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Indolamine 2,3‐dioxygenase is expressed in the CNS and down‐regulates autoimmune inflammation
Author(s) -
Kwidzinski Erik,
Bunse Jörg,
Aktas Orhan,
Richter Daniel,
Mutlu Leman,
Zipp Frauke,
Nitsch Robert,
Bechmann Ingo
Publication year - 2005
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.04-3228fje
Subject(s) - experimental autoimmune encephalomyelitis , indoleamine 2,3 dioxygenase , microglia , immunology , immune system , inflammation , multiple sclerosis , kynurenine pathway , kynurenine , biology , medicine , tryptophan , biochemistry , amino acid
The tryptophan (trp)‐catabolizing enzyme indolamine 2,3‐dioxygenase (IDO) is induced by the T helper 1 (Th 1) cytokine IFN‐γ during infections in various tissues including the brain. Recent studies demonstrated an immune modulatory function of this enzyme, since IDO‐mediated depletion of trp hinders T cell proliferation, while its inhibition by 1‐methyl‐tryptophan (1‐Mt) induces breakdown of immune tolerance in the placenta, leading to rejection of allogeneic concepti. Here, we tested IDO expression and function during experimental autoimmune encephalomyelitis (EAE) actively induced in adult SJL mice by immunization with PLP 139–151 . IDO activity (determined by HPLC analysis of the kynurenine/tryptophan ratio) was increased in the spleen during the preclinical phase, and within the brain and spinal cord at the onset of symptoms. Immunocytochemistry revealed macrophages/activated microglia expressing IDO during EAE and in vitro experiments confirmed IDO induction in microglia upon IFN‐γ treatment with synergistic effects of TNF‐α. Inhibition of IDO by systemic administration of 1‐Mt at clinical onset significantly exacerbated disease scores. From these data, it is tempting to speculate that IFN‐γ from encephalitogenic Th 1 cells induces local IDO expression, thereby initiating a negative feedback loop which may underlie the self‐limitation of autoimmune inflammation during EAE and multiple sclerosis.