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Double Mechanism for Apical Tryptophan Depletion in Polarized Human Bronchial Epithelium¹

Olga Zegarra-Moran^2,*, Chiara Folli^*, Benedetta Manzari, Roberto Ravazzolo^*,, Luigi Varesio and Luis J. V. Galietta^*

^* Laboratorio di Genetica Molecolare and Laboratorio di Biologia Molecolare, Istituto Giannina Gaslini, Genoa, Italy; and Dipartimento di Pediatria e Centro de Eccellenza per la Ricerca Biomedica, Università di Genova, Genoa, Italy

Indoleamine 2,3-dioxygenase is an enzyme that catabolizes tryptophan to kynurenine. We investigated the consequences of IDO induction by IFN- in polarized human bronchial epithelium. IDO mRNA expression was undetectable in resting conditions, but strongly induced by IFN-. We determined the concentration of tryptophan and kynurenine in the extracellular medium, and we found that apical tryptophan concentration was lower than the basolateral in resting cells. IFN- caused a decrease in tryptophan concentration on both sides of the epithelium. Kynurenine was absent in control conditions, but increased in the basolateral medium after IFN- treatment. The asymmetric distribution of tryptophan and kynurenine suggested the presence of a transepithelial amino acid transport. Uptake experiments with radiolabeled amino acids demonstrated the presence of a Na⁺-dependent amino acid transporter with broad specificity that was responsible for the tryptophan/kynurenine transport. We confirmed these data by measuring the short-circuit currents elicited by direct application of tryptophan or kynurenine to the apical surface. The rate of amino acid transport was dependent on the transepithelial potential, and we established that in cystic fibrosis epithelia, in which the transepithelial potential is significantly more negative than in noncystic fibrosis epithelia, amino acid uptake was reduced. This work suggests that human airway epithelial cells maintain low apical tryptophan concentrations by two mechanisms, a removal through a Na⁺-dependent amino acid transporter and an IFN--inducible degradation by IDO.

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