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Hildebrand D.,Medizinische Mikrobiologie und Hygiene | Sahr A.,Medizinische Mikrobiologie und Hygiene | Wolfle S.J.,Medizinische Mikrobiologie und Hygiene | Heeg K.,Medizinische Mikrobiologie und Hygiene | Kubatzky K.F.,Medizinische Mikrobiologie und Hygiene
Cell Communication and Signaling | Year: 2012

Abstract. Background: Lipopolysaccharide (LPS)-triggered Toll-like receptor (TLR) 4-signalling belongs to the key innate defence mechanisms upon infection with Gram-negative bacteria and triggers the subsequent activation of adaptive immunity. There is an active crosstalk between TLR4-mediated and other signalling cascades to secure an effective immune response, but also to prevent excessive inflammation. Many pathogens induce signalling cascades via secreted factors that interfere with TLR signalling to modify and presumably escape the host response. In this context heterotrimeric G proteins and their coupled receptors have been recognized as major cellular targets. Toxigenic strains of Gram-negative Pasteurella multocida produce a toxin (PMT) that constitutively activates the heterotrimeric G proteins Gq, G13 and G i independently of G protein-coupled receptors through deamidation. PMT is known to induce signalling events involved in cell proliferation, cell survival and cytoskeleton rearrangement. Results: Here we show that the activation of heterotrimeric G proteins through PMT suppresses LPS-stimulated IL-12p40 production and eventually impairs the T cell-activating ability of LPS-treated monocytes. This inhibition of TLR4-induced IL-12p40 expression is mediated by Gai-triggered signalling as well as by Gβγ-dependent activation of PI3kinase and JNK. Taken together we propose the following model: LPS stimulates TLR4-mediated activation of the NFB-pathway and thereby the production of TNF-, IL-6 and IL-12p40. PMT inhibits the production of IL-12p40 by Gai-mediated inhibition of adenylate cyclase and cAMP accumulation and by G-mediated activation of PI3kinase and JNK activation. Conclusions: On the basis of the experiments with PMT this study gives an example of a pathogen-induced interaction between G protein-mediated and TLR4-triggered signalling and illustrates how a bacterial toxin is able to interfere with the hosts immune response. © 2012 Hildebrand et al.; licensee BioMed Central Ltd. Source

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