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Bifunctional lipocalin ameliorates murine immune complex-induced acute lung injury

Roversi, Pietro; Ryffel, Bernard; Togbe, Dieudonnee; Maillet, Isabelle; Teixeira, Mauro; Ahmat, Nurfilza; Paesen, Guido C; Lissina, Olga; Boland, Wilhelm; Ploss, Kerstin; Caesar, Joseph J.E.; Leonhartsberger, Susanne; Lea, Susan M.; Nunn, Miles A.. 2013 Bifunctional lipocalin ameliorates murine immune complex-induced acute lung injury. Journal of Biological Chemistry, 288 (26). 18789-18802. 10.1074/jbc.M112.420331

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Abstract/Summary

Molecules that simultaneously inhibit independent or co-dependent proinflammatory pathways may have advantages over conventional monotherapeutics. OmCI is a bifunctional protein derived from blood-feeding ticks that specifically prevents complement (C) mediated C5 activation and also sequesters leukotriene B4 (LTB4) within an internal binding pocket. Here, we examine the effect of LTB4 binding on OmCI's structure and function and investigate the relative importance of C-mediated C5 activation and LTB4 in a mouse model of immune complex-induced acute lung injury (IC-ALI). We describe two crystal structures of bacterially expressed OmCI: one binding a C16 fatty-acid and the other LTB4 (C20). We show that the molecules C5 and LTB4-binding activities are independent of each other, and that OmCI is a potent inhibitor of experimental IC-ALI, equally dependent on both C5 inhibition and LTB4 binding for full activity. The data highlight the importance of LTB4 in IC-ALI and activation of C5 by the complement pathway C5 convertase rather than by non-C proteases. The findings suggest that dual inhibition of C5 and LTB4 may be useful for treatment of human immune-complex-dependent diseases.

Item Type: Publication - Article
Digital Object Identifier (DOI): 10.1074/jbc.M112.420331
Programmes: CEH Topics & Objectives 2009 - 2012 > Biodiversity
CEH Sections: Reynard
ISSN: 0021-9258
NORA Subject Terms: Biology and Microbiology
Date made live: 18 Mar 2014 15:50 +0 (UTC)
URI: http://nora.nerc.ac.uk/id/eprint/506182

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