Regulatory mechanisms of C4b‐binding protein (C4BP)α and β expression in rat hepatocytes by lipopolysaccharide and interleukin‐6

• Published in: Journal of thrombosis and haemostasis Vol. 6; no. 11; pp. 1858 - 1867
• Main Authors: KISHIWADA, M., HAYASHI, T., YUASA, H., FUJII, K., NISHIOKA, J., AKITA, N., TANAKA, H., IDO, M., OKAMOTO, T., GABAZZA, E. C., ISAJI, S., SUZUKI, K.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01-11-2008
• Subjects: Animals; C4b‐binding protein; CD14; Complement C4b-Binding Protein - analysis; Complement C4b-Binding Protein - genetics; Hepatocytes - metabolism; Interleukin-6 - pharmacology; interleukin‐6; Kinetics; lipopolysaccharide; Lipopolysaccharides - pharmacology; Liver - metabolism; MAP kinase; Mitogen-Activated Protein Kinases; NF-kappa B; NFκB; Protein S - metabolism; Rats; RNA, Messenger - analysis; STAT3 Transcription Factor; STAT‐3; toll‐like receptor‐4
• ISSN: 1538-7933; 1538-7836; 1538-7836
• DOI: 10.1111/j.1538-7836.2008.03129.x

Background: C4b‐binding protein (C4BP), a multimeric protein structurally composed of α chains (C4BPα) and a β chain (C4BPβ), regulates the anticoagulant activity of protein S (PS). Patients with sepsis have increased levels of plasma C4BP, which appears to be induced by interleukin (IL)‐6. However, it is not fully understood how lipopolysaccharide (LPS) and IL‐6 affect the plasma C4BP antigen level and C4BPα and C4BPβ expression in hepatocytes. Objectives: To assess the effect of LPS and IL‐6 on plasma C4BP, PS–C4BP complex levels, PS activity, and C4BP expression by rat liver in vivo and on C4BP expression by isolated rat hepatocytes in vitro. Results: Plasma C4BP antigen level transiently decreased from 2 to 12 h after LPS (2 mg kg−1) injection, and then it abruptly increased up to 24 h after LPS injection. Plasma C4BP antigen level increased until 8 h after IL‐6 (10 μg kg−1) injection, and then gradually decreased up to 24 h after IL‐6 injection. LPS significantly decreased the protein and mRNA expression of both C4BPα and C4BPβ in rat hepatocytes, and this effect was inhibited by NFκB and MEK/ERK inhibitors. IL‐6 mediated increase in C4BPβ expression in rat hepatocytes, which leads to increased plasma PS–C4BP complex level and to decreased plasma PS activity, was inhibited by inhibition of STAT‐3. Conclusion: LPS decreases both C4BPα and C4BPβ expression via the NFκB and MEK/ERK pathways, whereas IL‐6 specifically increases C4BPβ expression via the STAT‐3 pathway, causing an increase in plasma PS–C4BP complex, and thus decreasing the anticoagulant activity of PS.