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Published online before print June 18, 2008

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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0506345

Received for publication May 23, 2006.
Revised April 14, 2008.
Accepted for publication April 23, 2008.

Article

Single-stranded polyinosinic acid oligonucleotides trigger leukocyte production of proteins belonging to fibrinolytic and coagulation cascades

Department of Rheumatology and Inflammation Research, University of Göteborg, Sweden

^@ To whom correspondence should be addressed. E-mail: maria.bokarewa{at}rheuma.gu.se.

	Abstract

The present study assessed the inductory effects of ds- and ssRNA on the leukocyte production of proteins belonging to fibrinolytic and coagulation cascades. Murine splenocytes were stimulated with dsRNA [polyinosinic:polycytidylic acid (polyIC)] and ssRNA sequences [polyinosinic acid (polyI), polycytidylic acid (polyC), and polyuridylic acid (polyU)]. The expression of plasminogen (Plg), tissue factor (TF), IL-6, and IFN- was assessed. Intracellular tranduction mechanisms activated by oligonucleotides were evaluated using specific inhibitors of signaling pathways and genetically modified mice. polyIC efficiently and dose-dependently induced the expression of Plg, IL-6, and IFN-, whereas TF was not induced by polyIC. polyI was unable to trigger IFN- production, and it was efficiently inducing Plg and TF. IFN-R and dsRNA-dependent protein kinase signaling were not required for the polyI-induced production of Plg or TF. Neither polyU nor polyC induced the expression of Plg or TF. Importantly, the presence of U- and C-nucleotide strands in the dsRNA significantly reduced expression of Plg and TF compared with polyI alone. Exposure of splenocytes to polyI activated the NF-B pathway followed by the expression of TF and IL-6. In contrast, Plg production did not require NF-B, was only partly down-regulated by p38 MAPK inhibitor, and was efficiently inhibited by insulin, indicating a different mechanism for its induction. ssRNA exerts its TF-generating properties through NF-B activation in an IFN--independent manner. The expression of fibrinolytic versus coagulation proteins is regulated through distinctly different transduction pathways. As fibrinolytic and coagulation cascades are important components of inflammatory homeostatis, these findings might have importance for developement of new, targeted therapies.

Key Words: RNA • inflammation • plasminogen • tissue factor • coagulation • fibrinolysis