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This Article Full Text Full Text (PDF) All Versions of this Article: 293/4/F1373    most recent 00333.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Zager, R. A. Articles by Geballe, A. Search for Related Content PubMed PubMed Citation Articles by Zager, R. A. Articles by Geballe, A.

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

Departments of ¹Medicine and ²Microbiology, University of Washington, and ³Clinical and ⁴Human Biology Divisions, Fred Hutchinson Cancer Research Center, Seattle, Washington

Submitted 16 July 2007 ; accepted in final form 8 August 2007

Gentamicin is a mainstay in treating gram-negative sepsis. However, it also may potentiate endotoxin (LPS)-driven plasma TNF- increases. Because gentamicin accumulates in renal tubules, this study addressed whether gentamicin directly alters LPS-driven tubular cell TNF- production. HK-2 proximal tubular cells were incubated for 18 h with gentamicin (10–2,000 µg/ml). Subsequent LPS-mediated TNF- increases (at 3 or 24 h; protein/mRNA) were determined. Gentamicin effects on overall protein synthesis ([³⁵S]methionine incorporation), monocyte chemoattractant protein-1 (MCP-1) levels, and LPS-stimulated TNF- generation by isolated mouse proximal tubules also were assessed. Finally, because gentamicin undergoes partial biliary excretion, its potential influence on gut TNF-/MCP-1 mRNAs was probed. Gentamicin caused striking, dose-dependent inhibition of LPS-driven TNF- production (up to 80% in HK-2 cells/isolated tubules). Surprisingly, this occurred despite increased TNF- 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- increases, suggesting an aminoglycoside drug class effect. Gentamicin doubled basal TNF- mRNA in cecum and in small intestine after LPS. Gentamicin can suppress LPS-driven TNF- 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-/MCP-1 mRNAs, imply that gentamicin may exert protean, countervailing actions on systemic cytokine/chemokine production during gram-negative sepsis.

HK-2 cells; aminoglycosides; acute renal failure; tumor necrosis factor-