcomes) trial. Levels were analyzed at admission and after 1 month follow‐up. Associations between legumain and a composite of cardiovascular death, spontaneous myocardial infarction or stroke, and its individual components were assessed by multivariable Cox regression analyses. At baseline, a 50% increase in legumain level was associated with a hazard ratio (HR) of 1.13 (95% CI, 1.04–1.21), P =0.0018, for the primary composite end point, adjusted for randomized treatment. The association remained significant after adjustment for important clinical and demographic variables (HR, 1.10; 95% CI, 1.02–1.19; P =0.013) but not in the fully adjusted model. Legumain levels at 1 month were not associated with the composite end point but were negatively associated with stroke (HR, 0.62; 95% CI, 0.44–0.88; P =0.0069), including in the fully adjusted model (HR, 0.57; 95% CI, 0.37–0.88; P =0.0114). Conclusions Baseline legumain was associated with the primary outcome in patients with acute coronary syndrome, but not in the fully adjusted model. The association between high levels of legumain at 1 month and decreased occurrence of stroke could be of interest from a mechanistic point of view, illustrating the potential dual role of legumain during atherogenesis and acute coronary syndrome. Registration URL: https://www.clini​caltr​ials.gov ; Unique identifier: NCT00391872.

Background The immune response during falciparum malaria mediates both harmful and protective effects on the host; however the participating molecules have not been fully defined. Interleukin (IL)-27 is a pleiotropic cytokine exerting both inflammatory and anti-inflammatory effects, but data on IL-27 in malaria patients are scarce. Methods Clinical data and blood samples were collected from adults in Mozambique with P. falciparum infection, with (n = 70) and without (n = 61) HIV-1 co-infection, from HIV-infected patients with similar symptoms without malaria (n = 58) and from healthy controls (n = 52). In vitro studies were performed in endothelial cells and PBMC using hemozoin crystals. Samples were analyzed using enzyme immunoassays and quantitative PCR. Results (i) IL-27 was markedly up-regulated in malaria patients compared with controls and HIV-infected patients without malaria, showing no relation to HIV co-infection. (ii) IL-27 was correlated with P. falciparum parasitemia and von Willebrand factor as a marker of endothelial activation, but not with disease severity. (iii) In vitro, IL-27 modulated the hemozoin-mediated cytokine response in endothelial cells and PBMC with enhancing effects on IL-6 and attenuating effects on IL-8. Conclusion Our findings show that IL-27 is regulated during falciparum malaria, mediating both inflammatory and anti-inflammatory effects, potentially playing an immune-regulatory role during falciparum malaria.

Background Ketorolac is an effective non‐steroidal anti‐inflammatory drug, commonly used with local anaesthetics as part of local infiltration analgesia protocols following orthopaedic surgery. However, systemic uptake and drug action may be the major mechanism after local infiltration. The aims of this project were to study the effects of a small, systemically ineffective dose of ketorolac given intra‐articularly for post‐operative pain and also to study synovial inflammatory biomarkers. We investigated whether ketorolac affects pro‐inflammatory biomarkers in an in vitro model, as well. Methods In this placebo‐controlled, blind, randomized study, we analysed intra‐articular ketorolac (5 mg) in ambulatory minor knee surgery patients with moderate or severe pain (n = 44). We assessed post‐operative pain intensity (n = 44) and analysed microdialysis samples taken from knee synovial tissue every 20 min (n = 34). We also tested cyclooxygenase‐independent effects of ketorolac in synovial cells stimulated by prostaglandin E2 and chondroitin sulphate in vitro. Results Intra‐articular ketorolac (5 mg) administration did not reduce pain or synovial pro‐inflammatory cytokines CXCL1, IL‐8, and MCP‐1, 0–120 min after knee arthroscopy. Female gender was a risk factor for moderate or severe pain (relative risk 1.45, 95% confidence interval 1.04–2.01). Paradoxically, ketorolac increased the release of CXCL1 and IL‐8 in prostaglandin E2 and chondroitin sulphate‐stimulated synovial cells in vitro. Conclusion Ketorolac prescribed at a low dose intra‐articularly does not produce any detectable analgesic effect after minor knee surgery. This is the peer reviewed version of the article, which has been published in final form by Wiley. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions."

