PMID- 9575562
OWN - NLM
STAT- MEDLINE
DCOM- 19980710
LR  - 20041117
IS  - 0361-7742 (Print)
IS  - 0361-7742 (Linking)
VI  - 397
DP  - 1998
TI  - Endotoxin tolerance alters macrophage membrane regulatory G proteins.
PG  - 217-26
AB  - Administration of sublethal doses of endotoxin (LPS) or tumor necrosis 
      factor-alpha (TNF alpha) renders rats tolerant to supralethal doses of LPS. 
      Peritoneal macrophages from tolerant rats are refractory to LPS induced 
      arachidonic acid (AA) metabolism and cytokine production in vivo, and exhibit 
      reduced membrane GTPase activity and GTP gamma S binding. Since LPS stimulated AA 
      metabolism is mediated by Gi alpha proteins, we sought to determine whether Gi 
      alpha and/or other G proteins are reduced in LPS tolerance. Rats were rendered 
      tolerant by two daily sublethal doses of Salmonella enteritidis LPS, 100 
      micrograms/kg and 500 micrograms/kg administered intraperitoneally. Animals were 
      allowed to rest for 72 hours. Alternatively, tolerance to LPS was induced by 
      sublethal administration of human recombinant TNF alpha (10 micrograms/kg) 
      intraperitoneally 24 hrs before the experiments. Macrophage membrane G protein 
      content was determined by immunoblot analysis with specific antisera to Gi1,2 
      alpha, Gi3 alpha, Gs alpha and the G protein beta subunits (G beta). Membrane G 
      proteins were differentially decreased in tolerant macrophages. In macrophages 
      from rats rendered tolerant by sublethal doses of LPS, Gi3 alpha was reduced the 
      most to 48 +/- 8% of control (n = 3, P < 0.05) and this reduction was significant 
      compared to those of other G proteins. Gi1,2 alpha and G beta were reduced to 73 
      +/- 5% (n = 3, P < 0.05) and 65 +/- 4% (n = 3, P < 0.05) of control respectively. 
      Gs alpha(L) and Gs alpha(H) were also reduced to 61 +/- 5% (n = 3, P < 0.05) and 
      68 +/- 3% (n = 3, P < 0.05) of control, respectively. In contrast, only Gi3 alpha 
      was reduced in macrophage membranes from rats pretreated with TNF alpha. Gi3 
      alpha was reduced to 57 +/- 11% of control (n = 4, P < 0.05) whereas Gi1,2 alpha 
      and G beta were not significantly affected. These results demonstrate selective 
      changes in tolerant macrophage membrane G proteins and suggest a potential role 
      for Gi3 alpha in mediating LPS tolerance. The molecular mechanisms underlying 
      these changes and their significance in LPS tolerance merit further 
      investigation.
FAU - Makhlouf, M
AU  - Makhlouf M
AD  - Department of Physiology, Medical University of South Carolina, Charleston 29425, 
      USA.
FAU - Zingarelli, B
AU  - Zingarelli B
FAU - Halushka, P V
AU  - Halushka PV
FAU - Cook, J A
AU  - Cook JA
LA  - eng
PT  - Journal Article
PL  - United States
TA  - Prog Clin Biol Res
JT  - Progress in clinical and biological research
JID - 7605701
RN  - 0 (Lipopolysaccharides)
RN  - 0 (Recombinant Proteins)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - EC 3.6.1.- (GTP-Binding Proteins)
SB  - IM
MH  - Animals
MH  - Cell Membrane/drug effects/metabolism
MH  - Cells, Cultured
MH  - Drug Tolerance
MH  - GTP-Binding Proteins/*metabolism
MH  - Humans
MH  - Lipopolysaccharides/*pharmacology
MH  - Macrophages, Peritoneal/*drug effects
MH  - Male
MH  - Rats
MH  - Recombinant Proteins/pharmacology
MH  - Tumor Necrosis Factor-alpha/pharmacology
EDAT- 1998/05/12 00:00
MHDA- 1998/05/12 00:01
CRDT- 1998/05/12 00:00
PHST- 1998/05/12 00:00 [pubmed]
PHST- 1998/05/12 00:01 [medline]
PHST- 1998/05/12 00:00 [entrez]
PST - ppublish
SO  - Prog Clin Biol Res. 1998;397:217-26.