Interleukin-6 Induction of Protein S Is Regulated Through Signal Transducer and Activator of Transcription 3

• Published in: Arteriosclerosis, thrombosis, and vascular biology Vol. 26; no. 9; pp. 2168 - 2174
• Main Authors: de Wolf, Cornelia J.F, Cupers, Rosemiek M.J, Bertina, Rogier M, Vos, Hans L
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Heart Association, Inc 01.09.2006; Hagerstown, MD Lippincott
• Subjects: Associated diseases and complications; Atherosclerosis (general aspects, experimental research); Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Cell Line, Tumor; Diabetes. Impaired glucose tolerance; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Gene Expression Regulation; Humans; Interleukin-6 - pharmacology; Interleukin-6 - physiology; Medical sciences; Phosphorylation; Promoter Regions, Genetic; Protein S - biosynthesis; Protein S - genetics; Protein S - metabolism; Response Elements; RNA, Messenger - biosynthesis; STAT3 Transcription Factor - metabolism; STAT3 Transcription Factor - physiology; Vascular disease; Interleukin 6; C/EBPβ; PROS1; Cytokine; Atherosclerosis; STAT3; Cardiovascular disease; Protein S; Vitronectin; IL-6
• ISSN: 1079-5642; 1524-4636
• DOI: 10.1161/01.ATV.0000236202.39165.eb

OBJECTIVE—The protein C anticoagulant pathway is an essential process for attenuating thrombin generation by the membrane-bound procoagulant complexes tenase and prothrombinase. In this pathway, protein S (PS) serves as a cofactor for activated protein C. PS circulates in plasma both in a free form and in complex with complement component 4b-binding protein (C4BP). C4BP is a known acute phase reactant, thereby suggesting a relation between PS and the acute phase response. Interleukin (IL)-6 has been shown to increase both PS and C4BP gene expression. Our objective was to study the regulation of PS gene expression by IL-6 in detail. METHODS AND RESULTS—IL-6 upregulates both PS mRNA and protein levels in liver-derived HepG2 cells. The promoter of the PS gene (PROS1) was cloned upstream from a luciferase reporter gene. After transfection in HepG2 cells, the luciferase activity was shown to be stimulated by the addition of IL-6. IL-6 exerts its effect through Signal Transducer and Activator of Transcription 3 (STAT3) that interacts with the PROS1 promoter at a binding site in between nucleotides 229 to 207 upstream from the translational start. CONCLUSION—IL-6 induces PS expression via STAT3. A possible function for IL-6–induced PS expression in cell survival is discussed.