Background: The gut microbiota represents a potential treatment target in heart failure (HF) through microbial metabolites such as trimethylamine N-oxide (TMAO) and systemic inflammation. Treatment with the probiotic yeast Saccharomyces boulardii have been suggested to improve left ventricular ejection fraction (LVEF). Methods: In a multicentre, prospective randomized open label, blinded end-point trial, we randomized patients with LVEF

Common variable immunodeficiency (CVID) is the most common symptomatic primary immunodeficiency, characterized by inadequate antibody responses and recurrent bacterial infections. Paradoxically, a majority of CVID patients have non-infectious inflammatory and autoimmune complications, associated with systemic immune activation. Our aim was to explore if HDL, known to have anti-inflammatory properties, had impaired function in CVID patients and thereby contributed to their inflammatory phenotype. We found reduced HDL cholesterol levels in plasma of CVID patients compared to healthy controls, particularly in patients with inflammatory and autoimmune complications, correlating negatively with inflammatory markers CRP and sCD25. Reverse cholesterol transport capacity testing showed reduced serum acceptance capacity for cholesterol in CVID patients with inflammatory and autoimmune complications. They also had reduced cholesterol efflux capacity from macrophages to serum and decreased expression of ATP-binding cassette transporter ABCA1. Human HDL suppressed TLR2-induced TNF release less in blood mononuclear cells from CVID patients, associated with decreased expression of transcriptional factor ATF3. Our data suggest a link between impaired HDL function and systemic inflammation in CVID patients, particularly in those with autoimmune and inflammatory complications. This identifies HDL as a novel therapeutic target in CVID as well as other more common conditions characterized by sterile inflammation or autoimmunity. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

Background Termination of acute inflammation is an active process orchestrated by lipid mediators (LM) derived from polyunsaturated fatty acids, referred to as specialized pro-resolving mediators (SPM). These mediators also provide novel therapeutic opportunities for treating inflammatory disease. However, the regulation of these molecules following acute myocardial infarction (MI) remains of interest. Methods In this prospective observational study we aimed to profile plasma levels of SPMs in ST-elevation MI (STEMI) patients during the first week following MI. Plasma LM concentrations were measured in patients with STEMI (n = 15) at three time points and compared with stable coronary artery disease (CAD; n = 10) and healthy controls (n = 10). Findings Our main findings were: (i) Immediately after onset of MI and before peak troponin T levels, STEMI patients had markedly increased levels of SPMs as compared with healthy controls and stable CAD patients, with levels of these mediators declining during follow-up. (ii) The increase in SPMs primarily reflected an increase in docosapentaenoic acid- and docosahexaenoic acid-derived protectins. (iii) Several individual protectins were correlated with the rapid increase in neutrophil counts, but not with CRP. (iv) A shift in 5-LOX activity from the leukotriene B4 pathway to the pro-resolving RvTs was observed. Interpretation The temporal regulation of SPMs indicates that resolution mechanisms are activated early during STEMI as part of an endogenous mechanism to initiate repair. Thus strategies to boost the activity and/or efficacy of these endogenous mechanisms may represent novel therapeutic opportunities for treatment of patients with MI. Fund This work was supported by grants from the South-Eastern Norwegian regional health authority, the European Research Council under the European Union's Horizon 2020 research and innovation program, a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society, and the Barts Charity.

Background Lesional and systemic oxidative stress has been implicated in the pathogenesis of atherosclerosis, potentially leading to accumulation of DNA base lesions within atherosclerotic plaques. Although base excision repair (BER) is a major pathway counteracting oxidative DNA damage, our knowledge on BER and accumulation of DNA base lesions in clinical atherosclerosis is scarce. Here, we evaluated the transcriptional profile of a wide spectrum of BER components as well as DNA damage accumulation in atherosclerotic and non-atherosclerotic arteries. Methods BER gene expression levels were analyzed in 162 carotid plaques, 8 disease-free carotid specimens from patients with carotid plaques and 10 non-atherosclerotic control arteries. Genomic integrity, mitochondrial (mt) DNA copy number, oxidative DNA damage and BER proteins were evaluated in a subgroup of plaques and controls. Results Our major findings were: (i) The BER pathway showed a global increased transcriptional response in plaques as compared to control arteries, accompanied by increased expression of several BER proteins. (ii) Whereas nuclear DNA stability was maintained within carotid plaques, mtDNA integrity and copy number were decreased. (iii) Within carotid plaques, mRNA levels of several BER genes correlated with macrophage markers. (iv) In vitro , some of the BER genes were highly expressed in the anti-inflammatory and pro-resolving M2 macrophages, showing increased expression upon exposure to modified lipids. Conclusions The increased transcriptional response of BER genes in atherosclerosis may contribute to lesional nuclear DNA stability but appears insufficient to maintain mtDNA integrity, potentially influencing mitochondrial function in cells within the atherosclerotic lesion.

