Picolinic acid, a catabolite of tryptophan, as the second signal in the activation of IFN-γ-primed macrophages

We have studied the effects of picolinic acid, a product of tryptophan degradation, on the activation of mouse peritoneal macrophages (Mφ). Picolinic acid acts synergistically with IFN-γ in activating Mφ from C57BL/6 mice. Moreover, Mφ from C3H/HeJ mice and C3H/HeN that do not become cytotoxic in response to IFN-γ alone could be fully activated by exposure to picolinate plus IFN-γ. These results indicate that picolinic acid is a potent costimulator of Mφ activation that functions as a second signal. Inasmuch as we have previously demonstrated that the activation of cytotoxic Mφ correlates with specific changes in ribosomal RNA (rRNA), we investigated whether picolinic acid could modify Mφ RNA metabolism. Picolinic acid inhibited the synthesis of total Mφ RNA, the accumulation of newly synthesized 28S rRNA, and augmented the steady state levels of rRNA precursors (pre-rRNA). These changes in RNA metabolism were similar to those previously described in murine Mφ activated in vitro or in vivo to express tumoricidal activity. These results demonstrate that picolinic acid is a potent, biologic Mφ second signal, suggest that the changes in rRNA are causally connected with the expression of tumoricidal activity, and suggest the existance of an autocrine effect mediated by picolinic acid.