Pentoxifylline downregulares nitric oxide and tumor necrosis factor-a induced by mycobacterial lipoarabinomannan in a macrophage cell line

ABSTRACT

Pentoxifylline (PTX), a phosphodiesterase inhibitor, is known to downregulate tumor necrosis factor-alpha (TNF-alpha) secretion induced by lipopolysacchride (LPS) and gamma interferon (IFN-gamma). We have had limited success in treating leprosy reactions, including erythema nodosum leprosum (ENL), in which TNF-alpha has been identified as a major proinflammatory cytokine. PTX inhibited production of NO (IC50 approximately equal to 1.0 mg/ml) and TNF-alpha (IC50 approximately equal to 0.05 mg/ml) in a dose-dependent fashion. As little as 0.5 mg/ml of PTX decreased NO production and 0.01 mg/ml of PTX inhibited TNF-alpha production. Western blot analyses demonstrated that iNOS was suppressed by PTX. Northern blot analyses showed significant reduction of TNF-alpha mRNA. We conclude that PTX is an effective inhibitor of lipoarabinomannan (LAM)-induced TNF-alpha production at both the product and transcriptional levels in our macrophage cell line. PTX also showed moderate inhibition of NO at the product level as well as translation of iNOS.