Lipopolysaccharide induction of indoleamine 2,3-dioxygenase is mediated dominantly by an IFN-γ-independent mechanism

Indoleamine 2,3-dioxygenase (IDO) is a rate-limiting enzyme in the L-tryptophan-kynurenine pathway, which converts an essential amino acid, L-tryptophan, to N-formylkynurenine. It has been speculated that IFN-γ is a dominant IDO inducer in vivo. The present study used IFN-γ or TNF-α gene-disrupted mice and IFN-γ antibody-treated mice to demonstrate that lipopolysaccharide (LPS)-induced systemic IDO is largely dependent on TNF-α rather than IFN-γ. IFN-γ-independent IDO induction was also demonstrated in vitro with LPS-stimulated monocytic THP-1 cells. These findings clearly indicate that there is an IFN-γ-independent mechanism of IDO induction in addition to the IFN-γ-dependent mechanism.