Mammals including humans have evolved a complex, multifaceted host response to defend against bacterial, viral, or parasite invasion. This host response is largely controlled by a group of endogenous effector proteins called cytokines, which are mainly secreted by immune and inflammatory cells. Our work seeks to identify and characterize novel macrophage-derived elements of this host cytokine response. During the past award period, we described four novel monokines (which we call Macrophage Inflammatory Proteins or MIP's), and demonstrated the potential involvement of these MIPs in specific aspects of the host inflammatory response. This competing renewal proposal now focuses in on one subset of these novel monokines, related to the murine MIP-1 archetypes first characterized by us, that are themselves members of a larger family of cytokines with potent leukocyte chemotactic and activating properties. This group has come to be called the chemokine family. The chemokines, and cytokines in general, are coordinately regulated within a interactive cytokine network, wherein each element influences the expression and action of many other mediators, and target cells integrate cytokine messages from many sources to defend the host against invasion. Due to the cellular and molecular complexity of this interaction, it is nearly impossible to analyze the consequences of cytokine network activity except in grossly unbalanced cases such as septic shock, when cytokine activation cascades out of control with lethal consequences. A much better understanding of the more subtle interactions of the cytokine network is required in order to effectively intervene in immune and inflammatory processes for therapeutic benefit. We propose to examine the interactions of the chemokine elements MIP-1alpha and MIP-1beta, partly because of their inherently interesting bioactivity profiles as leukocyte proliferation and activation factors, and partly as a paradigm to better understand general principles and cellular mechanisms that govern interaction within the cytokine effector molecule """"""""network"""""""" that coordinately regulates and controls the response of the host to invasive disease. Our long-term objectives are to define the manner in which these cytokine effector molecules work together and in opposition to modulate the cellular and systemic responses of the host to invasion, and to characterize the molecular mechanisms of cytokine antagonism, thus addressing a central aspect of how the integrated action of multiple cytokines contributes to host defense, and identifying novel approaches for potential therapeutic intervention.
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