Regulation of macrophage interleukin-1 beta production

描述（由申请人提供）：在肺部，持续暴露

DESCRIPTION (provided by applicant): In the lung, which is constantly exposed to environmental pathogens, the alveolar macrophage represents the front line defense. Its ability to cope with invading microorganisms is critical to host survival. Proinflammatory cytokines released by tissue macrophages provide the early signaling molecules that gamer the host defenses. Underexpression of cytokines like IL-1beta can lead to overwhelming infection and death whereas overexpression of these molecules can lead to tissue injury and the adult respiratory distress syndrome. Thus a better understanding of IL-1 beta physiology is critical to understanding lung host defense and lung injury. The ability to process and release IL-1beta is a key immune function of the lung macrophage. However, despite the tremendous insights that have come from the discovery of IL-1 converting enzyme (ICE), the prototype of the caspase family of apoptotic enzymes, very little is known about how the inactive precursor for IL-1beta is processed by ICE (caspase-1). Furthermore, the release pathway used by signal peptide- and leader sequence-deficient IL-1beta has yet to be discovered. Therefore, the major emphasis of this proposal is directed at this question. We will test the hypothesis that activation events (occurring via Toll-like receptors) induce the organization of a multicomponent protein complex. This protein complex induces the activation of ICE and places it and IL-1 feta into a composite of release-regulating proteins that orchestrate mature cytokine export. In this context, we have recent evidence to support the hypothesis that IL-1beta processing and release is controlled by a complex of proteins (which we have termed the ICEasome) that has significant links to the NF-kB signalosome. We propose that ICE and novel IL-1 release-regulating molecules (recently identified by yeast two-hybrid screening) are linked to Toll-like receptor activation by complexes with I-kB kinases and by regulation through proteasome-mediated protein degradation. The specific aims of the proposal seek to test the hypothesis that IL-1beta release depends upon ICE in a manner that is independent of its convertase activity. ICE may function in part by its ability to form CARD-CARD interactions that link IL-1beta to the NF-kB pathway. We further propose that IL-1beta release is negatively regulated in a manner analogous to NF-kB's regulation by I-kBalpha. We hypothesize that MAIL, a novel protein homologue of I-kBalpha that we discovered by yeast two-hybrid screening negatively regulates prolL-1beta processing and release.