Die Inflammations-induzierte Synthese von IL-18: Molekulare Regulationsmechanismen und deren Modulation durch Gentherapie
Final Report Abstract
lnterleukin-18 (IL-18) has been suggested to play a central role in cytokine-induced organ dysfunction and failure during systemic inflammation. As a member of the classical proinflammatory cytokines, it appears to possess the unique ability of distinguishing between Gram positive and Gram negative pathogens in the consecutive inflammatory response to a microbial challenge. IL-18 is predominantly synthesized in peripheral mononuclear cells (PBMC) and monocytes, and is activated primarily by caspase-1 dependent, but also caspase-1 independent mechanisms. To date, little is known about the mechanisms by which gram-positive and gramnegative pathogens differentially regulate the synthesis and release of IL-18. Our invitro experiments comparing the characteristic cell-wall components of representative gram-positive and gram-negative bacteria (Staph. aureus vs. E. coli) was able to demonstrate, that the distinct increase of IL-18 production from isolated human monocytes was rather independent from TLR-mediated signalling sequences. Furthermore, the initial believe of differential caspase-1 activation being a key step in the enhanced cleavage of pro-IL-18 into its mature IL-18 upon a bacterial challenge with gram-psoitive Staph. aureus was not confirmed in our analyses. Although phagocytosis of respective bacteria by viable and activated monocytes/macrophages was not investigated in-vitro, pre-incubation of freshly isolated human monocytes with heparin and wortmannin significantly reduced Staph. aureus. induced IL-18 production. Thus, future studies will focus on the exact pathomechanism of this observation, to further characterize the therapeutic potential and relevance of applying such substances in an in-vivo model of gram-positive, gram-negative and polymicrobial sepsis.
Publications
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lnterleukin-18: a novel prognostic cytokine in bacteria-induced sepsis. Crit Care Med. 2006 Apr;34(4): 1225-33
Tschoeke SK, Oberholzer A, Moldawer LL
