The kynurenine pathway of tryptophan metabolism is an important regulator of CNS neuroglial activity and immune system function. Here, novel factors influencing the kynurenine pathway (KP) are presented, with preliminary data examining links with TNF, a mediator known to have substantial clinical relevance. Bone-marrow derived macrophages (BMDMs), THP-1 and, RAW264.7 lines and mice lacking TNF receptor 1 (TNFR1) were used. Gene expression was assessed by qRT-PCR. Results showed that the bacterial serine protease subtilisin and mammalian prostate specific antigen (PSA) induced expression of IDO1, IDO2 and cytokines in THP-1 and RAW264.7 cells. The bacterial quorum sensor PQS, synthesised from anthranilic acid, suppressed induction of IDO and pro-inflammatory cytokines. TNF weakly induced IDO1 and TDO. This was reduced by TNF antagonists etanercept and Fc-206 (TNFR1 selective). IFNγ induced IDO in THP-1 and RAW264.7 cells where it was unexpectedly reduced by TNF antagonists. LPS induction of TNF and CXCL-8 was partly TNF-dependent. IFNγ induced AFMID expression, partly via TNFR1; genes expressing KMO, KYNU and KATS 1-4 were unaffected. TNF and IFNγ induced IDO1, IL1β and TNF gene expression in BMDMs from WT but not TNFR1-/- animals. KMO expression tended to increase in TNFR-/- KO cells. It is concluded that serine protease induction of IDO may contribute to their effects on neuronal and glial activity, as well as affecting interactions between immune system cells and CNS. Endogenous TNF has direct and indirect effects on many aspects of neuroglial activity and synaptic transmission, some of which may involve the kynurenine pathway.