Human, porcine, and murine complement (C') fragment C5a has been shown to be both a potent inflammatory agent and more recently, a modifier of in vitro and in vivo immune responses. Besides the well characterized proinflammatory potential of C5a, this C' component enhance both in vitro humoral and cell-mediated immune (CMI) responses. Human C5a has been reported to induce the synthesis of important cytokines such as interleukin-1 (IL-1), interleukin-6 (IL-6) and tumor necrosis factor- alpha (TNF-alpha), which are known to play key roles as mediators of immune reactivity. In addition, the recent cloning of PMN chemotactic factor (interleukin-8; IL-8) and its demonstrated importance in the inflammatory process makes IL-8 along with IL-1, IL-6, and TNF-alpha likely candidates for involvement in C5a-mediated biological activity. The induction of cytokine synthesis by C5a is a controversial point. It has been suggested that a synergy between low levels of endotoxin (ET) and C5a is responsible for the observed effects. This initial cell """"""""priming"""""""" event may be necessary for the expression of C5a receptors (C5aR) on the appropriate cell population(s) prior to C5a exerting its modulatory effects. the possibility of a synergy between ET and C5a in vivo, although unproven, is appealing since this may represent a positive feed back mechanism that could result in an amplification of the immune response to invading pathogens. The major hypothesis in this proposal is that the proinflammatory and immunoregulatory activities associated with human C5a are due in part to the synthesis and action of multiple cytokines. the importance of C5a as a mediator of inflammation and its potential role in normal and aberrant immune function necessitates the elucidation of the complete mechanism of action of this C' fragment. In this proposal we will address the mechanism(s) of C5a-mediated immunoregulation and inflammation on the cellular and molecular levels. Specific questions asked include: 1) Which cell populations are stimulated by C5a to secrete cytokines and what is the cytokine profile produced by these cell populations?; 2) Is the expression of the C5a receptor on monocytes and lymphocytes a constitutive or inducible event?; 3) Are cytokines involved in C5a-mediated enhancement of T cell activation?; 4) What is the role of cell """"""""priming"""""""" in the C5a-mediated immunoenhancement?; and 6) Will modulation of C5a receptor expression suppress C5a-mediated immunoenhancement and inflammation?
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