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Am J Physiol Renal Physiol. 2007 Oct;293(4):F1373-80. Epub 2007 Aug 15.

Gentamicin suppresses endotoxin-driven TNF-alpha production in human and mouse proximal tubule cells.

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  • 1Department of Medicine, University of Washington, Seattle, Washington, USA.

Abstract

Gentamicin is a mainstay in treating gram-negative sepsis. However, it also may potentiate endotoxin (LPS)-driven plasma TNF-alpha increases. Because gentamicin accumulates in renal tubules, this study addressed whether gentamicin directly alters LPS-driven tubular cell TNF-alpha production. HK-2 proximal tubular cells were incubated for 18 h with gentamicin (10-2,000 microg/ml). Subsequent LPS-mediated TNF-alpha increases (at 3 or 24 h; protein/mRNA) were determined. Gentamicin effects on overall protein synthesis ([(35)S]methionine incorporation), monocyte chemoattractant protein-1 (MCP-1) levels, and LPS-stimulated TNF-alpha generation by isolated mouse proximal tubules also were assessed. Finally, because gentamicin undergoes partial biliary excretion, its potential influence on gut TNF-alpha/MCP-1 mRNAs was probed. Gentamicin caused striking, dose-dependent inhibition of LPS-driven TNF-alpha production (up to 80% in HK-2 cells/isolated tubules). Surprisingly, this occurred despite increased TNF-alpha mRNA accumulation. Comparable changes in MCP-1 were observed. These changes were observed at clinically relevant gentamicin concentrations and despite essentially normal overall protein synthetic rates. Streptomycin also suppressed LPS-driven TNF-alpha increases, suggesting an aminoglycoside drug class effect. Gentamicin doubled basal TNF-alpha mRNA in cecum and in small intestine after LPS. Gentamicin can suppress LPS-driven TNF-alpha production in proximal tubule cells, likely by inhibiting its translation. Overall preservation of protein synthesis and comparable MCP-1 suppression suggest a semiselective blockade within the LPS inflammatory mediator cascade. These results, coupled with increases in gut TNF-alpha/MCP-1 mRNAs, imply that gentamicin may exert protean, countervailing actions on systemic cytokine/chemokine production during gram-negative sepsis.

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