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J. Biol. Chem., Vol. 283, Issue 34, 22907-22917, August 22, 2008

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Lipopolysaccharide, a Key Molecule Involved in the Synergism between Temporins in Inhibiting Bacterial Growth and in Endotoxin Neutralization^*

Maria Luisa Mangoni¹, Raquel F. Epand, Yosef Rosenfeld^¶, Adi Peleg^¶, Donatella Barra, Richard M. Epand, and Yechiel Shai^¶

From the Istituto Pasteur-Fondazione Cenci Bolognetti, Dipartimento di Scienze Biochimiche Università La Sapienza, Piazzale Aldo Moro, 5-00185 Roma, Italy, the Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton L8N 3Z5, Ontario, Canada, and the ^¶Department of Biological Chemistry, The Weizmann Institute of Science, Rehovot-76100 Israel

Lipopolysaccharide (LPS) is the major structural component of the outer membrane of Gram-negative bacteria and shields them from a variety of host defense factors, including antimicrobial peptides (AMPs). LPS is also recognized by immune cells as a pathogen-associated molecular pattern and stimulates them to secrete pro-inflammatory cytokines that, in extreme cases, lead to a harmful host response known as septic shock. Previous studies have revealed that a few isoforms of the AMP temporin, produced within the same frog specimen, can synergize to overcome bacterial resistance imposed by the physical barrier of LPS. Here we found that temporins can synergize in neutralizing the LPS-induced macrophage activation. Furthermore, the synergism between temporins, to overcome the protective function of LPS as well as its endotoxic effect, depends on the length of the polysaccharide chain of LPS. Importantly, mode of action studies, using spectroscopic and thermodynamic methods, have pointed out different mechanisms underlying the synergism of temporins in antimicrobial and anti-endotoxin activities. To the best of our knowledge, such a dual synergism between isoforms of AMPs from the same species has not been observed before, and it might explain the ability of such amphibians to resist a large repertoire of microorganisms.

Received for publication, January 18, 2008 , and in revised form, May 21, 2008.

^* This work was supported in part by the Canadian Institutes of Health Research (Grant MOP 86608), the Italian Ministero dell'Università e Ricerca (PRIN 2005 protocol no. 2005062410), by grants from the Universitàdi Roma La Sapienza and Istituto di Biologia e Patologia Molecolari of the National Research Council, and by the Josef Cohn MINERVA Center for Biomembrane Research (to Y. S.). 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 To whom correspondence should be addressed: Unità di Diagnostica Molecolare Avanzata, II Facoltà di Medicina e Chirurgia, Azienda Ospedaliera S. Andrea, Via di Grottarossa 1035-00189 Roma, Italy. Tel.: 39-06-33775457; Fax: 39-06-33775405; E-mail: marialuisa.mangoni{at}uniroma1.it.

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