Cytokine Regulation of Tryptophan Metabolism in the Hypothalamic-Pituitary-Adrenal (HPA) Axis: Implications for Protective and Toxic Consequences in Neuroendocrine Regulation

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Abstract
1. Aim: Indoleamine 2,3-dioxygenase (IDO) catalyzation of tryptophan is the first rate-limiting step of the kynurenine pathway in the majority of tissues. The kynurenine pathway produces neurotoxic metabolites such as 3-hydroxykinurenine and quinolinic acid. IDO is inducible by the cytokine interferon-γ (IFN-γ) and has been proposed to mediate the sickness behavior of patients with infectious or other inflammatory diseases. To better understand the neuroendocrine component of cytokine induced sickness behavior we determined the effects of the pro-inflammatory cytokine IFN-γ and the anti-inflammatory cytokine IL-10 on IDO expression in cells derived from the hypothalamic-pituitary-adrenal axis (HPA): GT1-7 hypothalamic, AtT-20 pituitary, and Y-1 adrenal cells. 2. Methods: Reverse transcriptase polymerase chain reaction (RT-PCR) was performed to check the IDO expression from IFN-γ and IL-10 treated cells such as GT1-7, AtT-20 and Y-1 cells. 3. Results: We found that IFN-γ induces IDO expression after 4 h treatment in GT1-7 and AtT-20 cells. IL-10 was also able to suppress IFN-γ induced IDO expression in these cells. In Y-1 adrenal cells, IFN-γ treatment had no effect on IDO expression. 4. Conclusions: Our results indicate that cytokines such as IFN-γ and IL-10 are able to regulate IDO expression in cells of hypothalamic and pituitary origin. The ability of IL-10 to suppress IFN-γ induced IDO expression implies that IL-10 has a putative neuroprotective role in the HPA axis. It can act at two levels, systemically by inhibiting sickness behavior—related Th1 cytokine synthesis and more centrally by inhibiting the kynurenine pathway.