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

Abstract

The amiloride-inhibitable Na(+)/H(+) antiporter plays an important role in macrophage activation. The intracellular pathways leading to interleukin (IL)-12 p40 production by activated macrophages are incompletely understood. In the present study, we examined the contribution of the Na(+)/H(+) antiporter to the production of IL-12 p40. Amiloride or its analogs decreased the production of IL-12 p40 in macrophages stimulated with bacterial lipopolysaccharide and interferon-gamma. The order of potency of amiloride analogs was consistent with the proposition that the effect of amiloride is mediated by the inhibition of the Na(+)/H(+) antiporter. The effect of amiloride was post-transcriptional, as IL-12 p40 mRNA levels induced by lipopolysaccharide and interferon-gamma were not affected by this inhibitor. Furthermore, the inhibitory effect of amiloride on IL-12 p40 production was not a result of interference with the activation of the p38 and p42/44 mitogen-activated protein kinases or c-Jun kinase. In summary, the production of IL-12 p40 requires a functional Na(+)/H(+) antiporter.

Inhibition of Lipopolysaccharide-Induced Prostaglandin E2Production and Inflammation by the Na+/H+Exchanger Inhibitors

“…These findings suggested that the NHE inhibitors prevent the increase in the amount of COX-2 protein at the post-transcriptional level and not at the transcriptional level. LPS/interferon-␥-induced production of IL-12 p40 by mouse macrophages was also post-transcriptionally repressed by the NHE inhibitors (Németh et al, 2001). Therefore, the activation of NHE might affect the translational stage and/or the protein stability.…”

“…NHE inhibitors repress the production of cytokines and chemokines, such as TNF-␣, IL-1␤, and IL-8, in several types of cell, including macrophages (Rolfe et al, 1992;Németh et al, 2001Németh et al, , 2002aHaddad and Land, 2002). In this study, we revealed that the NHE inhibitor amiloride suppresses the LPS-induced production of PGE 2 in the mouse macrophage-like cell line RAW 264 (Fig.…”

“…C and D, levels of mRNA for COX-2 and glyceraldehyde 3-phosphate dehydrogenase were determined by reverse transcription-PCR. by amiloride in mouse peritoneal macrophages (Németh et al, 2001). The activation of NHE results in the accumulation of intracellular Na ϩ , which, in turn, increases [Ca 2ϩ ] i via the Na ϩ /Ca 2ϩ exchanger (Rosoff and Cantley, 1985).…”

“…It has been reported that PGE 2 negatively regulates the production of chemokines by various cells, such as macrophages (Takayama et al, 2002) and dendritic cells (Jing et al, 2003;McIlroy et al, 2006), and that indomethacin increases it (Janabi et al, 1999). In contrast, NHE inhibitors suppressed the production of several chemokines by macrophages (Rolfe et al, 1992;Németh et al, 2001) and the migration of neutrophils (Rosengren et al, 1994;Ritter et al, 1998). Therefore, it is possible that amiloride inhibited the infiltration of neutrophils into the pouch fluid by inhibiting the production of chemokines and the movement of leukocytes.…”

Inhibiting cytokines of the interleukin-12 family: recent advances and novel challenges

“…The effect of the former was post-translational, as IL-12 chain mRNA levels induced by IFN-® and LPS in the macrophage cell line J774 in the presence of amiloride were not affected (Ne meth et al 2001). Finally, extracellular ATP was reported to down-regulate production of IL-12 by mature dendritic cells, probably by a mechanism involving the family of ATP-gated P2X ion-channel receptors (la Sala et al 2001).…”