Inflammatory bowel disease: the role of inflammatory cytokine gene polymorphisms.

The mechanisms responsible for development of inflammatory bowel disease (IBD) have not been fully elucidated, although the main cause of disease pathology is attributed to up-regulated inflammatory processes. The aim of this study was to investigate frequencies of polymorphisms in genes encoding pro-inflammatory and anti-inflammatory markers in IBD patients and controls. We determined genotypes of patients with IBD (n= 172) and healthy controls (n= 389) for polymorphisms in genes encoding various cytokines (interleukin (IL)-1beta, IL-6, tumour necrosis factor (TNF), IL-10, IL-1 receptor antagonist). Association of these genotypes to disease incidence and pathophysiology was investigated. No strong association was found with occurrence of IBD. Variation was observed between the ulcerative colitis study group and the control population for the TNF-alpha-308 polymorphism (p= 0.0135). There was also variation in the frequency of IL-6-174 and TNF-alpha-308 genotypes in the ulcerative colitis group compared with the Crohn's disease group (p= 0.01). We concluded that polymorphisms in inflammatory genes are associated with variations in IBD phenotype and disease susceptibility. Whether the polymorphisms are directly involved in regulating cytokine production, and consequently pathophysiology of IBD, or serve merely as markers in linkage disequilibrium with susceptibility genes remains unclear

The monocyte protein C pathway : implications in human diseases

THESIS 7544The protein C (PC) pathway provides an important link between the coagulation, fibrinolytic, and inflammatory pathways. PC/activated protein C (APC) is one o f very few therapies shown to effectively reduce the morbidity and mortality states seen in severe sepsis and septic shock. Originally identified as a naturally occurring anti-coagulant, PC has subsequently been shown to have potent anti-inflammatory properties. Given the significance of activated monocytes in the pathophysiology of severe sepsis and the recent discovery of expression of the endothelial protein C receptor (EPCR) on the monocyte cell surface, we investigated the effect of PC on the gene expression profile of the monocytic cell line THP-1. Microarray technology was used to determine the effect of PC on the expression levels of approximately ten thousand human genes in untreated and LPS activated THP-1 cells. Results were confirmed by investigating the expression of a number of genes included in the microarray by real-time PCR and ELISA