Tumor necrosis factor alpha and interleukin 1beta are responsible for in vitro myocardial cell depression induced by human septic shock serum

Kumar, Anand; Thota, V; Dee, Linda; Olson, Jeanne; Uretz, Eugene; Je, Parrillo

doi:10.1016/s0300-9572(96)90072-6

Cited by 106 publications

(138 citation statements)

References 28 publications

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“…TNF-␣ and IL-1␤ levels in serum derived from healthy volunteers were not measurable at the detection limit of the assay, 0.5 pg/ml. All 10 HSS samples had previously been shown to exert substantial myocardial depressant effect in previous series of experiments, whereas such activity was absent in serum from normal volunteers (3)(4)(5)31).…”

Section: Resultsmentioning

confidence: 96%

“…The mechanism by which the heart becomes dysfunctional in septic shock and sepsis-associated organ failure has been the subject of recent investigations. Studies have implicated a circulating substance generated during human septic shock (3,4,31). Serum from patients with septic shock directly induces depression of maximum extent and peak velocity of contraction in beating rat ventricular myocytes in culture.…”

Section: Discussionmentioning

confidence: 99%

“…The 5Ј to 3Ј STAT, IRF, and NF-B sequences as indicated were annealed to the complementary bottom strand and used as the template for [␥-32 P]ATP labeling: 5Ј-TTCCGGGAA-3Ј for binding to STAT1; 5Ј-(AAGTGA) 4 -3Ј for IRF1 and IRF2; 5Ј-TGGGGACTTTCCGC-3Ј for NF-B. Where indicated, nuclear extracts were preincubated with antibody for 10 min at room temperature prior to the addition of the radiolabeled probe.…”

Section: Stat Irf and Nf-b Electrophoretic Mobility Shift Assay (Emmentioning

confidence: 99%

“…In either case, cardiac dysfunction is typical (1,2). Myocardial depression in human septic shock has been linked to circulating myocardial depressant substances (3,4). Although several potential mechanisms have been implicated in septic myocardial depression, including NO generation (5), adhesion molecule expression (6,7), and apoptosis (8 -10), the specific intracellular signaling mechanisms underlying the process have yet to be elucidated.…”

mentioning

confidence: 99%

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Human Serum from Patients with Septic Shock Activates Transcription Factors STAT1, IRF1, and NF-κB and Induces Apoptosis in Human Cardiac Myocytes

Kumar

Paul

et al. 2005

Journal of Biological Chemistry

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Proinflammatory cytokines have been linked to depression of myocardial contractility in vivo in patients with acute septic shock and in vitro models employing isolated myocytes exposed to serum from such patients. The key pathways involved in mediating this septic organ dysfunction (cell adhesion molecule expression, inducible nitric-oxide synthase induction, and apoptosis) are known to be regulated by transcription factors STAT1, IRF1, and NF-B. Utilizing a model that mimics human disease, we have demonstrated activation of the transcription factors STAT1, IRF1, and NF-B in human fetal myocytes exposed to human septic serum. Both reporter and electrophoretic mobility shift assays demonstrated a 5-19-fold increase in activation of transcription factors STAT1, IRF1, and NF-B in response to incubation with human septic serum. The addition of human septic serum to human fetal myocytes induced apoptosis in human fetal myocytes and activation of the mitogen-activated protein kinase c-Jun NH 2 -terminal kinase and caspase 1 as measured by Western blot. These data suggest that transcription factor activation and early myocyte apoptosis play a mechanistic role in septic myocardial depression and sepsis-induced organ dysfunction.