Aims/hypothesis Activation of inflammatory pathways is involved in the pathogenesis of type 2 diabetes mellitus. On the basis of its role in vascular inflammation and in metabolic disorders, we hypothesised that the TNF superfamily (TNFSF) member 14 (LIGHT/TNFSF14) could be involved in the pathogenesis of type 2 diabetes mellitus. Methods Plasma levels of LIGHT were measured in two cohorts of type 2 diabetes mellitus patients (191 Italian and 40 Norwegian). Human pancreatic islet cells and arterial endothelial cells were used to explore regulation and relevant effects of LIGHT in vitro. Results Our major findings were: (1) in both diabetic cohorts, plasma levels of LIGHT were significantly raised compared with sex- and age-matched healthy controls (n = 32); (2) enhanced release from activated platelets seems to be an important contributor to the raised LIGHT levels in type 2 diabetes mellitus; (3) in human pancreatic islet cells, inflammatory cytokines increased the release of LIGHT and upregulated mRNA and protein levels of the LIGHT receptors lymphotoxin β receptor (LTβR) and TNF receptor superfamily member 14 (HVEM/TNFRSF14); (4) in these cells, LIGHT attenuated the insulin release in response to high glucose at least partly via pro-apoptotic effects; and (5) in human arterial endothelial cells, glucose boosted inflammatory response to LIGHT, accompanied by an upregulation of mRNA levels of HVEM (also known as TNFRSF14) and LTβR (also known as LTBR). Conclusions/interpretation Our findings show that patients with type 2 diabetes mellitus are characterised by increased plasma LIGHT levels. Our in vitro findings suggest that LIGHT may contribute to the progression of type 2 diabetes mellitus by attenuating insulin secretion in pancreatic islet cells and by contributing to vascular inflammation. Electronic supplementary material The online version of this article (doi:10.1007/s00125-016-4036-y) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

Background and purpose γ-butyrobetaine (γBB) is a metabolite from dietary Carnitine, involved in the gut microbiota-dependent conversion from Carnitine to the pro-atherogenic metabolite trimethylamine-N-oxide (TMAO). Orally ingested γBB has a pro-atherogenic effect in experimental studies, but γBB has not been studied in relation to atherosclerosis in humans. The aim of this study was to evaluate associations between serum levels of γBB, TMAO and their common precursors Carnitine and trimethyllysine (TML) and carotid atherosclerosis and adverse outcome. Methods Serum γBB, Carnitine, TML and TMAO were quantified by high performance liquid chromatography in patients with carotid artery atherosclerosis (n = 264) and healthy controls (n = 62). Results Serum γBB (p = 0.024) and Carnitine (p = 0.001), but not TMAO or TML, were increased in patients with carotid atherosclerosis. Higher levels of γBB and TML, but not TMAO or Carnitine were independently associated with cardiovascular death also after adjustment for age and eGFR (adjusted HR [95%] 3.3 [1.9–9.1], p = 0.047 and 6.0 [1.8–20.34], p = 0.026, respectively). Conclusions Patients with carotid atherosclerosis had increased serum levels of γBB, and elevated levels of γBB and its precursor TML were associated with cardiovascular mortality. Long-term clinical studies of γBB, as a cardiovascular risk marker, and safety studies regarding dietary supplementation of γBB, are warranted.

