Suppression of human alveolar macrophage-derived cytokines by amiloride.
Various human alveolar macrophage (AM)-derived cytokines in the lungs have been shown to be present under conditions of normal homeostasis as well as during the pathogenesis of inflammation. Although extensive investigation has demonstrated the induction of cytokines from AM, relatively little is known regarding endogenous and exogenous regulation of their production. Several pharmacologic agents, including corticosteroids, cyclooxygenase inhibitors, prostaglandins, and methyl-xanthines have been examined for their role in the modulation of mononuclear phagocyte-derived cytokines. In this study, we examine the role of amiloride for the regulation of AM-derived interleukin (IL)-8, tumor necrosis factor (TNF), IL-6, and IL-1 beta. Amiloride in concentrations of 10(-4) to 10(-6) M, concentrations capable of being achieved in the distal airways via nebulization, were shown to inhibit lipopolysaccharide-stimulated, AM-derived IL-8 and TNF in both a time- and dose-dependent fashion. In addition, 5-(N,N-hexamethylene) amiloride hydrochloride, an amiloride analogue with specific sodium channel antiport inhibition, resulted in a similar dose-dependent suppression of lipopolysaccharide-stimulated, AM-derived IL-8 production. Furthermore, the suppressive effect of amiloride appeared to be at the level of mRNA for IL-8, TNF, IL-1 beta, and IL-6, whereas steady-state levels of beta-actin mRNA remained unaltered. These findings would suggest that amiloride has a potentially important modulating influence for the regulation of AM-derived cytokines.
Rolfe
M W
MW
Department of Internal Medicine, University of Michigan Hospitals, Ann Arbor.
Kunkel
S L
SL
Rowens
B
B
Standiford
T J
TJ
Cragoe
E J
EJ
Strieter
R M
RM
D000584:Amiloride / Q000494:pharmacology*; D001483:Base Sequence; D015152:Blotting, Northern; D004305:Dose-Response Relationship, Drug; D004926:Escherichia coli; D006801:Humans; D007375:Interleukin-1 / Q000096:biosynthesis*; D015850:Interleukin-6 / Q000096:biosynthesis*; D016209:Interleukin-8 / Q000096:biosynthesis*; D008070:Lipopolysaccharides; D008262:Macrophage Activation; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000378:metabolism*; D008969:Molecular Sequence Data; D012333:RNA, Messenger / Q000096:biosynthesis*; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
D007375:Interleukin-1; D015850:Interleukin-6; D016209:Interleukin-8; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D000584:Amiloride