Alternative titles; symbols
HGNC Approved Gene Symbol: IL4I1
Cytogenetic location: 19q13.33 Genomic coordinates (GRCh38): 19:49,889,654-49,929,504 (from NCBI)
IL4I1 is induced by treatment with IL4 (147780), a cytokine associated with antibody responses and, when in excess, autoimmune responses. IL4I1 is most similar to L-amino acid oxidases (LAAOs) and contains several residues important for substrate binding and catalysis (Chavan et al., 2002).
By low-stringency probing of human genomic DNA with mouse Fig1, followed by EST database analysis, screening genomic DNA libraries, and RT-PCR and RACE of IL4-induced human B-cell RNA, Chavan et al. (2002) cloned human IL4I1, which they called FIG1. The predicted 567-amino acid protein has a calculated molecular mass of 63 kD. It contains an N-terminal signal peptide, a central region that shares homology with nonmammalian LAAOs, and 3 conserved domains likely to be involved in FAD binding. The C terminus of human IL4I1 is 63 residues shorter than that of the mouse protein. Northern blot analysis revealed expression of a 1.7-kb transcript primarily in immune tissues, with highest levels in spleen and thymus, followed by placenta and lung. Expression of IL4I1 was induced by IL4 in human B cells.
Independently, Copie-Bergman et al. (2003) cloned and characterized IL4I1. RT-PCR analysis indicated that IL4I1 was preferentially expressed in primary mediastinal large B-cell lymphomas rather than nonmediastinal diffuse large B-cell lymphomas.
Wiemann et al. (2005) identified an IL4I1 variant, IL4I1-2, containing the first 2 exons of the upstream NUP62 gene (605815). They determined that expression of IL4I1-2 is driven by the apparent promoter of NUP62 and is specific to non-B cells, such as testis Sertoli cells and brain Purkinje cells. The IL4I1 and IL4I1-2 proteins differ only in the length of the signal sequence, and the processed proteins are identical.
Mason et al. (2004) showed that IL4I1, like other LAAOs, has a preference for aromatic amino acid substrates, particularly phenylalanine. It could be inhibited by aromatic competitors, but not by nonaromatic LAAO inhibitors. Confocal microscopy demonstrated colocalization of IL4I1 with lysosomal dyes, confirming predictions based on its higher enzymatic activity at acidic pH and its N-linked glycosylation. Mason et al. (2004) proposed that IL4I1 may have an important role in lysosomal antigen processing and presentation.
Using Western blot, enzymatic, and immunohistochemical analyses, Boulland et al. (2007) identified IL4I1 as a secreted, N-glycosylated enzyme located in germinal center macrophages and inflammatory myeloid cells. Highest enzyme levels were found in dendritic cells. IL4I1 inhibited proliferation of CD4 (186940)-positive, CD8 (see 186910)-positive, and, in particular, memory T cells stimulated by CD3 (see 186740) in a manner dependent on its enzymatic activity and H2O2 production. Flow cytometric analysis showed that the IL4I1 inhibitory effect was associated with transient downregulation of TCRZ (CD247; 186780) expression.
Santarlasci et al. (2012) noted that IL17A (603149)-producing T-helper (Th17) cells have a critical pathogenic role in chronic inflammatory disorders, but they are rarely found in inflammatory sites. Santarlasci et al. (2012) found that, unlike Th1 cells, human CD161 (KLRB1; 602890)-positive Th17 precursor cells did not proliferate and produce IL2 (147680) in response to anti-CD3/anti-CD28 (186760) stimulation. Th17 cells also proliferated poorly in response to IL2, in part due to lower expression of the transcription factors JUN (165160), FOS (164810), and NFATC1 (600489) and reduced surface expression of CD3E (186830) and CD3Z. Microarray and small interfering RNA analyses revealed high expression of IL4I1 in Th17 precursor cells and showed that IL4I1 upregulation was strictly dependent on RORC (602943), the Th17 master regulatory gene. Flow cytometric analysis revealed that Th17 cells also exhibited high CD28 expression that was RORC dependent, and stimulation of CD28 alone induced IL17 production and IL4I1 mRNA upregulation. Th17 cells from synovial fluid of patients with juvenile idiopathic arthritis (see 604302) also expressed higher levels of IL4I1 and CD28 than did Th1 cells. Santarlasci et al. (2012) concluded that the rarity of human Th17 cells in inflamed tissues results from RORC-dependent mechanisms that limit their expansion and, therefore, reduce their potential to cause damage.
