Abstract
Ion transport modulators are most commonly used to treat various noncommunicable diseases including diabetes and hypertension. They are also known to bind to receptors on various immune cells, but the immunomodulatory properties of most ion transport modulators have not been fully elucidated. We assessed the effects of thirteen FDA-approved ion transport modulators, namely, ambroxol HCl, amiloride HCl, diazoxide, digoxin, furosemide, hydrochlorothiazide, metformin, omeprazole, pantoprazole, phenytoin, verapamil, drug X, and drug Y on superoxide production, nitric oxide production, and cytokine expression by THP-1-derived macrophages that had been stimulated with ethanol-inactivated Mycobacterium bovis BCG. Ambroxol HCl, diazoxide, digoxin, furosemide, hydrochlorothiazide, metformin, pantoprazole, phenytoin, verapamil, and drug Y had an inhibitory effect on nitric oxide production, while all the test drugs had an inhibitory effect on superoxide production. Amiloride HCl, diazoxide, digoxin, furosemide, phenytoin, verapamil, drug X, and drug Y enhanced the expression of IL-1β and TNF-α. Unlike most immunomodulatory compounds currently in clinical use, most of the test drugs inhibited some inflammatory processes while promoting others. Ion pumps and ion channels could therefore serve as targets for more selective immunomodulatory agents which do not cause overt immunosuppression.
Highlights
The use of immunomodulators has increased significantly over the last few decades, in part due to a rise in the prevalence of autoimmune diseases worldwide [1, 2]
Nitric oxide production was lower in macrophages that were treated with ambroxol HCl, diazoxide, digoxin, furosemide, HCTZ, metformin, pantoprazole, phenytoin, verapamil, or drug Y than in drug-free controls (p < 0:001, Figure 1)
There was no significant difference in nitric oxide production between drug-free controls and cultures that were treated with omeprazole or drug X
Summary
The use of immunomodulators has increased significantly over the last few decades, in part due to a rise in the prevalence of autoimmune diseases worldwide [1, 2]. Corticosteroids and nonsteroidal anti-inflammatory drugs (NSAIDS) are two of the oldest and most commonly used classes of immunomodulators in clinical practice. Corticosteroids bind to cytoplasmic steroid receptors, following which the receptor-ligand complex traverses the nuclear membrane and modulates the transcription of various genes [3]. In addition to modulating transcription, corticosteroids can directly modulate the activity of various proteins including G-protein-coupled receptors [4]. Corticosteroids induce a wide range of physiological changes and are associated with numerous adverse effects including osteoporosis and Cushing’s syndrome [5]
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