Conte, Damiano2013-11-082013-11-0820042004Source: Dissertation Abstracts International, Volume: 66-05, Section: B, page: 2390.http://hdl.handle.net/10393/29089http://dx.doi.org/10.20381/ruor-12762The fundamental physiological process of apoptosis plays a crucial role in maintaining the homeostasis of the mammalian immune system. The major sites of apoptotic influence occur throughout lymphopoiesis, during the deletion of unwanted carcinogenic or virally infected cells and at the waning of an antigen-induced immune response. The c&barbelow;ellular i&barbelow;nhibitor of apoptosis 2&barbelow; (cIAP2) is a potent inhibitor of apoptotic death. In contrast to the other members of the inhibitor of apoptosis (IAP) family cIAP2 is NF-kappaB-inducible via pro-inflammatory cytokines, such as IL-1beta and TNFalpha, and via bacterial components, such as l&barbelow;ipop&barbelow;olys&barbelow;accharide (LPS). The following studies demonstrate that cIAP2 -/- mice exhibit significant resistance to LPS-induced endotoxic shock, specifically via an attenuated inflammatory response. We show that due to a lack of cIAP2, cIAP2-/- macrophage cells have a heightened susceptibility to apoptosis in a LPS-induced pro-inflammatory environment and hence are unable to maintain a normal inflammatory response. These results raise the intriguing possibility that pharmacological agents targeting and inhibiting cIAP2 expression may be sufficient to confer protection to the lethal onset of sepsis. The X&barbelow;-linked i&barbelow;nhibitor of apoptosis (XIAP) and other members of the i&barbelow;nhibitor of apoptosis (IAP) family can suppress apoptosis induced by a diverse variety of triggers. Functional studies done to date have focused upon tissue culture models and adenovirus over-expression of XIAP and other IAP proteins. These studies report the phenotype of the first engineered transgenic mouse over-expressing a human IAP, as well as assessing the long-term consequence of IAP over-expression. The relative protein expression levels of the endogenous murine homologue to XIAP within thymocyte and T cell sub-populations are also documented. The consequence of lymphoid-targeted over-expression of XIAP in transgenic mice suggests a physiological role for the endogenous murine XIAP. Xiap-transgenic mice accumulated thymocytes and/or T cells in primary and secondary lymphoid tissue, T cell maturation was perturbed, and transgenic thymocytes resisted a variety of apoptotic triggers both in vitro and in vivo. These observations imply a possible key function for the intrinsic cellular inhibitor XIAP in maintaining the homeostasis of the immune system.200 p.enBiology, Molecular.Biology, Genetics.Health Sciences, Immunology.Thesis