Cytokine responses to lipopolysaccharide in vivo and ex vivo : Genetic polymorphisms and inter-individual variation

Abstract

The host response to bacterial invasion requires first the recognition of the presence of pathogens. The presence of a pathogen is detected by binding of pathogen-preserved molecules called 'pathogen-associated molecular patterns' or PAMPs on cell surface receptors known as 'pattern recognition receptors' or PRRs. Lipopolysaccharide (LPS; endotoxin), one of the major outer membrane components of the Gram-negative bacterial cell wall, is an important PAMP. In the last decade the mechanisms by which the host responds to the presence of microbial pathogens on its mucosal surfaces or in the tissues, have been elucidated, most up to their molecular level. With the sequencing of the genome and recognition of the genetic variation within the human population, it became clear this variation is responsible for the inter-individual differences in cytokine release after challenge with microbial products. Such genetically determined variations in cytokine release could be relevant to explain the variability in susceptibility too, and outcome from, sepsis. The thesis focuses on genes that encode for proteins involved in the pathogenesis of sepsis including those involved in the initial recognition of bacterial products such as Toll-like receptors, and cytokines known to mediate the host inflammatory response, such as tumor necrosis factor (TNF)-α, interleukin(IL)-6 and IL-10.