Regulation of Toll-like receptor 4-mediated immune responses through Pasteurella multocida toxin-induced G protein signalling

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 Gαi-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 NF？B-pathway and thereby the production of TNF-α, IL-6 and IL-12p40. PMT inhibits the production of IL-12p40 by Gαi-mediated inhibition of adenylate cyclase and cAMP accumulation and by Gβγ-mediated activation of PI3kinase and JNK activation.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 host’s immune response.Monocytes are professional antigen presenting cells and carry out at least two important functions during infection. First of all they represent a barrier against pathogens through their antimicrobial activity and second they support the initiation of adaptive immune responses. The latter is exerted by the presentation of processed antigens on major histocompatibility complex (MHC) molecules to T lymphocytes, the expression of various costimulatory proteins on the cell surface and the production of cytokines [1,2]. To direct these functions during an immune response, monocytes become activated through binding of conserved microbial structures to their respective pattern-recognition receptors (PRRs). Within the group of PRRs, Toll like receptors (TLRs) play a well-known role in the initiation of such immune responses. Up to now, 10 functional TLRs have been identified in humans [3]. Each TLR detects distinct PAMPs derived from viruses, bacteria, mycobacteria, fungi, and parasites [3]. Gram-negative bacteria are typically sensed through the cell wa