Background Soluble lectin‐like oxidized low‐density lipoprotein receptor‐1 ( sLOX ‐1) has been shown to be increased in patients with acute ischemic stroke. Here, we evaluated plasma sLOX ‐1 levels and vascular carotid plaque LOX ‐1 (ie, OLR 1 ) gene expression in patients with ischemic stroke and transient ischemic attack ( TIA ) with particular focus on their relation to time since symptom onset. Methods and Results Plasma sLOX ‐1 (n=232) and carotid plaque OLR 1 gene expression (n=146) were evaluated in patients who were referred to evaluation for carotid endarterectomy, as well as in healthy control plasma (n=81). Patients were categorized according to presence of acute ischemic stroke or transient ischemic attack (n=35) ≤7 days, >7 days ≤3 months (n=90), >3 months (n=40), or no reported symptoms before study inclusion (n=67). Our major findings were the following: (1) Patients with carotid atherosclerosis had increased plasma sLOX ‐1 levels as compared with controls. (2) Plaque OLR 1 mRNA levels were increased in carotid plaques (n=146) compared with nonatherosclerotic vessels (ie, common iliac arteries of organ donors, n=10). (3) There were no differences in sLOX plasma levels or OLR 1 gene expression when analyzed according to the time since relevant cerebral ischemic symptoms. (4) Also patients with severe carotid atherosclerosis without any previous ischemic events had raised sLOX ‐1 levels. (5) Immunostaining showed colocalization between LOX ‐1 and macrophages within the carotid plaques. (6) Also patients with acute stroke (within 7 days) caused by atrial fibrillation (n=22) had comparable raised sLOX ‐1 levels. Conclusions sLOX ‐1 levels are elevated in patients with ischemic stroke and transient ischemic attack independent of cause and time since the ischemic event.

Background: Elevated interleukin-6 (IL-6) and complement activation are associated with detrimental effects of inflammation in coronary artery disease (CAD). The complement anaphylatoxins C5a and C3a interact with their receptors; the highly inflammatory C5aR1, and the C5aR2 and C3aR. We evaluated the effect of the IL-6 receptor (IL-6R)-antagonist tocilizumab on the expression of the anaphylatoxin receptors in whole blood from non-ST-elevation myocardial infarction (NSTEMI) patients. Separately, anaphylatoxin receptor expression in peripheral blood mononuclear cells (PBMC) from patients with different entities of CAD was investigated. Materials and Methods: NSTEMI patients were randomized to one dose of tocilizumab (n = 28) or placebo (n = 32) and observed for 6 months. Whole blood samples drawn at inclusion, at day 2, 3 and after 6 months were used for mRNA isolation. Plasma was prepared for analysis of complement activation measured as sC5b-9 by ELISA. Furthermore, patients with different CAD entities comprising stable angina pectoris (SAP, n = 22), non-ST-elevation acute coronary syndrome (NSTE-ACS, n = 21) and ST-elevation myocardial infarction (STEMI, n = 20) were included. PBMC was isolated from blood samples obtained at admission to hospital and mRNA isolated. Anaphylatoxin-receptor-expression was analyzed with qPCR using mRNA from whole blood and PBMC, respectively. Results: Our main findings were (i) Tocilizumab decreased C5aR1 and C5aR2 mRNA expression significantly (p < 0.001) and substantially (>50%) at day 2 and 3, whereas C3aR expression was unaffected. (ii) Tocilizumab did not affect complement activation. (iii) In analyzes of different CAD entities, C5aR1 expression was significantly increased in all CAD subgroups compared to controls with the highest level in the STEMI patients (p < 0.001). For C5aR2 and C3aR the expression compared to controls were more moderate with increased expression of C5aR2 in the STEMI group (p < 0.05) and C3aR in the NSTE-ACS group (p < 0.05). Conclusion: Expression of C5aR1 and C5aR2 in whole blood was significantly attenuated by IL-6R-inhibition in NSTEMI patients. These receptors were significantly upregulated in PBMC CAD patients with particularly high levels of C5aR1 in STEMI patients. Copyright © 2018 Orrem, Nilsson, Pischke, Kleveland, Yndestad, Ekholt, Damås, Espevik, Bendz, Halvorsen, Gregersen, Wiseth, Andersen, Ueland, Gullestad, Aukrust, Barratt-Due and Mollnes. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY).

