Gram negative bacteria are typically sensed through the cell wall constituent lipo polysaccharide that binds in complex with the LPS binding Protein to a receptor complex of TLR4, CD14 and an associated AZD9291 EGFR protein. The TLR4 mediated signalling cascades then modulate the gene expression towards the production of a variety of pro inflammatory cytokines Inhibitors,Modulators,Libraries such as Interleukin 6, Tumour necrosis factor and IL 12. In addition, these signalling events enhance the costimula tory function of monocytes. However, this TLR4 mediated induction of inflammation and activation of adaptive immunity is actively targeted and modulated by a variety of pathogens, presumably to impair the immune response. At this, heterotrimeric G proteins play an im portant role.

Bacterial toxins that act on heterotrimeric G proteins such as Cholera Toxin of Vibrio cholerae, heat labile enterotoxin of enteropathic Inhibitors,Modulators,Libraries Escherichia coli or Pertussis Toxin of Bordetella pertussis can therefore alter LPS induced cytokine release. This is achieved by heterotrimeric G protein mediated produc tion of cAMP which eventually results in an altered cyto kine release, Inhibitors,Modulators,Libraries most notably of IL 12, by human monocytic cells. The molecular mechanism of the effect is however only incompletely understood. Another toxin that targets heterotrimeric G proteins is produced by toxigenic strains of Gram negative Pasteur ella multocida bacteria that can be isolated from chronic respiratory infections in animals and from humans after cat or dog bites.

Pasteurella multocida toxin is known to activate Gq, Gi and G13 independ ently of a G protein coupled receptor through deamida tion resulting in the constitutively activation of the subunit and Inhibitors,Modulators,Libraries release of the B subunit. This leads to the downstream activation of signalling events Inhibitors,Modulators,Libraries such as phospholipase CB activation, induction of the mitogen activated protein kinase pathways, the RhoA Rho kinase pathway and the Janus kinase sig nal transducers of transcription pathway. Additionally, PMT activates Gi, thus inhibiting adenylate cyclase activity and cAMP accumulation. In this study we investigated how the activation of het erotrimeric G proteins through PMT influences the TLR4 mediated activation of human blood derived monocytes and their ability to induce T cell proliferation. Our data demonstrate that PMT modulates TLR4 mediated cytokine production. This effect was most pronounced for the release of IL 12p40, a cytokine important for T cell activation. The suppression of IL 12p40 release resulted in the inhibition of the T cell activating ability of LPS activated hBDMs. This block could be restored by adding IL 12 containing superna tants of LPS stimulated hBDMs to the mixed lympho cyte reaction, showing that IL http://www.selleckchem.com/products/Perifosine.html 12 was both, necessary and sufficient.