Cardiotrophin-1 induces tumor necrosis factor alpha synthesis in human peripheral blood mononuclear cells.
Chronic heart failure (CHF) is associated with elevated concentrations of tumor necrosis factor (TNF) alpha and cardiotrophin-1 (CT-1) and altered peripheral blood mononuclear cell (PBMC) function. Therefore, we tested whether CT-1 induces TNFalpha in PBMC of healthy volunteers. CT-1 induced in PBMC TNFalpha protein in the supernatant and TNFalpha mRNA in a concentration- and time-dependent manner determined by ELISA and real-time PCR, respectively. Maximal TNFalpha protein was achieved with 100 ng/mL CT-1 after 3-6 hours and maximal TNFalpha 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 TNFalpha expression. CT-1 caused a dose dependent nuclear factor (NF) kappaB translocation. Parthenolide inhibited both NFkappaB translocation and TNFalpha protein expression indicating that NFkappaB seems to be necessary. We revealed a new mechanism for elevated serum TNFalpha concentrations and PBMC activation in CHF besides the hypothesis of PBMC activation by bacterial translocation from the gut.
Division of Cardiology, Department of Internal Medicine I, Friedrich-Schiller-University of Jena, Erlanger Allee 101, 07740 Jena, Germany. michael.fritzenwanger@med.uni-jena.de
Michael
M
Fritzenwanger
Katharina
K
Meusel
Christian
C
Jung
Marcus
M
Franz
Zhenhua
Z
Wang
Martin
M
Foerster
Hans-R
HR
Figulla
D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism*; D006333:Heart Failure / Q000378:metabolism; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*
D016207:Cytokines; D016328:NF-kappa B; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C092073:cardiotrophin 1