Bod et al. (2018) found that Il4i1 deficiency impaired B-cell development, as immature B cells egressed from bone marrow more rapidly in Il4i1-knockout mice than in wildtype, resulting in accumulation of peripheral follicular B cells. Il4i1-knockout mice showed higher serum levels of natural Ig and self-reactive antibodies. The authors showed that Il4i1 controlled central tolerance and decreased B-cell receptor (BCR) signaling-induced B-cell proliferation to limit specific antibody production and reduce natural Ig levels in serum in response to T-dependent antigens. The molecular mechanism underlying Il4i1 control of BCR-mediated B-cell responses involved Il4i1 negatively regulating BCR-induced signaling by dampening Src (190090), Syk (600085), PI3K (see 601232)/Akt (see 164730), and mTorc1 (601231)/S6rp (RPS6; 180460) activation and calcium mobilization.
Chavan et al. (2002) determined that the IL4I1 gene contains 8 exons.
By genomic sequence analysis, Chavan et al. (2002) mapped the IL4I1 gene to chromosome 19q13.3-q13.4, between the FUT1 (211100) and KLK1 (147910) genes. The 5-prime end of IL4I1 is adjacent to NUP62.
Bod, L., Douguet, L., Auffray, C., Lengagne, R., Bekkat, F., Rondeau, E., Molinier-Frenkel, V., Castellano, F., Richard, Y., Prevost-Blondel, A. IL-4-induced gene 1: a negative immune checkpoint controlling B cell differentiation and activation. J. Immun. 200: 1027-1038, 2018. [PubMed: 29288206] [Full Text: https://doi.org/10.4049/jimmunol.1601609]
Boulland, M.-L., Marquet, J., Molinier-Frenkel, V., Moller, P., Guiter, C., Lasoudris, F., Copie-Bergman, C., Baia, M., Gaulard, P., Leroy, K., Castellano, F. Human IL4I1 is a secreted L-phenylalanine oxidase expressed by mature dendritic cells that inhibits T-lymphocyte proliferation. Blood 110: 220-227, 2007. [PubMed: 17356132] [Full Text: https://doi.org/10.1182/blood-2006-07-036210]
Chavan, S. S., Tian, W., Hsueh, K., Jawaheer, D., Gregersen, P. K., Chu, C. C. Characterization of the human homolog of the IL-4 induced gene-1 (Fig1). Biochim. Biophys. Acta 1576: 70-80, 2002. [PubMed: 12031486] [Full Text: https://doi.org/10.1016/s0167-4781(02)00295-6]
Copie-Bergman, C., Boulland, M.-L., Dehoulle, C., Moller, P., Farcet, J.-P., Dyer, M. J. S., Haioun, C., Romeo, P.-H., Gaulard, P., Leroy, K. Interleukin 4-induced gene 1 is activated in primary mediastinal large B-cell lymphoma. Blood 101: 2756-2761, 2003. [PubMed: 12446450] [Full Text: https://doi.org/10.1182/blood-2002-07-2215]
Mason, J. M., Naidu, M. D., Barcia, M., Porti, D., Chavan, S. S., Chu, C. C. IL-4-induced gene-1 is a leukocyte L-amino acid oxidase with an unusual acidic pH preference and lysosomal localization. J. Immun. 173: 4561-4567, 2004. [PubMed: 15383589] [Full Text: https://doi.org/10.4049/jimmunol.173.7.4561]
Santarlasci, V., Maggi, L., Capone, M., Querci, V., Beltrame, L., Cavalieri, D., D'Aiuto, E., Cimaz, R., Nebbioso, A., Liotta, F., De Palma, R., Maggi, E., Cosmi, L., Romagnani, S., Annunziato, F. Rarity of human T helper 17 cells is due to retinoic acid orphan receptor-dependent mechanisms that limit their expression. Immunity 36: 201-214, 2012. [PubMed: 22326581] [Full Text: https://doi.org/10.1016/j.immuni.2011.12.013]
Wiemann, S., Kolb-Kokocinski, A., Poustka, A. Alternative pre-mRNA processing regulates cell-type specific expression of the IL4I1 and NUP62 genes. BMC Biol. 3: 16, 2005. Note: Electronic Article. [PubMed: 16029492] [Full Text: https://doi.org/10.1186/1741-7007-3-16]