Fig. 4.

Mechanisms of the depressing effects of cytokines on mood. Activation of the innate immune system is triggered by cytokine immunotherapy or psychosocial stressors (via a β2adrenergic receptor). It results in the overproduction of proinflammatory cytokines. The same condition occurs during chronic inflammation. Cytokines, such as TNF-α and IFN-γ, increase activity of the enzyme, IDO, that degrades tryptophan along the kynurenine/quinolinic acid metabolic pathway, resulting in a decrease in tryptophan and an increase in kynurenine. The decreased tryptophan bioavailability leads to decreased serotoninergic neurotransmission and depressed mood. Depression itself can be accompanied by altered immunity, including activation of the innate immune system, further increasing the proinflammatory cytokine load.