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Astroglial expression of the P-glycoprotein is controlled by intracellular CNTF.

Monville C, Fages C, Feyens AM, D'Hondt V, Guillet C, Vernallis A, Gascan H, Peschanski M - BMC Cell Biol. (2002)

Bottom Line: 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).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.

View Article: PubMed Central - HTML - PubMed

Affiliation: INSERM U421/IM3, Créteil, France. monvillec@cf.ac.uk

ABSTRACT

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.

Conclusion: 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.

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Tentative mechanistic model of P-gp regulation by CNTF based upon the results of the present study.
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Figure 8: Tentative mechanistic model of P-gp regulation by CNTF based upon the results of the present study.

Mentions: In a mechanistic model based upon this hypothesis, endogenous astroglial CNTF would most likely not appear as a usual cytokine activating signalling pathways after binding to a transmembrane receptor system, but as a "sensor", itself modulated by extrinsic cues. The changes induced in the intracellular concentration of this "sensor" might affect the activity of the P-gp transmembrane transporter and, eventually, lead to a modulation of its gene expression (Fig. 8). Such a scheme suggests a physiological role for CNTF, a cytokine which, because of the absence of a signal peptide and the lack of a quantifiable release in the culture medium of cells that synthesise it [32,39,40], was not thought to play a physiological role in the absence of a lesion [41]. Whether P-gp is the only target of the effects of CNTF, or just the first one identified is obviously an open question at this point.


Astroglial expression of the P-glycoprotein is controlled by intracellular CNTF.

Monville C, Fages C, Feyens AM, D'Hondt V, Guillet C, Vernallis A, Gascan H, Peschanski M - BMC Cell Biol. (2002)

Tentative mechanistic model of P-gp regulation by CNTF based upon the results of the present study.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC117802&req=5

Figure 8: Tentative mechanistic model of P-gp regulation by CNTF based upon the results of the present study.
Mentions: In a mechanistic model based upon this hypothesis, endogenous astroglial CNTF would most likely not appear as a usual cytokine activating signalling pathways after binding to a transmembrane receptor system, but as a "sensor", itself modulated by extrinsic cues. The changes induced in the intracellular concentration of this "sensor" might affect the activity of the P-gp transmembrane transporter and, eventually, lead to a modulation of its gene expression (Fig. 8). Such a scheme suggests a physiological role for CNTF, a cytokine which, because of the absence of a signal peptide and the lack of a quantifiable release in the culture medium of cells that synthesise it [32,39,40], was not thought to play a physiological role in the absence of a lesion [41]. Whether P-gp is the only target of the effects of CNTF, or just the first one identified is obviously an open question at this point.

Bottom Line: 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).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.

View Article: PubMed Central - HTML - PubMed

Affiliation: INSERM U421/IM3, Créteil, France. monvillec@cf.ac.uk

ABSTRACT

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.

Conclusion: 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.

Show MeSH