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CD39 modulates IL-1 release from activated endothelial cells
M Imai1, C Goepfert, E Kaczmarek
1Department of Surgery, Harvard Medical School, Boston, Massachusetts 02215, USA.
Abstract:
The activation of endothelial cells (EC) and monocyte-macrophages (Mφ) by lipopolysaccharide (LPS) is considered an important element of the vascular injury observed in endotoxemia. Interleukin-1 (IL-1) beta release from Mφ in response to LPS, appears to be mediated by the autocrine/paracrine release of ATP via P2X7 receptor activation. In EC, similar nucleotide-mediated signaling pathways may be influenced by high levels of expression of CD39, the vascular nucleoside triphosphate diphosphohydrolase (NTPDase; ENTPD I). To determine whether CD39 modulates ATP-mediated release of IL-1 from EC, we stimulated human EC with LPS and measured levels of ATP secretion and IL-1 release. LPS triggered ATP secretion from EC that was soon followed by IL-1alpha release. Overexpression of CD39 following infection with recombinant CD39 adenoviral vectors (AdCD39) abrogated the initial phase of ATP secretion and inhibited IL-1alpha release; comparable results were obtained with soluble NTPDase. These data demonstrate that CD39/NTPDase modulates IL-1alpha release from LPS stimulated human EC.
Insights
Lipopolysaccharide (LPS) triggers ATP release from endothelial cells (EC), leading to Interleukin-1 alpha (IL-1α) release. CD39/nucleoside triphosphate diphosphohydrolase (NTPDase) inhibits this ATP-mediated IL-1α release in EC.
Area of Science:
- Vascular biology
- Immunology
- Cell signaling
Background:
- Endothelial cell (EC) and monocyte-macrophage activation by lipopolysaccharide (LPS) contributes to vascular injury in endotoxemia.
- Interleukin-1 beta (IL-1β) release from macrophages involves ATP release via P2X7 receptor activation.
- CD39 (nucleoside triphosphate diphosphohydrolase; NTPDase) is highly expressed in EC and may influence nucleotide-mediated signaling.
Purpose of the Study:
- To investigate whether CD39 modulates ATP-mediated Interleukin-1 (IL-1) release from LPS-stimulated human EC.
- To elucidate the role of CD39 in the signaling pathway linking LPS, ATP, and IL-1 release in EC.
Main Methods:
- Human EC were stimulated with LPS.
- ATP and IL-1α secretion levels were measured.
- CD39 was overexpressed using recombinant adenoviral vectors (AdCD39) or by using soluble NTPDase.
Main Results:
- LPS stimulation induced ATP secretion from EC, followed by IL-1α release.
- Overexpression of CD39 abrogated the initial ATP secretion phase and inhibited IL-1α release.
- Soluble NTPDase yielded comparable inhibitory results on IL-1α release.
Conclusions:
- CD39/NTPDase plays a significant role in modulating IL-1α release from LPS-stimulated human EC.
- The findings highlight a novel mechanism involving CD39 in regulating inflammatory responses in EC during endotoxemia.