Inflammation, a normal physiologic response essential for survival, must be tightly regulated to prevent damage to tissues and organs. Project 2 is designed to elucidate the cellular, molecular and physiologic mechanisms whereby TGF-B1, glucocorticoids (GCs) and IL-10 interact to prevent excessive a damaging responses to inflammatory stimuli such as bacterial lipopolysaccharide (LPS). Recently, long term """"""""memory"""""""" of neonatal challenge with LPS has been observed in adult animals, dramatically demonstrating the critical importance of regulating the surge of glucocorticoids and immune cytokines that occurs during the acute response to inflammatory stimuli. We can now begin to understand the mechanisms-genetic hormonal and immune-which dictate a protective response for some individuals and life threatening pathology for others. Project 2 takes advantage of a new collaboration between the P.I. and mentor to address interactive mechanisms whereby cytokines and glucocorticoids (GCs) regulate immune homeostasis. The primary thrust of this proposal retains the established focus of the P.I. on TGF-B, but now addresses mechanisms whereby the interplay of TGF-B, IL-10, and GCs impacts macrophage activation and the host response to inflammatory stimuli.
Specific Aim 1 : to define in murine model systems the mechanism(s) by which TGF-B1, GCs, and IL-10 modify LPS-induced responses in macrophages (MOs).
Specific Aim 2 : to test in murine model systems the hypothesis that TGF-BI is a physiologic antagonist of LPS- and cytokine-induced inflammatory responses in mice in vivo.
Specific Aim 3 builds on new findings of the P.I. and mentor to examine the mechanisms by which LPS signaling to human MOs is regulated by TGF-B1, GCs and IL-10. It will examine the regulation of MO function in cell culture assays and in vivo, including human studies designed to definitively identify the parameters that lead to glucocorticoid enhancement or inhibition of inflammatory cytokine production following challenge with LPS.
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