Although the tryptophan-degrading enzyme, indoleamine 2,3-dioxygenase (IDO), is a pivotal mediator of inflammation-induced depression, its mechanism of regulation has not yet been investigated in this context. Here, we demonstrate an essential role for interferon (IFN)gamma and tumor necrosis factor (TNF)alpha in the induction of IDO and depressive-like behaviors in response to chronic immune activation. Wild-type (WT) control mice and IFNgammaR(-/-) mice were inoculated with an attenuated form of Mycobacterium bovis, bacille Calmette-Guérin (BCG). Infection with BCG induced an acute episode of sickness that was similar in WT and IFNgammaR(-/-) mice. Increased immobility during the forced swim and tail suspension tests occurred in WT mice 7 d after BCG inoculation but was entirely absent in IFNgammaR(-/-) mice. In WT mice, these indices of depressive-like behavior were associated with chronic upregulation of IFNgamma, interleukin(IL)-1beta, TNFalpha, and IDO. Proinflammatory cytokine expression was elevated in BCG-infected IFNgammaR(-/-) mice as well, but upregulation of lung and brain IDO mRNA was completely abolished. This was accompanied by an attenuation of BCG-induced TNFalpha mRNA and the lack of an increase in plasma kynurenine/tryptophan ratio in the BCG-inoculated IFNgammaR(-/-) mice compared with WT controls. Pretreatment of mice with the TNFalpha antagonist, etanercept, partially blunted BCG-induced IDO activation and depressive-like behavior. In accordance with these in vivo data, IFNgamma and TNFalpha synergized to induce IDO in primary microglia. Together, these data demonstrate that IFNgamma, with TNFalpha, is necessary for induction of IDO and depressive-like behavior in mice after BCG infection.