Submitted July 18, 2006
Accepted March 7, 2007
Human IL4I1 is a secreted L-phenylalanine oxidase expressed by mature dendritic cells which inhibits T lymphocyte proliferation
Marie-Laure Boulland, Jeanine Marquet, Valerie Molinier-Frenkel, Peter Moller, Chrystelle Guiter, Fanette Lasoudris, Christiane Copie-Bergman, Maryse Baia, Philippe Gaulard, Karen Leroy, and Flavia Castellano*
INSERM, Unite 841, IMRB, Dept Immunologie-Oncologie-Dermatologie, Equipe 09, Creteil, France
Universite Paris 12, Faculte de Medecine, IFR10, Creteil, France
Groupe Henri Mondor-Albert Chenevier, Service d'Immunologie Biologique, Creteil, France
Abteilung fur Pathologie des Universitatklinikums Ulm, Ulm, Germany
Groupe Henri Mondor-Albert Chenevier, Service de Pathologie, Creteil, France
* Corresponding author; email: falvia.castellano{at}creteil.inserm.fr.
Interleukin-4 Induced Gene 1 (IL4I1) was first described as a B cell IL4-inducible gene and is highly expressed in primary mediastinal B cell lymphomas. We established stable HEK293 clones expressing human and mouse IL4I1 to examine their biochemical properties and function. Both proteins were secreted into the culture medium and we observed the secretion of endogenous human IL4I1 (hIL4I1) protein in a mediastinal lymphoma B cell line, MedB-1. We showed that IL4I1 has L amino-acid oxidase activity, optimal at physiological pH and primarily directed towards phenylalanine. Immunohistochemical analysis of secondary lymphoid organs showed staining of germinal center macrophages and inflammatory myeloid cells. In vitro, functional enzyme was highest in mature dendritic cells (DC), suggesting a role in antigen presenting cell-T lymphocyte cross-talk. Indeed, hIL4I1 inhibited the proliferation of CD3-stimulated T lymphocytes with a similar effect on CD4+ and CD8+ T cells. In contrast, memory T cells were more strongly affected by hIL4I1 and its catabolite H2O2 than naive T cells. hIL4I1 inhibitory effect was dependent on enzymatic activity and H2O2 production and associated with a transient down-regulation of TCR
expression. Altogether these data suggest IL4I1 as a new immunomodulatory enzyme produced by DC.
