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Mol. Cell. Biol. doi:10.1128/MCB.01814-06
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Toll and IMD pathways synergistically activate innate immune response in Drosophila

Program in Molecular Medicine, Department of Cell Biology, and Program in Cell Dynamics, University of Massachusetts Medical School, 373 Plantation Street, Worcester, MA 01605, USA; Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, UK

^* To whom correspondence should be addressed. Email: Tony.Ip{at}umassmed.edu.

	Abstract

The inducible expression of antimicrobial peptide genes in Drosophila is regulated by the conserved Toll and PGRP-LC/IMD signaling pathways. It has been proposed that the two pathways have independent functions and mediate the specificity of innate immune response towards different microorganisms. Scattering evidence also suggests that some antimicrobial target genes can be activated by both Toll and IMD, albeit to different extents. This dual activation can be mediated by independent stimulation or by cross-regulation of the two pathways. We show in this report that the Toll and IMD pathways can interact synergistically, demonstrating that cross-regulation occurs. The presence of Spätzle (the Toll ligand) and Gram-negative peptidoglycan (the PGRP-LC ligand) together caused synergistic activation of representative target genes of the two pathways, including Drosomycin, Diptericin, and AttacinA. Constitutive activation of Toll and PGRP-LC/IMD could mimic the synergistic stimulation. RNA interference assays and promoter analyses demonstrate that cooperation of different NF-B-related transcription factors mediates the synergy. These results illustrate how specific ligand binding by separate upstream pattern recognition receptors can be translated into broad-spectrum host response, a hallmark of innate immunity.