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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.

PubMed | Medizinische Mikrobiologie und Hygiene
Type: Journal Article | Journal: Cellular microbiology | Year: 2010

Pasteurella multocida Toxin (PMT) is a mitogenic protein toxin that manipulates signal transduction cascades of mammalian host cells and upregulates Janus kinase (JAK) and signal transducers of transcription (STAT) activity. Here we show that in the presence of PMT, increased levels of suppressors of cytokine signalling-1 (SOCS-1) proteins significantly enhance STAT activity. This occurs via PMT-induced expression of the serine/threonine kinase Pim-1 and subsequent threonine phosphorylation of SOCS-1. The ability of SOCS-1 to act as an E3 ubiquitin ligase is regulated by its phosphorylation status. Thus, the tyrosine kinase JAK2 cannot be marked for proteasomal degradation by threonine phosphorylated SOCS-1. Consequently, the expression levels of JAK2 are increased, eventually leading to hyperactivity of JAK2 and its target, the transcription factor STAT3. Eventually this causes increased anchorage-independent cell growth that correlates with the expression levels of SOCS-1. Interestingly, endogenous SOCS-1 production after Toll-like receptor activation also causes STAT3 hyperactivation. Thus we hypothesize that P. multocida Toxin alters host cell signalling using mechanisms that have so far only been known to be employed by oncogenic viral kinases to avoid host immune defence mechanisms.

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