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 toward 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 (DCs), suggesting a role in antigenpresenting 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. IntroductionInterleukin-4 (IL4) is the master cytokine for T-helper type 2 (Th2) lymphocyte differentiation and function. Along with its important role in B-lymphocyte stimulation by T-helper cells in germinal centers of secondary lymphoid organs, it also regulates the growth and function of many different cell types of the immune system. 1 IL4 transcriptional effects are primarily mediated by the signalization and transcription factor 6 (STAT6), which is responsible for the induction and repression of multiple target genes. 2 An immediate-early IL4-inducible gene called interleukin fourinduced gene 1 (FIG1/IL4I1) has first been described in the mouse 3 and subsequently characterized in human B cells. 4 IL4I1 mRNA expression is restricted to lymphoid tissues, with the highest levels found in lymph nodes and spleen. 4,5 IL4-activated murine B cells express IL4I1 within 2 hours of stimulation. We have demonstrated that high levels of expression of this gene are characteristic of primary mediastinal large B-cell lymphoma (PMBL), a specific subtype of diffuse large B-cell lymphoma. 5 The high expression of IL4I1 by PMBL may result from the constitutive activation of STAT6 in these tumors. 6 Both human and mouse IL4I1 mRNA sequences encode a protein containing a putative signal peptide indicative of potential secretion and a large central domain, highly homologous to flavin-containing amino acid oxidases. 3,4 While sharing high similarity over the majority of the sequence (547 amino acids of the 567 in the human sequence), the human and mouse proteins diverge substantially at their C-terminal region. 4 The IL4I1 protein shares the highest similarity with proteins presenting L-amino acid oxidase (LAAO) activity, such as snake venom LAAO,7,8 and mouse milk LAAO. 9 Recently, Mason et al have demonstrated that mouse IL4I1 (mIL4I1) possesses an LAAO activity toward aromatic amino acids. The enzyme was mostly active at acidic pH, in contrast to other known members of the LAAO family, and its expression was restricted primarily to lysosomes. 10 In this work, w...
MU and DC are key elements in the control of tissue homeostasis and response to insult. In this work, we demonstrate that MU and DC are the major producers of the phenylalanine catabolizing enzyme IL-4-induced gene 1 (IL4I1) under inflammatory conditions. IL4I1 was first described in B cells, which indeed can produce IL4I1 in vitro, although at much lower levels. In vivo, IL4I1 is highly expressed by MU and DC of Th1 granulomas (sarcoidosis, tuberculosis) but poorly detected in Th2 granulomas (schistosomiasis). In vitro, expression of the enzyme is induced in mononuclear phagocytes by various proinflammatory stimuli through the activation of the transcription factors NF-jB and/or STAT1. B cells also express IL4I1 in response to NF-jB-activating stimuli such as CD40L; however, in contrast to myeloid cells, B cells are insensitive to IFN-c but respond to stimulation of the IL-4/STAT6 axis. As we show that the expression of IL4I1 by a monocytic cell line inhibits T-cell proliferation and production of IFN-c and inflammatory cytokines, we propose that IL4I1 participates in the downregulation of Th1 inflammation in vivo.
The L-phenylalanine oxidase IL4I1 inhibits T-cell proliferation in vitro through H 2 O 2 production, and is highly expressed in tumor-associated macrophages. IL4I1 is also detected by immunohistochemistry in neoplastic cells from several B-cell lymphomas and some nonlymphoid tumors. To evaluate IL4I1's effect on tumor growth, we developed a mouse melanoma model constitutively coexpressing IL4I1 and the GP33 epitope. After GP33 vaccination, tumors developed more frequently in mice injected with IL4I1-expressing cells in comparison with mice receiving control cells. Tumor escape was preceded by a rapid diminution of IFNc-producing cytotoxic antitumor CD8 1 T cells. Moreover, tumor incidence was already increased when only 20% of the injected cells expressed IL4I1. The minimal IL4I1 activities leading to tumor escape were close to those detected in human melanoma and mesothelioma. Thus, we demonstrate the immunosuppressive functions of IL4I1 in vivo and suggest that IL4I1 facilitates human tumor growth by inhibiting the CD8 1 antitumor T-cell response.Keywords: IL4I1 . Immunoediting . Mice . Phenylalanine oxidase . Tumor escape Supporting Information available online IntroductionNeoplastic cells adopt multiple strategies to survive and grow despite tumor surveillance by the immune system. Sabotage strategies often exploit regulating cell populations, which naturally prevent autoimmunity and chronic inflammation in healthy individuals, such as regulatory T cells (Tregs), myeloidderived suppressor cells, tolerogenic dendritic cells and alternatively activated macrophages (reviewed in [1][2][3][4][5]). In the past decade, a family of enzymes has been described participating in the immunosuppressive capacity of the tumor-activated myeloid cell populations. The activity and functions of indoleamine-2,3-dioxygenase [6], arginase 1 [7] and inducible nitric oxide synthase [8] have been extensively explored. These enzymes à These authors contributed equally to this work. share several properties [9]. First, they are produced by myeloids cells in lymphoid organs and in the tumor bed and/or by the tumor cells themselves [10][11][12]. Second, their expression involves cytokines from the Th1/Th2 family. Third, their immunosuppressive properties are based on their amino-acid catabolizing activity, which leads to the depletion of essential amino acids and to the production of metabolites that are toxic for anti tumor effector T cells [13][14][15]. Several reports have established the role of these enzymes in tumor escape from immunosurveillance [10][11][12]16]. IL-4 Induced Gene 1 (IL4I1) was identified as an IL-4-inducible gene in B lymphocytes [17]. The human and mouse IL4I1 mRNA share a strong sequence homology and encode a secreted protein [18,19]. We have shown that this protein is an L-aminoacid oxidase that primarily deaminates the essential amino-acid phenylalanine to produce H 2 O 2 . IL4I1 inhibits human CD4 Thus, IL4I1 meets the criteria of an immunosuppressive enzyme [3,9], suggesting that it may participate in tumor ...
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