PMID- 17699551
OWN - NLM
STAT- MEDLINE
DCOM- 20071130
LR  - 20110428
IS  - 1931-857X (Print)
IS  - 1522-1466 (Linking)
VI  - 293
IP  - 4
DP  - 2007 Oct
TI  - Gentamicin suppresses endotoxin-driven TNF-alpha production in human and mouse 
      proximal tubule cells.
PG  - F1373-80
AB  - 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.
FAU - Zager, Richard A
AU  - Zager RA
AD  - Department of Medicine, University of Washington, Seattle, Washington, USA.
FAU - Johnson, Ali C M
AU  - Johnson AC
FAU - Geballe, Adam
AU  - Geballe A
LA  - eng
GR  - AI026672/AI/NIAID NIH HHS/United States
GR  - DK-38432/DK/NIDDK NIH HHS/United States
GR  - DK-68520/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20070815
PL  - United States
TA  - Am J Physiol Renal Physiol
JT  - American journal of physiology. Renal physiology
JID - 100901990
RN  - 0 (Anti-Bacterial Agents)
RN  - 0 (CCL2 protein, human)
RN  - 0 (Ccl2 protein, mouse)
RN  - 0 (Chemokine CCL2)
RN  - 0 (Endotoxins)
RN  - 0 (Gentamicins)
RN  - 0 (RNA, Messenger)
RN  - 0 (Tumor Necrosis Factor-alpha)
SB  - IM
MH  - Animals
MH  - Anti-Bacterial Agents/*pharmacology
MH  - Cell Line
MH  - Cells, Cultured
MH  - Chemokine CCL2/metabolism
MH  - Dose-Response Relationship, Drug
MH  - Endotoxins/*pharmacology
MH  - Gentamicins/*pharmacology
MH  - Humans
MH  - Kidney Tubules, Proximal/cytology/drug effects/*metabolism
MH  - Male
MH  - Mice
MH  - Mice, Inbred Strains
MH  - RNA, Messenger/metabolism
MH  - Tumor Necrosis Factor-alpha/*metabolism
EDAT- 2007/08/19 09:00
MHDA- 2007/12/06 09:00
CRDT- 2007/08/19 09:00
PHST- 2007/08/19 09:00 [pubmed]
PHST- 2007/12/06 09:00 [medline]
PHST- 2007/08/19 09:00 [entrez]
AID - 00333.2007 [pii]
AID - 10.1152/ajprenal.00333.2007 [doi]
PST - ppublish
SO  - Am J Physiol Renal Physiol. 2007 Oct;293(4):F1373-80. doi: 
      10.1152/ajprenal.00333.2007. Epub 2007 Aug 15.