Cytokine regulation of tryptophan metabolism in the hypothalamic-pituitary-adrenal (HPA) axis: implications for protective and toxic consequences in neuroendocrine regulation.
OBJECTIVE
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-gamma (IFN-gamma) 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-gamma 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.


METHODS
Reverse transcriptase polymerase chain reaction (RT-PCR) was performed to check the IDO expression from IFN-gamma and IL-10 treated cells such as GT1-7, AtT-20 and Y-1 cells.


RESULTS
We found that IFN-gamma induces IDO expression after 4 h treatment in GT1-7 and AtT-20 cells. IL-10 was also able to suppress IFN-gamma induced IDO expression in these cells. In Y-1 adrenal cells, IFN-gamma treatment had no effect on IDO expression.


CONCLUSIONS
Our results indicate that cytokines such as IFN-gamma and IL-10 are able to regulate IDO expression in cells of hypothalamic and pituitary origin. The ability of IL-10 to suppress IFN-gamma 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.
Tu
Huolin
H
Department of Microbiology, University of Texas Medical Branch, Medical Research Building. 4.174, Galveston, Texas 77555, USA.
Rady
Peter L
PL
Juelich
Terry
T
Smith
Eric M
EM
Tyring
Stephen K
SK
Hughes
Thomas K
TK
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002460:Cell Line; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000276:immunology; D007030:Hypothalamo-Hypophyseal System / Q000166:cytology / Q000378:metabolism*; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007371:Interferon-gamma / Q000494:pharmacology; D016753:Interleukin-10 / Q000494:pharmacology*; D007736:Kynurenic Acid / Q000378:metabolism; D051379:Mice; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology; D009498:Neurotoxins / Q000378:metabolism; D010913:Pituitary-Adrenal System / Q000166:cytology / Q000378:metabolism*; D014364:Tryptophan / Q000378:metabolism*; D014366:Tryptophan Oxygenase / Q000235:genetics / Q000378:metabolism
D000970:Antineoplastic Agents; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D018696:Neuroprotective Agents; D009498:Neurotoxins; D016753:Interleukin-10; D007371:Interferon-gamma; D014364:Tryptophan; D014366:Tryptophan Oxygenase; D007736:Kynurenic Acid