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Published on: March 24, 2017
Inhibitory effect of recombinant intracellular interleukin 1 receptor antagonist on endothelial cell activation
R Bertini1, M Sironi, I Martin-Padura
1Instituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
Insights
Intracellular interleukin-1 receptor antagonist (icIL-1ra) blocks IL-1 effects on human endothelial cells, including IL-6/IL-8 production and adhesion molecule induction. However, icIL-1ra does not affect lipopolysaccharide (LPS) activation, suggesting distinct inflammatory pathways.
Area of Science:
- Immunology
- Cell Biology
- Vascular Biology
Background:
- Interleukin-1 (IL-1) is a key mediator in inflammatory responses.
- Vascular cells play a crucial role in inflammation and immunity.
- Interleukin-1 receptor antagonist (IL-1ra) is known to inhibit IL-1 activity.
Purpose of the Study:
- To investigate the role of intracellular IL-1ra (icIL-1ra) in modulating IL-1 actions on vascular cells.
- To determine if icIL-1ra affects IL-1-induced inflammatory responses in human endothelial cells (HEC).
- To explore the interaction between icIL-1ra, IL-1, and lipopolysaccharide (LPS) in endothelial cell activation.
Main Methods:
- Utilized recombinant icIL-1ra in experiments with human endothelial cells (HEC).
- Assessed the impact of icIL-1ra on IL-1-induced production of IL-6, IL-8, and monocyte chemotactic protein.
- Evaluated the effect of icIL-1ra on IL-1-induced expression of adhesion molecules in HEC.
- Compared the effects of icIL-1ra on IL-1-stimulated versus LPS-stimulated HEC.
- Analyzed IL-1ra mRNA transcripts in endothelial cells using northern blot analysis.
Main Results:
- Recombinant icIL-1ra significantly inhibited IL-1-induced production of IL-6, IL-8, and monocyte chemotactic protein in HEC.
- icIL-1ra also suppressed the induction of adhesion molecules on HEC by IL-1.
- icIL-1ra did not interfere with the activation of HEC by lipopolysaccharide (LPS).
- Endothelial cells showed minimal IL-1ra mRNA expression under various stimulation conditions.
Conclusions:
- Intracellular IL-1ra effectively blocks IL-1-mediated inflammatory signaling in vascular endothelial cells.
- The lack of interference with LPS activation suggests that extracellular IL-1 is not a primary mediator in LPS-induced endothelial cell responses.
- IL-1ra produced by mononuclear phagocytes may act as a critical regulator of IL-1's effects on endothelial cells, influencing vascular inflammation and immune responses.
Abstract:
This investigation was designed to elucidate whether an intracellular version of interleukin 1 receptor antagonist (icIL-1ra) interferes with the action of IL-1 at the level of vascular cells. Recombinant icIL-1ra inhibited the IL-1-induced production of IL-6, IL-8 and monocyte chemotactic protein by human endothelial cells (HEC). Moreover, icIL-1ra inhibited induction of adhesion molecules by IL-1. Endotoxin lipopolysaccharide (LPS), an IL-1 inducer, stimulated a spectrum of functions in EC similar to that activated by IL-1, but icIL-1ra did not interfere with the LPS activation of EC. This observation suggests that induction of extracellular IL-1 is not an important intermediate event in the response of EC to LPS. Unlike LPS-stimulated monocytes, EC exposed to different inducers did not express appreciable levels of IL-1ra mRNA transcripts as assessed by northern blot analysis. IL-1ra produced by mononuclear phagocytes, represents a negative regulator circuit of the action of IL-1 on EC and could be important in the control of vascular participation in inflammation and immunity.
