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This Article Full Text Full Text (PDF) All Versions of this Article: jimmunol.0901260v1 183/7/4449    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Guidarelli, A. Articles by Cantoni, O. PubMed PubMed Citation Articles by Guidarelli, A. Articles by Cantoni, O.

Differentiation-Associated Loss of Ryanodine Receptors: A Strategy Adopted by Monocytes/Macrophages to Prevent the DNA Single-Strand Breakage Induced by Peroxynitrite¹

Andrea Guidarelli^2,*, Liana Cerioni^2,*, Mara Fiorani and Orazio Cantoni^3,*

^* Istituto di Farmacologia e Farmacognosia and Dipartimento di Scienze Biomolecolari, Università degli Studi di Urbino "Carlo Bo," Urbino, Italy

Monocytes/macrophages respond to peroxynitrite with the triggering of events leading to prevention of an otherwise prompt lethal response. This survival signaling regulated by molecules of the arachidonate cascade however presents a hypothetical critical limitation. In human promonocytic cell lines, peroxynitrite indeed promotes ryanodine receptor-derived Ca²⁺-dependent mitochondrial formation of H₂O₂, entirely responsible for the ensuing DNA strand scission. The occurrence of the same events in monocytes/macrophages at the inflammatory sites would therefore enhance the extent of DNA strand scission in viable cells, thereby increasing the rate of mutation and neoplastic transformation. The present study illustrates the details of a novel strategy based on a differentiation-associated loss of expression of ryanodine receptors. These cells simply do not accumulate mitochondrial Ca²⁺ in response to peroxynitrite and therefore fail to generate superoxide/H₂O₂, thereby preserving the integrity of their DNA. We propose that an important component of the overall strategy adopted by monocytes/macrophages to survive to peroxynitrite, with no increased risk of neoplastic transformation, involves down-regulation of ryanodine receptor expression.

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.

¹ This work was supported by grants from Ministero dell’Università e della Ricerca Scientifica e Tecnologica, Progetti di Ricerca di Interesse Nazionale, and Associazione Italiana per la Ricerca sul Cancro (to O.C.).

² A.G. and L.C. contributed equally to this work described in this article.

³ Address correspondence and reprint requests to Dr. Orazio Cantoni, Istituto di Farmacologia e Farmacognosia, Università degli Studi di Urbino "Carlo Bo," via Santa Chiara 27, 61029 Urbino (PU), Italy. E-mail address: orazio.cantoni{at}uniurb.it

⁴ Abbreviations used in this paper: Ry, ryanodine; 4-CmC, 4-chloro-m-cresol; DHR, dihydrorhodamine 123; D-U937, differentiated U937 cell; U-U937, undifferentiated U937 cell; RR, ruthenium red; RyR, Ry receptor; Cf, caffeine.