PMID- 7791126
OWN - NLM
STAT- MEDLINE
DCOM- 19950721
LR  - 20131121
IS  - 0022-3565 (Print)
IS  - 0022-3565 (Linking)
VI  - 273
IP  - 3
DP  - 1995 Jun
TI  - Specific transcriptional inhibition of bone marrow-derived macrophage tumor 
      necrosis factor-alpha gene expression and protein production using novel 
      enantiomeric carbocyclic nucleoside analogues.
PG  - 1506-18
AB  - Tumor necrosis factor-alpha (TNF-alpha) is a powerful macrophage-derived 
      proinflammatory cytokine, via both direct effects on host tissues as well as 
      indirectly through the induction of other proinflammatory mediators, including 
      interleukin- (IL) 1 beta and IL-6. Activation of murine bone marrow-derived 
      macrophages (BMDM phi) with lipopolysaccharide (LPS) causes rapid expression of 
      TNF-alpha, which as an autocrine factor enhances BMDM phi function through IL-1 
      beta and IL-6 production. In this study, we have examined the specific 
      transcriptional inhibition of BMDM phi TNF-alpha using novel enantiomeric 
      carbocyclic nucleoside analogues. BMDM phi were derived in vitro from murine bone 
      marrow progenitors using colony stimulating factor-1 and treated with 
      combinations of LPS (1-100 nG/ml) and the enantiomeric carbocyclic nucleoside 
      (10-100 microM) analogues MDL 201, 112 (9-[(1S,3R)-cis-cyclopentan-3-ol]adenine); 
      MDL 201,451 (9-[1R,3S)-cis-cyclopentan-3-ol]adenine); MDL 201,449 
      (9-[(1R,3R)-trans-cyclopentan-3-ol]adenine) and MDL 201,484 
      (9-[(1S,3S)-trans-cyclopentan-3-ol]adenine). Northern blot analysis showed that 
      MDL 201,449 was the most effective agent in vitro at selectively inhibiting 
      TNF-alpha. MDL 201,449 reduced TNF-alpha mRNA levels by nearly 50% for up to 4 hr 
      after the simultaneous addition of LPS and the synthetic agent. In contrast, mRNA 
      and secreted protein levels for IL-1 beta (measured by the D10.S bioassay) and 
      mRNA for TNF-alpha receptor p60 and TNF-alpha receptor p80 were not significantly 
      affected. Carbocyclic nucleoside analogues were effective when added to BMDM phi 
      up-to 2 hr after LPS treatment and at concentrations as low as 10 microM. 
      Regulation of BMDM phi IL-6 by carbocyclic nucleoside analogues in response to 
      LPS appears to be both concentration and time dependent, because IL-6 mRNA and 
      secreted protein levels were inhibited at only high drug concentrations (100 
      microM) and effective only at longer exposure times (+4 hr of incubation) to LPS. 
      These data support the concept that M phi-derived proinflammatory cytokine gene 
      expression is differentially, rather than coordinately, regulated by selective 
      signal transduction and/or molecular pathways. Enantiomeric carbocyclic 
      nucleoside analogues that specifically inhibit TNF-alpha may have therapeutic 
      potential in inflammatory diseases, such as systemic inflammatory response 
      syndrome, where TNF-alpha has been shown to have an important role in initiating 
      the early stages of disease.
FAU - Bradshaw, M
AU  - Bradshaw M
AD  - Department of Animal Sciences, University of Illinois at Urbana-Champaign, USA.
FAU - Rutherford, M S
AU  - Rutherford MS
FAU - Hoeper, B J
AU  - Hoeper BJ
FAU - McWhinney, C D
AU  - McWhinney CD
FAU - Borcherding, D R
AU  - Borcherding DR
FAU - Schook, L B
AU  - Schook LB
FAU - Edwards, C K 3rd
AU  - Edwards CK 3rd
LA  - eng
PT  - Journal Article
PL  - United States
TA  - J Pharmacol Exp Ther
JT  - The Journal of pharmacology and experimental therapeutics
JID - 0376362
RN  - 0 (Lipopolysaccharides)
RN  - 0 (Nucleosides)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - JAC85A2161 (Adenine)
SB  - IM
MH  - Adenine/*analogs & derivatives
MH  - Animals
MH  - *Bone Marrow Cells
MH  - Female
MH  - Gene Expression Regulation
MH  - Lipopolysaccharides/pharmacology
MH  - Macrophages/*metabolism
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Nucleosides/*pharmacology
MH  - Stereoisomerism
MH  - Transcription, Genetic/*drug effects
MH  - Tumor Necrosis Factor-alpha/biosynthesis/*genetics
EDAT- 1995/06/01 00:00
MHDA- 1995/06/01 00:01
CRDT- 1995/06/01 00:00
PHST- 1995/06/01 00:00 [pubmed]
PHST- 1995/06/01 00:01 [medline]
PHST- 1995/06/01 00:00 [entrez]
PST - ppublish
SO  - J Pharmacol Exp Ther. 1995 Jun;273(3):1506-18.