PMID- 10404396
OWN - NLM
STAT- MEDLINE
DCOM- 19990830
LR  - 20131121
IS  - 0730-2312 (Print)
IS  - 0730-2312 (Linking)
VI  - 74
IP  - 2
DP  - 1999 Aug 1
TI  - Ethanol inhibits prolactin-induced activation of the JAK/STAT pathway in cultured 
      astrocytes.
PG  - 278-91
AB  - Alcohol consumption has multiple effects in the central nervous system (CNS). 
      Whereas, alcohol is an immunosuppressive drug the effect of alcohol on the 
      neuroimmune system, remains unclear. In cultured astrocytes, prolactin (PRL) 
      induces mitogenesis and the expression of inflammatory cytokines, including tumor 
      necrosis factor-alpha (TNF alpha). We have recently shown that whereas ethanol 
      does not inhibit PRL receptor binding, it markedly inhibits PRL-induced 
      mitogenesis and TNF alpha secretion in cultured astrocytes. It is clear that PRL 
      activates the tyrosine phosphorylation of several proteins, including members of 
      a novel family of protein tyrosine kinases, the Janus Kinases (JAKs). The aims of 
      this study were to characterize PRL-induced activation of the JAK/STAT (signal 
      transducers and activators of transcription) pathway, and to determine if ethanol 
      affects JAK/STAT activation in cultured astrocytes. We found that PRL 
      specifically increases the tyrosine phosphorylation of JAK2, but not JAK1, JAK3, 
      or Tyk2, and the subsequent phosphorylation of STAT1 alpha, STAT5a, and STAT5b. 
      Preincubation of astrocytes with ethanol markedly inhibited phosphorylation of 
      JAK2, STAT1 alpha, STAT5a, and STAT5b. In PRL-stimulated astrocytes, ethanol 
      inhibited binding of nuclear proteins to oligonucleotides corresponding to the 
      gamma-interferon activated sequence (GAS). Further, ethanol blocked PRL-induced 
      increases in interferon regulatory factor-1 (IRF-1) mRNA, a PRL/cytokine 
      inducible transcription factor involved in the regulation of a number of cytokine 
      inducible genes. The inhibition of tyrosine phosphorylation by ethanol was not a 
      general effect, however, as we found that ethanol increased basal and NGF-induced 
      tyrosine phosphorylation of extracellular signal-activated protein kinase-1 
      (ERK-1). These data indicate that ethanol inhibits PRL-induced tyrosine 
      phosphorylation of the JAK/STAT pathway resulting in decreased nuclear GAS DNA 
      binding and inhibition of the PRL inducible gene, IRF-1. Thus, suggesting that 
      ethanol-induced inhibition of JAK2 phosphorylation may be one mechanism though 
      which ethanol could after the brain's response to injury or infection.
FAU - DeVito, W J
AU  - DeVito WJ
AD  - Division of Endocrinology, University of Massachusetts Medical Center, Worcester 
      01655, USA.
FAU - Stone, S
AU  - Stone S
LA  - eng
GR  - AA11277/AA/NIAAA NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - J Cell Biochem
JT  - Journal of cellular biochemistry
JID - 8205768
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (Transcription Factors)
RN  - 3K9958V90M (Ethanol)
RN  - 42HK56048U (Tyrosine)
RN  - 9002-62-4 (Prolactin)
RN  - 9007-49-2 (DNA)
RN  - EC 2.7.10.1 (Protein-Tyrosine Kinases)
RN  - EC 2.7.10.2 (Jak2 protein, rat)
RN  - EC 2.7.10.2 (Janus Kinase 2)
SB  - IM
MH  - Animals
MH  - Astrocytes/*drug effects/metabolism
MH  - Base Sequence
MH  - Cells, Cultured
MH  - DNA
MH  - Enzyme Activation
MH  - Ethanol/*pharmacology
MH  - Female
MH  - Janus Kinase 2
MH  - Phosphorylation
MH  - Pregnancy
MH  - Prolactin/pharmacology
MH  - Protein-Tyrosine Kinases/*metabolism
MH  - *Proto-Oncogene Proteins
MH  - Rats
MH  - Signal Transduction
MH  - Transcription Factors/*metabolism
MH  - Tyrosine/metabolism
EDAT- 1999/07/15 10:00
MHDA- 2000/06/20 09:00
CRDT- 1999/07/15 10:00
PHST- 1999/07/15 10:00 [pubmed]
PHST- 2000/06/20 09:00 [medline]
PHST- 1999/07/15 10:00 [entrez]
AID - 10.1002/(SICI)1097-4644(19990801)74:2<278::AID-JCB12>3.0.CO;2-P [pii]
PST - ppublish
SO  - J Cell Biochem. 1999 Aug 1;74(2):278-91.