PMID- 22973436
OWN - NLM
STAT- MEDLINE
DCOM- 20141230
LR  - 20211021
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 7
IP  - 8
DP  - 2012
TI  - Pro-inflammatory cytokine regulation of P-glycoprotein in the developing 
      blood-brain barrier.
PG  - e43022
LID - 10.1371/journal.pone.0043022 [doi]
LID - e43022
AB  - Placental P-glycoprotein (P-gp) acts to protect the developing fetus from 
      exogenous compounds. This protection declines with advancing gestation leaving 
      the fetus and fetal brain vulnerable to these compounds and potential teratogens 
      in maternal circulation. This vulnerability may be more pronounced in pregnancies 
      complicated by infection, which is common during pregnancy. Pro-inflammatory 
      cytokines (released during infection) have been shown to be potent inhibitors of 
      P-gp, but nothing is known regarding their effects at the developing blood-brain 
      barrier (BBB). We hypothesized that P-gp function and expression in endothelial 
      cells of the developing BBB will be inhibited by pro-inflammatory cytokines. We 
      have derived brain endothelial cell (BEC) cultures from various stages of 
      development of the guinea pig: gestational day (GD) 50, 65 (term ~68 days) and 
      postnatal day (PND) 14. Once these cultures reached confluence, BECs were treated 
      with various doses (10(0)-10(4 )pg/mL) of pro-inflammatory cytokines: 
      interleukin-1beta (IL-1beta), interleukin-6 (IL-6) or tumor necrosis factor- alpha (TNF-alpha). 
      P-gp function or abcb1 mRNA (encodes P-gp) expression was assessed following 
      treatment. Incubation of GD50 BECs with IL-1beta, IL-6 or TNF-alpha resulted in no 
      change in P-gp function. GD65 BECs displayed a dose-dependent decrease in 
      function with all cytokines tested; maximal effects at 42%, 65% and 34% with 
      IL-1beta, IL-6 and TNF-alpha treatment, respectively (P<0.01). Inhibition of P-gp 
      function by IL-1beta, IL-6 and TNF-alpha was even greater in PND14 BECs; maximal effects 
      at 36% (P<0.01), 84% (P<0.05) and 55% (P<0.01), respectively. Cytokine-induced 
      reductions in P-gp function were associated with decreased abcb1 mRNA expression. 
      These data suggest that BBB P-gp function is increasingly responsive to the 
      inhibitory effects of pro-inflammatory cytokines, with increasing developmental 
      age. Thus, women who experience infection and take prescription medication during 
      pregnancy may expose the developing fetal brain to greater amounts of exogenous 
      compounds - many of which are considered potentially teratogenic.
FAU - Iqbal, Majid
AU  - Iqbal M
AD  - Department of Physiology, University of Toronto, Toronto, Ontario, Canada. 
      majid.iqbal@utoronto.ca
FAU - Ho, Hay Lam
AU  - Ho HL
FAU - Petropoulos, Sophie
AU  - Petropoulos S
FAU - Moisiadis, Vasilis G
AU  - Moisiadis VG
FAU - Gibb, William
AU  - Gibb W
FAU - Matthews, Stephen G
AU  - Matthews SG
LA  - eng
GR  - FRN-57746/Canadian Institutes of Health Research/Canada
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20120813
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (ATP Binding Cassette Transporter, Subfamily B, Member 1)
RN  - 0 (Cytokines)
RN  - 0 (Interleukin-1beta)
RN  - 0 (Interleukin-6)
RN  - 0 (Tumor Necrosis Factor-alpha)
SB  - IM
MH  - ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics/*metabolism
MH  - Animals
MH  - Blood-Brain Barrier/drug effects/*metabolism
MH  - Cytokines/*pharmacology
MH  - Female
MH  - Gene Expression Regulation, Developmental/drug effects
MH  - Guinea Pigs
MH  - Interleukin-1beta/pharmacology
MH  - Interleukin-6/pharmacology
MH  - Male
MH  - Pregnancy
MH  - Tumor Necrosis Factor-alpha/pharmacology
PMC - PMC3433182
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2012/09/14 06:00
MHDA- 2014/12/31 06:00
PMCR- 2012/08/13
CRDT- 2012/09/14 06:00
PHST- 2012/04/18 00:00 [received]
PHST- 2012/07/16 00:00 [accepted]
PHST- 2012/09/14 06:00 [entrez]
PHST- 2012/09/14 06:00 [pubmed]
PHST- 2014/12/31 06:00 [medline]
PHST- 2012/08/13 00:00 [pmc-release]
AID - PONE-D-12-11013 [pii]
AID - 10.1371/journal.pone.0043022 [doi]
PST - ppublish
SO  - PLoS One. 2012;7(8):e43022. doi: 10.1371/journal.pone.0043022. Epub 2012 Aug 13.