Systemic multi-organ injury is an important component associated with sepsis. Multi-organ dysfunction during sepsis can be caused by a myriad of factors, including endotoxin and systemic production of proinflammatory cytokines, such as TNFalpha and IL-1beta. The liver is a major source of cytokine expression in response to endotoxin and hence plays a critical role in mediating systemic organ injury during sepsis. Hepatic responses to LPS that control proinflammatory cytokine production include a number of receptor-mediated signal transduction pathways, of which NF-kappaB is one of the most important. In this context, NF-kappaB activation in the liver directly controls the induction of TNFalpha in response to LPS and mediates signals that are important to hepatic cell survival. We have determined that IL-1beta and LPS share interesting similarities and differences in their mechanisms of NF-kappaB activation. Both involve redox-sensitive pathways that appear to be controlled by NADPH oxidase activation and converge at the level of the IKB kinase (IKK) complex. LPS and IL-1beta activation of NF-kappaB also utilize two related receptors (TLR4 and IL-1R) that share similar effector complexes. Despite the similar dependence of both these pathways on the intracellular production of reactive oxygen species (ROS), LPS and IL-1beta activate NF-kappaB through distinct subunits of the IKK complex. The manner in which ROS uniquely control NF-kappaB activation by LPS and IL-1beta remains unclear. This project proposes to dissect the redox-mediated events that control these activation pathways using both in vitro and in vivo mouse models. In vitro studies will evaluate LPS and IL-1beta responses in hepatocytes and Kupffer cell line models in order to identify the redox-regulated components of the TLR4 and IL-1R receptor complexes that mediate activation of specific IKK kinases. An important aspect of these mechanisms involves the formation of redox-active endosomes (termed redoxosomes) that appear to cluster ligand-activated receptors into NADPH oxidase active endosomes. We hypothesize that redoxosomes help partition ROS to redox-dependent TLR4 and IL-1R effector domains. Through this process, endosomal compartmentalization of ROS allows only ligand-activated receptor/effector complexes to be influenced by NADPH oxidase. In vivo studies will utilize mouse models of endotoxemia to study redoxosomal functions in vivo and their contribution to hepatic NF-kappaB activation pathways. Findings from these studies may lead to alternative therapeutic approaches targeting the liver by which to abrogate the detrimental effects of systemic cytokine production during sepsis.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Study Section
Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Carrington, Jill L
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University of Iowa
Anatomy/Cell Biology
Schools of Medicine
Iowa City
United States
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Oakley, Fredrick D; Smith, Rachel L; Engelhardt, John F (2009) Lipid rafts and caveolin-1 coordinate interleukin-1beta (IL-1beta)-dependent activation of NFkappaB by controlling endocytosis of Nox2 and IL-1beta receptor 1 from the plasma membrane. J Biol Chem 284:33255-64
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