Recent metabolomic, experimental and clinical studies have demonstrated that trimethylamine-N-oxide (TMAO), a microbiota-dependent metabolite from dietary phosphatidylcholine and carnitine, is a strong predictor of coronary artery disease (CAD). This finding suggests a link between the gut microbiota and atherosclerosis. The potential impact of TMAO in chronic heart failure (HF) is unknown. We hypothesized that TMAO levels would provide prognostic information about adverse outcomes in chronic HF.Prospective, observational study including 155 consecutive patients with chronic HF. In addition, 100 patients with stable CAD without HF and 33 matched healthy individuals were included as controls. Plasma levels of TMAO and its precursors choline and betaine were measured, and associations with symptoms, aetiology and transplant-free survival in the patients with HF were explored.Plasma levels of TMAO (P = 0.01), choline (P0.001) and betaine (P0.001) were elevated in patients with chronic HF compared to control subjects, with the highest levels in patients with New York Heart Association (NYHA) classes III and IV. Furthermore, TMAO levels were highest in individuals with ischaemic HF, followed by those with stable CAD and nonischaemic HF. TMAO, but not choline or betaine, was associated with reduced transplant-free survival: approximately 50% of patients in the upper tertile of TMAO levels died or received a heart transplant during 5.2 years of follow-up (unadjusted Cox-regression: hazard ratio 2.24, 95% confidence interval 1.28-3.92, P = 0.005).TMAO levels were elevated in patients with HF and associated with NYHA class, ischaemic aetiology and adverse outcomes. Future studies should focus on gut microbiota, dietary composition and intestinal dysfunction in relation to TMAO levels and clinical outcome in HF.

Aim Interleukin-27 (IL-27) is involved in different inflammatory diseases; however, its role in atherosclerosis is unclear. In this study we investigated the expression of IL-27 and its receptor in patients with carotid atherosclerosis and if IL-27 could modulate the inflammatory effects of the NLRP3 inflammasome in vitro. Methods Plasma IL-27 was measured by enzyme immunoassay in patients with carotid stenosis (n = 140) and in healthy controls (n = 19). Expression of IL-27 and IL-27R was analyzed by quantitative PCR and immunohistochemistry in plaques from patients and in non-atherosclerotic vessels. THP-1 monocytes, primary monocytes and peripheral blood mononuclear cells (PBMCs) were used to study effects of IL-27 in vitro. Results Our main findings were: (i) Plasma levels of IL-27 were significantly elevated in patients with carotid atherosclerotic disease compared to healthy controls. (ii) Gene expression of IL-27 and IL-27R was significantly elevated in plaques compared to control vessels, and co-localized to macrophages. (iii) In vitro, IL-27 increased NLRP3 inflammasome activation in monocytes with enhanced release of IL-1 β. Conclusions We demonstrate increased levels of IL-27 and IL-27R in patients with carotid atherosclerosis. Our in vitro findings suggest an inflammatory role for IL-27, which can possibly be linked to atherosclerotic disease development. © 2017 Gregersen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

The cysteine protease legumain has been shown to be up-regulated in unstable atherosclerotic plaques. This study aims to further elucidate legumain in atherosclerosis, by examining legumain in plasma and carotid plaques from patients with carotid stenosis. Furthermore, legumain secretion from monocyte-derived macrophages treated with atherogenic lipids during macrophage polarization was studied.Plasma levels of legumain from patients with carotid stenosis (n = 254), healthy controls (n = 91), and secreted from monocyte-derived macrophages were assessed by enzyme-linked-immunosorbent assay. Quantitative PCR and immunoblotting of legumain were performed on isolated plaques and legumain localization was visualized by immunohistochemistry and fluorescence microscopy. Monocyte-derived macrophages polarized to M1 or M2 macrophages were treated with VLDL, oxLDL or cholesterol crystals (CC) and the level of legumain analysed.Patients with carotid stenosis had significantly higher levels of plasma legumain compared with healthy controls (median 2.0 versus 1.5 ng/ml, respectively; p = 0.003), although there was no correlation between the level of legumain and the degree of stenosis, and legumain was not an independent factor to identify patients with carotid plaques. Moreover, patients with symptoms the last 2 months had higher expressions of mature legumain, cystatin C and E/M, and the macrophage markers CD80 (M1) and CD163 (M2). Legumain co-localized with both M1 and M2 macrophages within plaques, whereas legumain mRNA expression was significantly higher (p 0.0001) in plaques compared to non-atherosclerotic arteries (controls). Furthermore, in vitro studies showed significantly increased secretion of legumain from pro-inflammatory M1 compared to pro-resolving M2 macrophages (p = 0.014), and particularly in M1 treated with CC. In plaques, legumain was localized to structures resembling foam cells.Legumain is increased in both plasma and plaques of patients with carotid stenosis and might be a new and early biomarker of atherosclerosis.

