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J. Biol. Chem. 276 (28): 25692-25696

© 2001 by The American Society for Biochemistry and Molecular Biology, Inc.

The Stimulation of Inducible Nitric-oxide Synthase by the Prion Protein Fragment 106-126 in Human Microglia Is Tumor Necrosis Factor-alpha -dependent and Involves p38 Mitogen-activated Protein Kinase*

Cinzia FabriziDagger , Valerio SileiDagger , Marta Menegazzi§, Mario Salmona, Orso Bugiani||, Fabrizio Tagliavini||, Hisanori Suzuki§, and Giuliana Maria LauroDagger **

From the Dagger  Dipartimento di Biologia, Università di "Roma Tre," Viale Marconi 446, 00146, Roma, Italy, § Dipartimento di Scienze Neurologiche, Sez. Chimica Biologica, Università di Verona, 37134 Verona, Italy,  Istituto di Ricerche Farmacologiche "Mario Negri," 20157 Milano, Italy, and || Istituto Nazionale Neurologico "Carlo Besta," 20133 Milano, Italy

A synthetic peptide consisting of amino acid residues 106-126 of the human prion protein (PrP-(106-126)) has been previously demonstrated to be neurotoxic and to induce microglial activation. The present study investigated the expression of the inducible form of the nitric-oxide synthase (NOS-II) in human microglial cells treated with PrP-(106-126). Using reverse transcriptase-polymerase chain reaction, we found that PrP-(106-126) induces NOS-II gene expression after 24 h of treatment and that this effect is accompanied by a peak of nuclear factor kappa B (NF-kappa B) binding at 30 min as evaluated by electrophoretic mobility shift assay. Since our previous data demonstrated tumor necrosis factor-alpha (TNF-alpha ) to be a potent inducer of NOS-II in these cells, we analyzed the expression of this cytokine in PrP-(106-126)-treated microglia. PrP-(106-126) caused the release of TNF-alpha as detected by enzyme-linked immunosorbent assay, and a blocking antibody, anti-TNF-alpha , abolished NOS-II induction elicited by this peptide. Moreover, PrP-(106-126) activates p38 mitogen-activated protein kinase, and the inhibition of this pathway determines the ablation of NF-kappa B binding induced by this fragment peptide.

* This work was supported in part by Italian Ministry of Health, Department of Social Service, Grant RF99.38, by European Community Grant BMH4 CT-98-6011 (to G. M. L. and F. T.), and by grants from Consiglio Nazionale delle Ricerche "Target Oriented Project Biotecnology" (to G. M. L. and H. S.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

** To whom correspondence should be addressed. Fax: 39-06 55176321; E-mail:

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.

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