Ion Transport Modulators Differentially Modulate Inflammatory Responses in THP-1-Derived Macrophages

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.

Captopril Combined with Furosemide or Hydrochlorothiazide Affects Macrophage Functions in Mouse Contact Hypersensitivity Response

“…Furosemide inhibits the expression of iNOS and the production of nitric oxide [ 17 , 67 ]. Similar to the research of the cited authors, our studies have shown that furosemide reduces NO secretion and, interestingly, is the strongest drug inhibiting NO secretion from the studied drugs (even stronger than combined drugs, e.g., furosemide + captopril).…”

“…Hydrochlorothiazide inhibits T cell function in spontaneous hypertension [ 72 ]. This diuretic was found to inhibit the production of nitric oxide [ 17 , 73 ]. Our studies also showed that hydrochlorothiazide reduces NO secretion, this effect is slightly stronger in the case of the combined drug (captopril + hydrochlorothiazide) than with hydrochlorothiazide alone.…”

“…Moreover, therapeutic targeting of these ion channels on macrophages has recently emerged as an effective mechanism to control various macrophage immune activities, as reviewed elsewhere [ 39 ]. Accordingly, recent studies confirmed that furosemide and hydrochlorothiazide can target macrophages directly to induce an inhibitory effect, which brings further evidence for an immunomodulatory potential of diuretics [ 17 ], that likely results from the affected ion channel activity on macrophages. However, very little is known about the impact of these drugs on macrophage activity in cell-mediated immunity.…”

“…In turn, such dysregulated inflammatory responses seem to additionally drive hypertension and its complications. Immune system cells (macrophages especially) may sense the ion changes caused by the drugs [ 17 ]. In parallel, drugs can target cells directly due to the expressions of particular receptors, e.g., the angiotensin II receptor, which macrophages have on their surface [ 18 , 19 ].…”

Ambroxol for neuropathic pain: hiding in plain sight?

“…30 In brief, in vitro and in vivo investigations have shown clinically significant protective antioxidative effects, such as direct scavenging of various reactive oxygen species, inhibition of reactive oxygen and nitrogen species production by stimulated immune cells, and inhibition of lipid peroxidation. 23,53,62,64,78…”