Interleukin-6 induction of protein s is regulated through signal transducer and activator of transcription 3.
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.


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.


CONCLUSIONS
IL-6 induces PS expression via STAT3. A possible function for IL-6-induced PS expression in cell survival is discussed.
de Wolf
Cornelia J F
CJ
Hemostasis and Thrombosis Research Center, Department of Hematology, Leiden, The Netherlands.
Cupers
Rosemiek M J
RM
Bertina
Rogier M
RM
Vos
Hans L
HL
D045744:Cell Line, Tumor; D005786:Gene Expression Regulation; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology / Q000502:physiology*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D017293:Protein S / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D020218:Response Elements; D050796:STAT3 Transcription Factor / Q000378:metabolism / Q000502:physiology*
D015850:Interleukin-6; D017293:Protein S; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor