Robert Wood Johnson Medical School
Dept of Pharmacology
Child Health Institute
89 French Street
New Brunswick, NJ 08901
Apoptosis in lymphocytes. immune regulation. psychoneuroimmunology. and bone-lymphocyte connection
Our group is interested in the mechanisms regulating the immune system. with particular emphasis on the role of apoptosis. With a model system. using a T-cell hybridoma. we established activation-induced cell death (AICD) and found that AICD is dependent on protooncogene. c-myc. Our recent studies have demonstrated that c-myc is involved in the induction of FasL. through the activity of cdc25A in a cell-cycle-dependent manner. Although Fas is also induced by activation. its expression does not require c-myc; instead it requires translocation of protein kinase C (PKC) via activation of the TDAG51 gene. Since the expression and subsequent interaction of Fas and FasL are absolutely required for AICD. the determination of the molecular mechanisms of c-myc-mediated FasL expression and PKC-mediated Fas expression will lead to a fundamental understanding of the regulation of the immune system. In addition. we have recently shown that activation through TCR in these cells also leads to the expression of other members of the TNF family including RANKL. OX40L. Light. and TRAIL. providing us with a unique opportunity to ask how multiple members of the TNF family contibuting to the regulation of the immune system. We found that the expression of these genes is controlled by distinct molecular mechanisms with distinct kinetics. One of our recent findings is the differential regulation of the expression of FasL and TRAIL during Th1 and Th2 differentiation and have revealed the importance of apoptosis in this process. In addtion. we also found that Fas and FasL play a critical role in stress- and opioid-meidated immune response. These studies will shed new light on the understanding of the molecular mechanisms by which the immune system is regulated through apoptosis. Since the expression of TNF family molecules has been implicated in autoimmunity. allergy. arhtritis. tumor immunity. and the communication of immune system with skeletal and neurol systems. the elucidation of the mechanisms regulating the expression of these molecules will enable better management and prognosis of diseases such as AIDS. cancer. allergy. and arthritis.