Recombinant IL-37 Exerts an Anti-inflammatory Effect on Human Aortic Valve Interstitial Cells through Extracellular...

Area of Science:

• Cardiovascular Biology
• Immunology
• Cell Biology

Background:

• Calcific aortic valve disease (CAVD) is a progressive inflammatory condition.
• Interleukin-37 (IL-37) has shown anti-inflammatory properties in aortic valve interstitial cells (AVICs).
• The intracellular mechanisms of IL-37's anti-inflammatory action in CAVD are not fully understood.

Purpose of the Study:

• To investigate the intracellular anti-inflammatory effects of recombinant IL-37 in human AVICs.
• To determine the role of endocytosis and nuclear targeting in IL-37's mechanism of action.
• To elucidate the distinct pathways of IL-37's extracellular and intracellular anti-inflammatory activities.

Main Methods:

• Human AVICs were treated with recombinant IL-37 and soluble extracellular matrix (ECM) proteins.
• Endocytic pathways were blocked to assess IL-37 internalization.
• IL-37 and a nuclear-localized mutant (IL-37D20A) were overexpressed in AVICs.
• NF-κB activation, ICAM-1, and VCAM-1 expression were analyzed.

Main Results:

• Recombinant IL-37 suppressed AVIC inflammatory responses to soluble ECM proteins.
• IL-37 was internalized by AVICs via endocytosis, independent of IL-18Rα.
• Blocking endocytosis reduced IL-37's anti-inflammatory potency.
• Overexpression of wild-type IL-37, but not IL-37D20A, inhibited NF-κB activation and inflammatory marker production.
• IL-37 acts intracellularly through a nucleus-targeting mechanism.

Conclusions:

• Recombinant IL-37 exerts potent anti-inflammatory effects in CAVD AVICs through both extracellular and intracellular mechanisms.
• IL-37 internalization via endocytosis is crucial for its intracellular anti-inflammatory action.
• Nuclear targeting of IL-37 is essential for its intracellular anti-inflammatory effects, including NF-κB inhibition.