PMID- 17032936
OWN - NLM
STAT- MEDLINE
DCOM- 20070327
LR  - 20220408
IS  - 1931-857X (Print)
IS  - 1522-1466 (Linking)
VI  - 292
IP  - 2
DP  - 2007 Feb
TI  - Endotoxin and cisplatin synergistically stimulate TNF-alpha production by renal 
      epithelial cells.
PG  - F812-9
AB  - Acute renal failure often occurs in the clinical setting of multiple renal 
      insults. Tumor necrosis factor-alpha (TNF-alpha) has been implicated in the 
      pathogenesis of cisplatin nephrotoxicity, ischemia-reperfusion injury, and 
      endotoxin-induced acute renal failure. The current studies examined the 
      interactions between cisplatin and endotoxin with particular emphasis on 
      TNF-alpha production. Treatment of cultured murine proximal tubule cells (TKPTS 
      cells) with cisplatin resulted in a modest production of TNF-alpha, while 
      treatment with endotoxin did not result in any TNF-alpha production. However, the 
      combination of cisplatin and endotoxin resulted in large amounts of TNF-alpha 
      synthesis and secretion. The stimulation of TNF-alpha production was dependent on 
      cisplatin-induced activation of p38 MAPK and was associated with phosphorylation 
      of the translation initiation factor eIF4E and its upstream kinase Mnk1. 
      Inhibition of p38 MAPK and, to a lesser extent, ERK, reduced 
      cisplatin+endotoxin-stimulated TNF-alpha production and phosphorylation of Mnk1 
      and eIF4E. Synergy between cisplatin and endotoxin was also observed in certain 
      tumor cell lines, but not in macrophages. In macrophages, in contrast to TKPTS 
      cells, endotoxin alone activated p38 MAPK and stimulated TNF-alpha production 
      with no added impact by cisplatin. The combination of cisplatin and endotoxin did 
      not result in synergistic production of other cytokines, e.g., MCP-1 and MIP2, by 
      TKPTS cells. In summary, these studies indicate that cisplatin sensitizes renal 
      epithelial cells to endotoxin and dramatically increases the translation of 
      TNF-alpha mRNA in a p38 MAPK-dependent manner. These interactions between 
      cisplatin and endotoxin may be relevant to the pathogenesis of cisplatin 
      nephrotoxicity in humans.
FAU - Ramesh, Ganesan
AU  - Ramesh G
AD  - Div. of Nephrology, Pennsylvania State University College of Medicine, Hershey, 
      PA 17033, USA.
FAU - Kimball, Scot R
AU  - Kimball SR
FAU - Jefferson, Leonard S
AU  - Jefferson LS
FAU - Reeves, W Brian
AU  - Reeves WB
LA  - eng
GR  - R01-DK-063120/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20061010
PL  - United States
TA  - Am J Physiol Renal Physiol
JT  - American journal of physiology. Renal physiology
JID - 100901990
RN  - 0 (Ccl2 protein, mouse)
RN  - 0 (Chemokine CCL2)
RN  - 0 (Chemokine CXCL2)
RN  - 0 (Endotoxins)
RN  - 0 (Eukaryotic Initiation Factor-4E)
RN  - 0 (Monokines)
RN  - 0 (RNA, Messenger)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - EC 2.7.1.- (Mknk1 protein, mouse)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases)
RN  - Q20Q21Q62J (Cisplatin)
SB  - IM
MH  - Animals
MH  - Cells, Cultured
MH  - Chemokine CCL2/biosynthesis
MH  - Chemokine CXCL2
MH  - Cisplatin/*pharmacology
MH  - Drug Synergism
MH  - Endotoxins/*pharmacology
MH  - Epithelial Cells/*drug effects/*metabolism
MH  - Eukaryotic Initiation Factor-4E/metabolism
MH  - Humans
MH  - Kidney/*cytology
MH  - Kidney Tubules, Proximal/cytology
MH  - Mice
MH  - Monokines/biosynthesis
MH  - Phosphorylation
MH  - Protein Serine-Threonine Kinases/metabolism
MH  - RNA, Messenger/metabolism
MH  - Tumor Necrosis Factor-alpha/*biosynthesis
MH  - p38 Mitogen-Activated Protein Kinases/physiology
EDAT- 2006/10/13 09:00
MHDA- 2007/03/28 09:00
CRDT- 2006/10/13 09:00
PHST- 2006/10/13 09:00 [pubmed]
PHST- 2007/03/28 09:00 [medline]
PHST- 2006/10/13 09:00 [entrez]
AID - 00277.2006 [pii]
AID - 10.1152/ajprenal.00277.2006 [doi]
PST - ppublish
SO  - Am J Physiol Renal Physiol. 2007 Feb;292(2):F812-9. doi: 
      10.1152/ajprenal.00277.2006. Epub 2006 Oct 10.