Apoptosis of inflammatory leukocytes is widely thought to be crucial for the regulation of inflammatory responses. The direct investigation of this idea has been hampered by the inability to demonstrate regulatory molecules specific to these cells that might permit experimental manipulation of the apoptotic response. We have isolated and described such a candidate molecule, a Bcl-2 related anti-apoptotic protein named A1. A1 is rapidly induced in macrophages by pro-inflammatory mediators, and is strongly up-regulated during acute pathogenic inflammation in mice. The objective of this project is to clarify the functional roles of A1 in the regulation of cell death processes during the progress and resolution of inflammatory responses. The application proposes a model for apoptotic regulation in the acute response to a pathogen is divided into two stages. In stage one, the innate immune response generates effector molecules such as nitric oxide that are vital for host defense but are also pro-apoptotic for macrophages. At this stage, A1 expression protects the macrophage and permits the inflammatory response to continue. In stage two, pathogen has been largely cleared, and inflammatory macrophages are now removed by a second wave of pro-apoptotic stimuli. This second wave, which may be derived from activated T-cells, is able to override the protective effects of A1.
The Specific Aims will test and refine this idea will focus on the following three hypotheses: (1) Mediators of host defense include both 'A1-sensitive' and 'A1-resistant' apoptotic stimuli. (2) During the acute response to T. gondii infection, a shift occurs in the inflammatory environment from A1-mediated protection of macrophages to A1-resistant macrophage apoptosis. (3) Protection of macrophages during inflammation is mediated by A1 and is vital for host defense.
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| Orlofsky, Amos; Weiss, Louis M; Kawachi, Nicole et al. (2002) Deficiency in the anti-apoptotic protein A1-a results in a diminished acute inflammatory response. J Immunol 168:1840-6 |
| Somogyi, R D; Wu, Y; Orlofsky, A et al. (2001) Transient expression of the Bcl-2 family member, A1-a, results in nuclear localization and resistance to staurosporine-induced apoptosis. Cell Death Differ 8:785-93 |
| Kausalya, S; Somogyi, R; Orlofsky, A et al. (2001) Requirement of A1-a for bacillus Calmette-Guerin-mediated protection of macrophages against nitric oxide-induced apoptosis. J Immunol 166:4721-7 |
| Orlofsky, A; Somogyi, R D; Weiss, L M et al. (1999) The murine antiapoptotic protein A1 is induced in inflammatory macrophages and constitutively expressed in neutrophils. J Immunol 163:412-9 |
