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Time‐dependent tumor necrosis factor (TNF)‐α signaling to P‐glycoprotein (P‐gp) in rat brain capillaries
Author(s) -
Miller David S,
Hartz Anika M.S.,
Bauer Bjorn
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a378-b
Subject(s) - tumor necrosis factor alpha , blood–brain barrier , receptor , inflammation , microbiology and biotechnology , endocrinology , signal transduction , p glycoprotein , medicine , chemistry , transcription factor , endothelin receptor , biology , immunology , biochemistry , central nervous system , antibiotics , multiple drug resistance , gene
The ATP‐driven drug efflux pump, P‐gp, is a critical, selective element of the blood‐brain barrier and a primary impediment to CNS pharmacotherapy. We recently demonstrated rapid and reversible inactivation of P‐gp in rat brain capillaries signaled through the brain’s innate immune response (LPS and TNF‐α) and the endothelin (ET) B‐type receptor (Hartz et al, Mol Pharm 66:387, 2004, and in press). Neither tight junctional permeability nor p‐gp expression were altered. Here we show here that P‐gp activity and expression changed in a complex manner in capillaries exposed continuously to low levels of TNF‐α or ET‐1. The initial reduction in transport activity with unaltered expression was followed by a 2‐3 h plateau and then by increased activity and expression; after 6 h, both had increased to twice control levels. Signaling involved the following sequence:1) TNF‐α binding to TNF‐R1, 2) big‐ET release and cleavage, 3) ET binding to ET A and ET B receptors, 4) NOS activation, 5) PKC activation, 6) NF‐κB activation and translocation from cytoplasm to nucleus, and 7) increased P‐gp expression and function. These results imply a tightening of the selective blood‐brain barrier with chronic, low level inflammation. Moreover, by implicating NF‐κB, they raise the possibility that other effectors acting through this transcription factor may also similarly induce the selective component of the barrier.