Astroglial expression of the P-glycoprotein is controlled by intracellular CNTF.
BACKGROUND
The P-glycoprotein (P-gp), an ATP binding cassette transmembrane transporter, is expressed by astrocytes in the adult brain, and is positively modulated during astrogliosis. In a search for factors involved in this modulation, P-gp overexpression was studied in long-term in vitro astroglial cultures.


RESULTS
Surprisingly, most factors that are known to induce astroglial activation in astroglial cultures failed to increase P-gp expression. The only effective proteins were IFNgamma and those belonging to the IL-6 family of cytokines (IL-6, LIF, CT-1 and CNTF). As well as P-gp expression, the IL-6 type cytokines (but not IFNgamma) stimulated the expression of endogenous CNTF in astrocytes. In order to see whether an increased intracellular level of CNTF was necessary for induction of P-gp overexpression by IL-6 type cytokines, by the same cytokines analysis was carried out on astrocytes obtained from CNTF knockout mice. In these conditions, IFNgamma produced increased P-gp expression, but no overexpression of P-gp was observed with either IL-6, LIF or CT-1, pointing to a role of CNTF in the intracellular signalling pathway leading to P-gp overexpression. In agreement with this suggestion, application of exogenous CNTF (which is internalised with its receptor) produced an overexpression of P-gp in CNTF-deficient astrocytes.


CONCLUSIONS
These results reveal two different pathways regulating P-gp expression and activity in reactive astrocytes, one of which depends upon the intracellular concentration of CNTF. This regulation of P-gp may be one of the long searched for physiological roles of CNTF.
Monville
Christelle
C
INSERM U421/IM3, Créteil, France. monvillec@cf.ac.uk
Fages
Christiane
C
Feyens
Anne-Marie
AM
D'Hondt
Veronique
V
Guillet
Catherine
C
Vernallis
Ann
A
Gascan
Hugues
H
Peschanski
Marc
M
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D020934:Ciliary Neurotrophic Factor / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D016207:Cytokines / Q000494:pharmacology; D003593:Cytoplasm; D005786:Gene Expression Regulation; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D012333:RNA, Messenger / Q000096:biosynthesis
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D020934:Ciliary Neurotrophic Factor; D016207:Cytokines; D012333:RNA, Messenger