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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:2168.)
© 2006 American Heart Association, Inc.

Thrombosis

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

Cornelia J.F. de Wolf; Rosemiek M.J. Cupers; Rogier M. Bertina; Hans L. Vos

From the Hemostasis and Thrombosis Research Center, Department of Hematology, Leiden, The Netherlands.

Correspondence to Hans Vos, Leiden University Medical Center, Hemostasis and Thrombosis Research Center, Department of Hematology C2R-139, Leiden, NL-2300 RC, The Netherlands. E-mail h.l.vos{at}lumc.nl

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.

The important anticoagulant Protein S forms inactive complexes with complement component 4b-binding protein (C4BP), which is a known acute phase reactant. This raises the question how Protein S gene (PROS1) transcription is regulated during acute phase. Here we show that PROS1 transcription is upregulated by IL-6 via the STAT3 pathway.

Key Words: protein S • PROS1 • IL-6 • STAT3 • C/EBPß