Cardiotrophin-1 Induces Tumor Necrosis Factor Synthesis in Human Peripheral Blood Mononuclear Cells

Michael Fritzenwanger,Hans-R Figulla,Martin Foerster,Zhenhua Wang,Christian Jung,Katharina Meusel,Marcus Franz

doi:10.1155/2009/489802

Abstract

Chronic heart failure (CHF) is associated with elevated concentrations of tumor necrosis factor (TNF) α and cardiotrophin-1 (CT-1) and altered peripheral blood mononuclear cell (PBMC) function. Therefore, we tested whether CT-1 induces TNFα in PBMC of healthy volunteers. CT-1 induced in PBMC TNFα protein in the supernatant and TNFα mRNA in a concentration- and time-dependent manner determined by ELISA and real-time PCR, respectively. Maximal TNFα protein was achieved with 100 ng/mL CT-1 after 3–6 hours and maximal TNFα mRNA induction after 1 hour. ELISA data were confirmed using immunofluorescent flow cytometry. Inhibitor studies with actinomycin D and brefeldin A showed that both protein synthesis and intracellular transport are essential for CT-1 induced TNFα expression. CT-1 caused a dose dependent nuclear factor (NF) κB translocation. Parthenolide inhibited both NFκB translocation and TNFα protein expression indicating that NFκB seems to be necessary. We revealed a new mechanism for elevated serum TNFα concentrations and PBMC activation in CHF besides the hypothesis of PBMC activation by bacterial translocation from the gut.

Highlights

Chronic heart failure (CHF) is the failure of the heart to generate sufficient cardiac output, but is a multisystemic disorder with immune activation leading to increased concentrations of several cytokines [1].In CHF several studies showed increased concentrations of proinflammatory cytokines such as TNFα, interleukin (IL)-1, IL-6, IL-18, and cardiotrophin-1 (CT-1) [2,3,4,5]
In monocytes we found a concentration-dependent increase of intracellular TNFα after CT-1 application (Figure 1(b))
These results showed that CT-1 induced TNFα in PBCM independent of culture conditions and independent of determination methodes

Summary

Introduction

CHF is the failure of the heart to generate sufficient cardiac output, but is a multisystemic disorder with immune activation leading to increased concentrations of several cytokines [1]. In CHF several studies showed increased concentrations of proinflammatory cytokines such as TNFα, interleukin (IL)-1, IL-6, IL-18, and cardiotrophin-1 (CT-1) [2,3,4,5]. One of the most examined proinflammatory molecules in CHF is TNFα. The effects of TNFα on cardiac function are concentration and timedependent. Short-term TNFα expression is thought to be an adaptive mechanism; whereas prolonged expression causes left ventricular dysfunction and cardiomyopathy leading to CHF propagation. TNFα influences the heart itself but causes endothelial dysfunction and peripheral muscle wasting [6]

Methods

Results

Conclusion