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Published on: May 31, 2018
IL-33 stimulates the release of procoagulant microvesicles from human monocytes and differentially increases tissue
Stefan Stojkovic, Åsa Thulin, Lena Hell
1Johann Wojta, Department of Internal Medicine II and Core Facilities, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria, Telephone: +43 1 40400/73500, Fax: +43 1 40400/73587, E-mail: johann.wojta@meduniwien.ac.at, or, Agneta Siegbahn, Department of Medical Sciences, Clinical Chemistry and Science for Life Laboratory, University Hospital and Uppsala University, SE 751 85 Uppsala, Sweden, Tel.: +46 18 611 4251, Fax: +46 18 552562,
Abstract:
Monocytes and monocyte-derived microvesicles (MVs) are the main source of circulating tissue factor (TF). Increased monocyte TF expression and increased circulating levels of procoagulant MVs contribute to the formation of a prothrombotic state in patients with cardiovascular disease. Interleukin (IL)-33 is a pro-inflammatory cytokine involved in atherosclerosis and other inflammatory diseases, but its role in regulating thrombosis is still unclear. The aim of the present study was to investigate the effects of IL-33 on the procoagulant properties of human monocytes and monocyte-derived MVs. IL-33 induced a time- and concentration-dependent increase of monocyte TF mRNA and protein levels via binding to the ST2-receptor and activation of the NF-κB-pathway. The IL-33 treated monocytes also released CD14+TF+ MVs and IL-33 was found to increase the TF activity of both the isolated monocytes and monocyte-derived MVs. The monocytes were classified into subsets according to their CD14 and CD16 expression. Intermediate monocytes (IM) showed the highest ST2 receptor expression, followed by non-classical monocytes (NCM), and classical monocytes (CM). IL-33 induced a significant increase of TF only in the IM (p<0.01), with a tendency in NCM (p=0.06), but no increase was observed in CM. Finally, plasma levels of IL-33 were positively correlated with CD14+TF+ MVs in patients undergoing carotid endarterectomy (r=0.480; p=0.032; n=20). We hereby provide novel evidence that the proinflammatory cytokine IL-33 induces differential TF expression and activity in monocyte subsets, as well as the release of procoagulant MVs. In this manner, IL-33 may contribute to the formation of a prothrombotic state characteristic for cardiovascular disease.
Insights
Interleukin-33 (IL-33) increases tissue factor (TF) in specific monocyte subsets, promoting procoagulant microvesicles. This cytokine may drive the prothrombotic state seen in cardiovascular disease.
Area of Science:
- Immunology
- Cardiovascular Biology
- Thrombosis Research
Background:
- Monocytes and their microvesicles (MVs) are key sources of circulating tissue factor (TF).
- Elevated monocyte TF and procoagulant MVs contribute to a prothrombotic state in cardiovascular disease (CVD).
- The role of the pro-inflammatory cytokine Interleukin-33 (IL-33) in thrombosis remains unclear.
Purpose of the Study:
- To investigate the impact of IL-33 on the procoagulant properties of human monocytes and their derived MVs.
- To elucidate the mechanisms by which IL-33 influences TF expression and activity.
Main Methods:
- Assessed IL-33 effects on monocyte TF mRNA and protein levels.
- Analyzed MV release and TF activity following IL-33 treatment.
- Investigated monocyte subset responses (Classical, Intermediate, Non-classical) based on CD14/CD16 expression.
- Correlated plasma IL-33 levels with CD14+TF+ MVs in patients undergoing carotid endarterectomy.
Main Results:
- IL-33 dose- and time-dependently increased monocyte TF via ST2 receptor and NF-κB pathway activation.
- IL-33 stimulated the release of CD14+TF+ MVs and enhanced TF activity in monocytes and MVs.
- Intermediate monocytes exhibited the highest ST2 expression and significantly increased TF upon IL-33 stimulation.
- Plasma IL-33 levels positively correlated with CD14+TF+ MVs in patients undergoing carotid endarterectomy.
Conclusions:
- IL-33 differentially induces TF expression and activity in human monocyte subsets.
- IL-33 promotes the release of procoagulant microvesicles.
- IL-33 may contribute to the prothrombotic state in cardiovascular disease.
