Differential effects of synthetic indoloquinolizines on in vitro rat lymphocyte and macrophage functions

Indoloquinolizines are natural alkaloid indole products grouped as beta-carbolines. These compounds are commonly associated with neurological activities, but little is known about their role as immunomodulating agents. The present study was undertaken to evaluate the effects of synthetic indoloquinolizines on in vitro parameters of rat lymphocyte and macrophage functions. It was observed that proliferation of thymic lymphocytes was significantly (p<0.05) increased (20-30% increase) by dihydro-indoloquinolizinium chloride (2). dihydro-indoloquinolizinyl-ethanone (3). and dimeric dihydro-indoloquinolizinium dichloride (6). whereas dimeric indoloquinolizine (7). caused up to 40% increase in lymphoproliferation at concentrations ranging from 10(-11) to 10(-5) M, compared with untreated control. In contrast, indoloquinolizinium chloride (4) and indoloquinolizine (5). were toxic for lymphocytes at concentrations from 10(-9) to 10(-5) M, and compounds 6 and 7 were toxic at 10(-5) M. In addition, nitric oxide production by LPS-treated peritoneal macrophages was significantly (p<0.05) increased (up to 30% increase) by compounds 4 and 5 at concentrations of 10(-11) to 10(-5) M, and 10(-5) M, respectively; however, compounds 6 and 7 were toxic for macrophages at all concentrations tested. Furthermore, TNF-alpha production was also significantly increased (p<0.01) by compounds 4 and 5 (up to 30-fold increase) compared with untreated control. These novel synthetic indoloquinolizines could serve as immunotherapeutic agents by selectively increasing the pool of activated T lymphocytes or stimulating macrophage functions, with potential use in the treatment of infectious diseases including AIDS and cancer.