Host-pathogen systems biology: logical modelling of hepatocyte growth factor and Helicobacter pylori induced c-Met signal transduction

<p>Abstract</p> <p>Background</p> <p>The hepatocyte growth factor (HGF) stimulates mitogenesis, motogenesis, and morphogenesis in a wide range of tissues, including epithelial cells, on binding to the receptor tyrosine kinase c-Met. Abnormal c-Met signalling contributes to tumour genesis, in particular to the development of invasive and metastatic phenotypes. The human microbial pathogen <it>Helicobacter pylori </it>can induce chronic gastritis, peptic ulceration and more rarely, gastric adenocarcinoma. The <it>H. pylori </it>effector protein cytotoxin associated gene A (CagA), which is translocated via a type IV secretion system (T4SS) into epithelial cells, intracellularly modulates the c-Met receptor and promotes cellular processes leading to cell scattering, which could contribute to the invasiveness of tumour cells. Using a logical modelling framework, the presented work aims at analysing the c-Met signal transduction network and how it is interfered by <it>H. pylori </it>infection, which might be of importance for tumour development.</p> <p>Results</p> <p>A logical model of HGF and <it>H. pylori </it>induced c-Met signal transduction is presented in this work. The formalism of logical interaction hypergraphs (LIH) was used to construct the network model. The molecular interactions included in the model were all assembled manually based on a careful meta-analysis of published experimental results. Our model reveals the differences and commonalities of the response of the network upon HGF and <it>H. pylori </it>induced c-Met signalling. As another important result, using the formalism of minimal intervention sets, phospholipase Cγ1 (PLCγ1) was identified as knockout target for repressing the activation of the extracellular signal regulated kinase 1/2 (ERK1/2), a signalling molecule directly linked to cell scattering in <it>H. pylori </it>infected cells. The model predicted only an effect on ERK1/2 for the <it>H. pylori </it>stimulus, but not for HGF treatment. This result could be confirmed experimentally in MDCK cells using a specific pharmacological inhibitor against PLCγ1. The <it>in silico </it>predictions for the knockout of two other network components were also verified experimentally.</p> <p>Conclusion</p> <p>This work represents one of the first approaches in the direction of host-pathogen systems biology aiming at deciphering signalling changes brought about by pathogenic bacteria. The suitability of our network model is demonstrated by an <it>in silico </it>prediction of a relevant target against pathogen infection.</p

Tamo gdje završava drama mentaliteta započinje drama političkog trenutka. Ivan Vidić, Octopussy, HNK, Zagreb & Veliki bijeli zec, ZeKaeM

<p><b>Copyright information:</b></p><p>Taken from "Host-pathogen systems biology: logical modelling of hepatocyte growth factor and induced c-Met signal transduction"</p><p>http://www.biomedcentral.com/1752-0509/2/4</p><p>BMC Systems Biology 2008;2():4-4.</p><p>Published online 14 Jan 2008</p><p>PMCID:PMC2254585.</p><p></p

Cholera toxin promotes the generation of semi-mature porcine monocyte-derived dendritic cells that are unable to stimulate T cells

Cholera toxin (Ctx) is a powerful mucosal adjuvant with potential applications for oral vaccination of swine. Dendritic cells (DC) play a key role in the decision between immunity and tolerance, and are likely target cells for mediating Ctx functions in vivo. Therefore, we examined the capacity of Ctx to enhance stimulatory activity of porcine monocyte-derived DC (MoDC). Ctx promoted the development of a semi-mature DC phenotype, with decreased levels of MHC class II and CD40, but increased CD80/86 expression. These changes were associated with activation of extracellular signal-regulated kinase (ERK), but not NF${\kappa}$B or c-Jun N-terminal kinase (JNK). Functionally, Ctx-priming greatly diminished T cell stimulatory capacity both in antigen-specific and superantigen-induced proliferation assays. The lower proliferation rate was not due to increased apoptosis of either DC or T cells. Ctx suppressed TNF${\alpha}$ secretion by MoDC, but induced IL-10 production. The observed effects on T cell proliferation could only be partially mimicked by IL-10 alone. However, addition of recombinant TNF${\alpha}$ to co-cultures of Ctx-primed MoDC and lymphocytes restored lymphocyte proliferation in a concentration-dependent manner. Ctx-primed DC were not actively tolerogenic, since they could not suppress proliferative T cell reactions induced by untreated DC

Robustness and Information Transfer within IL-6-induced JAK/STAT Signalling

Cellular communication via intracellular signalling pathways is crucial. Expression and activation of signalling proteins is heterogenous between isogenic cells of the same cell-type. However, mechanisms evolved to enable sufficient communication and to ensure cellular functions. We use information theory to clarify mechanisms facilitating IL-6-induced JAK/STAT signalling despite cell-to-cell variability. We show that different mechanisms enabling robustness against variability complement each other. Early STAT3 activation is robust as long as cytokine concentrations are low. Robustness at high cytokine concentrations is ensured by high STAT3 expression or serine phosphorylation. Later the feedback-inhibitor SOCS3 increases robustness. Channel Capacity of JAK/STAT signalling is limited by cell-to-cell variability in STAT3 expression and is affected by the same mechanisms governing robustness. Increasing STAT3 amount increases Channel Capacity and robustness, whereas increasing STAT3 tyrosine phosphorylation reduces robustness but increases Channel Capacity. In summary, we elucidate mechanisms preventing dysregulated signalling by enabling reliable JAK/STAT signalling despite cell-to-cell heterogeneity.status: publishe

Host-pathogen systems biology: logical modelling of hepatocyte growth factor and induced c-Met signal transduction-3

<p><b>Copyright information:</b></p><p>Taken from "Host-pathogen systems biology: logical modelling of hepatocyte growth factor and induced c-Met signal transduction"</p><p>http://www.biomedcentral.com/1752-0509/2/4</p><p>BMC Systems Biology 2008;2():4-4.</p><p>Published online 14 Jan 2008</p><p>PMCID:PMC2254585.</p><p></p

Host-pathogen systems biology: logical modelling of hepatocyte growth factor and induced c-Met signal transduction-7

<p><b>Copyright information:</b></p><p>Taken from "Host-pathogen systems biology: logical modelling of hepatocyte growth factor and induced c-Met signal transduction"</p><p>http://www.biomedcentral.com/1752-0509/2/4</p><p>BMC Systems Biology 2008;2():4-4.</p><p>Published online 14 Jan 2008</p><p>PMCID:PMC2254585.</p><p></p