A novel function of IL-12p40 as a chemotactic molecule for macrophages

IL-12p70 plays a pivotal role in regulating the Th1/Th2, balance in the ini tial stage of immune responses, In contrast, IL-12p40, which is produced ex cess over IL-12p70, has been known to down-regulate IL-12p70-mediated respo nses by acting as an antagonist. To investigate in vivo function of IL-12p4 0, RH7777 rat hepatoma cells were engineered to inducibly express mouse IL- 12p40 under the tight control of doxycycline (dox), In the absence of dox, s.c. injection of these cells into syngeneic rat was shown to generate tumo rs. However, the induction of IL-12p40 by dox was sufficient for inhibiting tumor formation, as well as for tumor regression. Immunohistochemical anal ysis showed that macrophages, but not CD4(+) T, CD8(+) T,and NK cells, were predominantly recruited into tumor sites as early as 3 days after IL-12p40 induction. These results were further supported by the observation that IL -12p40, but not C-terminal deletion mutants by more than 5 amino acids, was able to chemoattract peritoneal macrophages in vitro, suggesting that IL-1 2p40, when produced in a large excess over IL-12p70 in vivo, can initially amplify the immune responses against tumors by directly recruiting macropha ges, Our findings indicate that IL-12p40 may function as an effector molecu le as well as an antagonist of IL-12p70.