Inhibition of the Na+/H+ antiporter suppresses IL-12 p40 production by mouse macrophages

The amiloride-inhibitable Na+/H+ antiporter plays an important role in macr ophage activation. The intracellular pathways leading to interleukin (IL)-1 2 p40 production by activated macrophages are incompletely understood. In t he present study, we examined the contribution of the Na+/H+ antiporter to the production of IL-12 p40. Amiloride or its analogs decreased the product ion of IL-12 p40 in macrophages stimulated with bacterial lipopolysaccharid e and interferon-gamma. The order of potency of amiloride analogs was consi stent with the proposition that the effect of amiloride is mediated by the inhibition of the Na+/H+ antiporter. The effect of amiloride was post-trans criptional, as IL-12 p40 mRNA levels induced by lipopolysaccharide and inte rferon-gamma were not affected by this inhibitor. Furthermore, the inhibito ry effect of amiloride on IL-12 p40 production was not a result of interfer ence with the activation of the p38 and p42/44 mitogen-activated protein ki nases or c-Jun kinase. In summary, the production of IL-12 p40 requires a f unctional Na+/H+ antiporter. (C) 2001 Elsevier Science B.V. All rights rese rved.