P353	Cardiotrophin-1 induces monocyte chemoattractant protein-1 synthesis in human umbilical vein endothelial cells.
M.Fritzenwanger, F.Kuethe, H.R.Figulla
Department of Internal Medicine I, Friedrich-Schiller-University, Jena, DE.

Background: In chronic heart failure (CHF) Cardiotrophin-1 (CT-1) and monocyte chemoattractant protein-1 (MCP-1) plasma concentrations are elevated. CT-1 is a cytokine of the interleukin-6 (IL-6) superfamily. Most members of the IL-6 family are able to activate human umbilical vein endothelial cells (HUVEC) but so far there are no data which demonstrate that CT-1 can activate HUVEC. Because MCP-1 - as a marker of endothelial activation - is elevated in CHF we examined whether CT-1 will induce MCP-1 production in HUVEC. Methods: MCP-1 mRNA levels were determined by real time PCR and RT-PCR and MCP-1 protein concentrations in the supernatant by ELISA. Signal transducer and activator of transcription 3 (STAT3) and phosphorylated STAT3 (pSTAT3) were determined by western blot analysis. Results: HUVEC were incubated with different CT-1 concentrations for various time periods. CT-1 induced in a time and concentration dependent manner MCP-1 mRNA. Maximal MCP-1 mRNA was reached after 6 hours. After 24 hours CT-1 caused a significant induction of MCP-1 protein in the supernatant compared to control. CT-1 caused a concentration dependent phosphorylation of STAT3 without any change in total-STAT3 concentration. Piceatannol - a specific blocker of STAT3 phosphorylation - inhibited CT-1 induced MCP-1 induction, completely. AG490 – a blocker of JAK2 – was also able to inhibit CT-1 induced MCP-1 induction, indicating that the JAK2 pathway is also necessary for MCP-1 induction. Parthenolide – a blocker of NFkB – inhibited CT-1 induced MCP-1 expression, completely Conclusion: Our data show that CT-1 induces in a concentration and time dependent manner MCP-1 mRNA and protein in HUVEC. STAT3 phosphorylation, the activation of JAK2 and NFkB are involved in this pathway. In CHF CT-1 may be able to induce MCP-1 and this may be responsible for progression of heart failure either by recruiting inflammatory cells within the myocardium or by a direct modulation of myocyte function.

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