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Blood, 1 October 2005, Vol. 106, No. 7, pp. 2375-2381.
Prepublished online as a Blood First Edition Paper on June 9, 2005; DOI 10.1182/blood-2005-03-0979.
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IMMUNOBIOLOGY
A two-step induction of indoleamine 2,3 dioxygenase (IDO) activity during dendritic-cell maturation
Deborah Braun,
Randy S. Longman, and
Matthew L. Albert
From the Institut Pasteur, Paris, France; and the Institut National de la Santé et de la Recherche Médicale (INSERM) AV0201, Paris, France.
Prostaglandins, a family of lipidic molecules released during inflammation, display immunomodulatory properties in several models. One use includes exposure of monocyte-derived dendritic cells (DCs) to a cocktail of cytokines that contains prostaglandin E2 (PGE2) for purposes of maturation; such cells are currently being used for cancer immunotherapy trials. Our analysis of the transcription profile of DCs matured in the presence of tumor necrosis factor  (TNF) and PGE2 revealed a strong up-regulation of indoleamine 2-3 dioxygenase (IDO), an enzyme involved in tryptophan catabolism and implicated in both maternal and T-cell tolerance. Using quantitative assays to monitor levels of IDO mRNA, protein expression, and enzyme activity, we report that PGE2 induces mRNA expression of IDO; however, a second signal through TNF receptor (TNF-R) or a Toll-like receptor (TLR) is necessary to activate the enzyme. Interestingly, use of TNF, lipopolysaccharide, or Staphylococcus aureus Cowan I strain (SAC) alone does not induce IDO. The effect of PGE2 is mediated by activation of adenylate cyclase via the Gs-protein-coupled receptor E prostanoid-2 (EP2). A better understanding of these regulatory mechanisms and the crosstalk between TNF-R/TLR and EP2 signaling pathways will provide insight into the regulation of T-cell activation by DCs and may help to improve existing immunotherapy protocols.
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