Objective: Atherosclerosis is a chronic inflammatory disorder that involves a range of inflammatory mediators. Although interleukin (IL)-9 has been related to inflammation, there are at present no data on its role in atherosclerosis. Here we have examined IL-9 and IL-9 receptor (IL-9R) systemically and locally in patients with coronary and carotid atherosclerosis. Methods: Plasma IL-9 was quantified by enzyme immunoassay and multiplex technology. IL-9 and IL-9R mRNA were quantified by real-time RT-PCR, and their localization within the lesion was assessed by immunohistochemistry. Results: The main findings were: (i) Patients with carotid atherosclerosis had significantly raised IL-9 plasma levels compared with healthy controls (n = 28), with no differences between asymptomatic (n = 56) and symptomatic (n = 88) patients. (ii) On admission, patients with acute ST-elevation myocardial infarction (STEMI) (n = 42) had markedly raised IL-9 plasma levels which gradually declined during the first week post-MI. (iii) T cells and monocytes from patients with unstable angina (n = 17) had increased mRNA levels of IL-9 as compared with controls (n = 11). (iv) Carotid plaques (n = 68) showed increased mRNA levels of IL-9 and IL-9R compared to non-atherosclerotic vessels (n = 10). Co-localization to T cells (IL-9 and IL-9R) and macrophages (IL-9) were shown by immunohistochemistry. (v) IL-9 increased IL-17 release in peripheral blood mononuclear cells from patients with unstable angina (n = 5) and healthy controls (n = 5) with a particularly enhancing effect in cells from the patient group. Conclusion: Our findings show increased IL-9 levels in different atherosclerotic disorders both systemically and within the lesion, suggesting a role for the IL-9/IL-9R axis in the atherosclerotic process, potentially involving IL-17 mediated mechanisms. However, the functional consequences of these findings should be further investigated.

Background and Purpose— Interleukin (IL)-23 is a cytokine in the IL-12 family, mainly produced by antigen-presenting cells with a central role in inflammation. We hypothesize that IL-23 is also important in atherogenesis and investigate this in a population with carotid atherosclerosis. Methods— Plasma levels of IL-23 were measured in patients with carotid artery stenosis and in healthy controls. The mRNA levels of IL-23 and its receptor, IL-23R, were measured in atherosclerotic plaques, nonatherosclerotic vessels, peripheral blood mononuclear cells, and plasmacytoid dendritic cells. Results— Our findings were as follows: (1) patients with carotid atherosclerosis (n=177) had significantly raised plasma levels of IL-23 when compared with healthy controls (n=24) with particularly high levels in those with the most recent symptoms. (2) mRNA levels of IL-23 and IL-23R were markedly increased in carotid plaques (n=68) when compared with nonatherosclerotic vessels (n=8–10). Immunostaining showed colocalization to plaque macrophages. (3) Patients with carotid atherosclerosis had increased mRNA levels of both IL-23 and IL-23R in plasmacytoid dendritic cells, but not in peripheral blood mononuclear cells. (4) IL-23 increased IL-17 release in monocytes and particularly in peripheral blood mononuclear cells from patients with carotid atherosclerosis, but not in cells from healthy controls. (5) IL-23 gave a prominent tumor necrosis factor release in monocytes from patients with carotid atherosclerosis but not in cells from healthy controls. (6) High plasma levels of IL-23 were associated with increased mortality during follow-up. Conclusions— We have shown an association between IL-23 and disease progression in patients with carotid atherosclerosis, potentially involving IL-17-related mechanisms.