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Section: Resultsmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Section: Stat Irf and Nf-b Electrophoretic Mobility Shift Assay (Emmentioning

confidence: 99%

mentioning

confidence: 99%

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Human Serum from Patients with Septic Shock Activates Transcription Factors STAT1, IRF1, and NF-κB and Induces Apoptosis in Human Cardiac Myocytes

Kumar

Paul

et al. 2005

Journal of Biological Chemistry

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“…IL-1␤ and TNF-␣ have also been implicated in the pathogenesis of human myocardial suppression in sepsis (30,31). The mechanism(s) by which IL-1␤ and TNF-␣ induce contractile dysfunction has also been linked to NO and changes in cellular calcium handling (31).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of caspase 1 reduces human myocardial ischemic dysfunction via inhibition of IL-18 and IL-1β

Pomerantz

Reznikov

Harken

et al. 2001

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

284

188

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The proinflammatory cytokine IL-18 was investigated for its role in human myocardial function. An ischemia͞reperfusion (I͞R) model of suprafused human atrial myocardium was used to assess myocardial contractile force. Addition of IL-18 binding protein (IL-18BP), the constitutive inhibitor of IL-18 activity, to the perifusate during and after I͞R resulted in improved contractile function after I͞R from 35% of control to 76% with IL-18BP. IL-18BP treatment also preserved intracellular tissue creatine kinase levels (by 420%). Steady-state mRNA levels for IL-18 were elevated after I͞R, and the concentration of IL-18 in myocardial homogenates was increased (control, 5.8 pg͞mg vs. I͞R, 26 pg͞mg; P < 0.01). Active IL-18 requires cleavage of its precursor form by the IL-1␤-converting enzyme (caspase 1); inhibition of caspase 1 also attenuated the depression in contractile force after I͞R (from 35% of control to 75.8% in treated atrial muscle; P < 0.01). Because caspase 1 also cleaves the precursor IL-1␤, IL-1 receptor blockade was accomplished by using the IL-1 receptor antagonist. IL-1 receptor antagonist added to the perifusate also resulted in a reduction of ischemia-induced contractile dysfunction. These studies demonstrate that endogenous IL-18 and IL-1␤ play a significant role in I͞R-induced human myocardial injury and that inhibition of caspase 1 reduces the processing of endogenous precursors of IL-18 and IL-1␤ and thereby prevents ischemia-induced myocardial dysfunction.

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Interleukin‐1 blockade in heart failure with preserved ejection fraction: rationale and design of the Diastolic Heart Failure Anakinra Response Trial 2 (D‐HART2)

Tassell

Buckley

Carbone

et al. 2017

Clinical Cardiology

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Heart failure with preserved ejection fraction (HFpEF) now accounts for the majority of confirmed HF cases in the United States. However, there are no highly effective evidence-based treatments currently available for these patients. Inflammation correlates positively with adverse outcomes in HF patients. Interleukin (IL)-1, a prototypical inflammatory cytokine, has been implicated as a driver of diastolic dysfunction in preclinical animal models and a pilot clinical trial. The Diastolic Heart Failure Anakinra Response Trial 2 (D-HART2) is a phase 2, 2:1 randomized, double-blind, placebo-controlled clinical trial that will test the hypothesis that IL-1 blockade with anakinra (recombinant human IL-1 receptor antagonist) improves (1) cardiorespiratory fitness, (2) objective evidence of diastolic dysfunction, and (3) elevated inflammation in patients with HFpEF (http://www.ClinicalTrials.gov NCT02173548). The co–primary endpoints will be placebo-corrected interval changes in peak oxygen consumption and ventilatory efficiency at week 12. In addition, secondary and exploratory analyses will investigate the effects of IL-1 blockade on cardiac structure and function, systemic inflammation, endothelial function, quality of life, body composition, nutritional status, and clinical outcomes. The D-HART2 clinical trial will add to the growing body of evidence on the role of inflammation in cardiovascular disease, specifically focusing on patients with HFpEF.

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Tumor necrosis factor alpha and interleukin 1beta are responsible for in vitro myocardial cell depression induced by human septic shock serum

Cited by 106 publications

References 28 publications

Human Serum from Patients with Septic Shock Activates Transcription Factors STAT1, IRF1, and NF-κB and Induces Apoptosis in Human Cardiac Myocytes

Human Serum from Patients with Septic Shock Activates Transcription Factors STAT1, IRF1, and NF-κB and Induces Apoptosis in Human Cardiac Myocytes

Inhibition of caspase 1 reduces human myocardial ischemic dysfunction via inhibition of IL-18 and IL-1β

Interleukin‐1 blockade in heart failure with preserved ejection fraction: rationale and design of the Diastolic Heart Failure Anakinra Response Trial 2 (D‐HART2)

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