Endothelial nitric oxide synthase is a key mediator of interleukin-2-induced hypotension and vascular leak syndrome

Area of Science:

• Immunology
• Pharmacology
• Oncology

Background:

• Interleukin-2 (IL-2) is an immunotherapy effective against metastatic melanoma and renal cancer.
• Severe toxicities, including hypotension and vascular leak syndrome (VLS), limit IL-2 clinical use.
• Nitric oxide (NO) is implicated in IL-2-induced toxicities, with endothelial nitric oxide synthase (eNOS) as a potential key source.

Purpose of the Study:

• To investigate the role of eNOS in IL-2-induced hypotension and VLS.
• To determine if inhibiting eNOS-derived NO can mitigate IL-2 toxicities without compromising anti-tumor effects.

Main Methods:

• Mice lacking the eNOS gene (eNOS knockout) were treated with IL-2.
• Blood pressure and vascular leak were assessed.
• Inhibitors of superoxide, NO, and soluble guanylate cyclase (sGC) were used to elucidate mechanisms.
• Methylene blue (MB), an sGC inhibitor, was tested for its effect on IL-2 toxicity and anti-tumor activity.

Main Results:

• eNOS knockout mice were resistant to IL-2-induced hypotension and VLS, unlike wild-type or inducible NO synthase knockout mice.
• IL-2 treatment increased eNOS expression and NO metabolite excretion in eNOS knockout mice.
• Vascular leak was mediated by NO, while hypotension involved superoxide or peroxynitrite.
• Methylene blue treatment inhibited VLS without affecting IL-2's anti-tumor efficacy.

Conclusions:

• Endothelial nitric oxide synthase (eNOS) is a critical mediator of IL-2-induced vascular leak syndrome and hypotension.
• Targeting the eNOS pathway, potentially with agents like methylene blue, may reduce IL-2 toxicity.
• These findings support clinical trials investigating methylene blue co-administration with IL-2 therapy.