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J. Biol. Chem., Vol. 280, Issue 14, 14264-14271, April 8, 2005

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Direct Effects of Polymyxin B on Human Dendritic Cells Maturation

THE ROLE OF IB-/NF-B AND ERK1/2 PATHWAYS AND ADHESION^*

Barbara Valentinis, Alessandro Bianchi, Dan Zhou, Arcadi Cipponi¶, Federica Catalanotti, Vincenzo Russo¶, and Catia Traversari

From the Molmed, Via Olgettina 58, 20132 Milan, Italy and ^¶Cancer Immunotherapy & Gene Therapy Program, H. San Raffaele Scientific Institute, Via Olgettina 58, 20132 Milan, Italy

Polymyxin B is a lipopolysaccharide binding antibiotic used to inactivate potential lipopolysaccharide contaminations when evaluating the activity of different agents on innate immune cells. We report that polymyxin B is able to induce directly in monocyte-derived human dendritic cells (DCs) several functional and molecular modifications characteristic of DCs undergoing a maturation process. DCs incubated with polymyxin B up-regulate the expression of HLA class I and II, the co-stimulatory CD86 molecule, and show an increase in the fraction of adherent cells at short time, which persist at 48 h of incubation. Adhesion to the plate was required for the polymyxin B-induced DCs maturation. A transient activation of IB-/NF-B and ERK1/2 pathways at short time and a further ERK1/2 activation at long term were also detected. Neither up-regulation of the maturation marker CD83 nor activation of p38 nor induction of cytokines secretion was observed in DCs treated with polymyxin B. We demonstrated that inhibition of IB-/NF-B pathway abolishes polymyxin B effects. ERK1/2 inhibition instead allowed DCs treated with polymyxin B to progress in their maturation process as revealed by the increased up-regulation of the CD83 co-stimulatory molecules, the activation of p38, and the reduced adhesion to culture plates at 48 h of incubation. Our results indicate that polymyxin B induces a partial maturation of human DCs through increased adhesion to a substrate and activation of the IB-/NF-B pathway. The increased ERK1/2 activation observed, even though correlating with the initial phases of the maturation process, actually inhibits the occurrence of full maturation.

Received for publication, September 20, 2004 , and in revised form, December 22, 2004.

^* This study was supported by European Community Grants QLK3-CT-1999-00064 and QLK3-CT2002-02017. The costs of publication of this article were defrayed in part by the payment of page charges. This 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: Molmed, Via Olgettina 58, 20132 Milan, Italy. Tel.: 39-2-21277-333; Fax: 39-2-21277-325; E-mail: barbara.valentinis{at}molmed.com.

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