Disease relevance of Il4i1

• IL-4-induced gene-1 (Il4i1 or Fig1) initially isolated as a gene of unknown function from mouse B lymphocytes, is limited in expression to primarily immune tissues and genetically maps to a region of susceptibility to autoimmune disease [1].
• When present later, during the period of T cell priming, IL-4 induced TH2 differentiation and progressive leishmaniasis in resistant mice [2].
• To elucidate the molecular mechanism underlying IL-4-induced tumor rejection, we challenged mice with a mouse adenocarcinoma cell line, colon 26, genetically engineered to express constitutively IL-4 gene (colon 26/IL-4) [3].
• These data indicate that CD8+ T cells and AsGM1+ cells are involved in IL-4-induced regression of established renal cell carcinoma [4].
• The hydrogen peroxide produced by the LAAO activity was recognized to be involved in the cytotoxicity, and the cell death seemed to be due to the direct toxicity of this substance [5].

High impact information on Il4i1

• Lack of IL-4-induced Th2 response and IgE class switching in mice with disrupted Stat6 gene [6].
• The murine H46 locus on chromosome 7 was thus found to encode the interleukin 4-induced IL4i1 gene [7].
• The IL4i1 precursor contains the HAFVEAIPELQGHV peptide which is presented by A(b) major histocompatibility complex class II molecule via an endogenous pathway in professional antigen presenting cells [7].
• Moreover, when the l-arginine metabolism of macrophages is diverted towards ornithine generation by interleukin 4-induced arginase I, parasite growth is promoted [8].
• It was found that IL-4-induced phosphorylation of Janus kinases 1 and 3, IL-4R alpha, signal transducer and activator of transcription 6, and insulin receptor substrate 2 was strikingly but transiently inhibited by TCR ligation both in conventional and TCR transgenic T cells [9].

Biological context of Il4i1

• To address this issue, this study examined whether IL-4-induced STAT6 transcription factor blocks NF-kappaB transactivation [10].
• We also examined the effect of IL-21 on IL-4-induced IgE production from B cells and antigen-induced T-helper 2 (T(h)2) cell differentiation [11].
• An additional finding was that only CpG-DNA could counteract IL-4-induced apoptosis in ppDC [12].
• Molecular mechanisms of interleukin-4-induced up-regulation of type I collagen gene expression in murine fibroblasts [13].
• The inability to bind complexes appeared to be mainly due to an alteration of Fc gamma R (Fc Receptors) II rather than down-regulation of receptor expression because IL-4 induced only a moderate reduction in the binding of two Fc gamma R II specific mAb (20% for 2.4G2 and 32% for K9.361) [14].

Anatomical context of Il4i1

• Fig1, an interleukin 4-induced mouse B cell gene isolated by cDNA representational difference analysis [15].
• B cells, but not T cells or mast cells, express Fig1 in response to IL-4 within 2 hr in a cycloheximide resistant manner [15].
• IL-4-induced gene-1 is a leukocyte L-amino acid oxidase with an unusual acidic pH preference and lysosomal localization [1].
• Thus, IL4I1 is a unique mammalian LAAO targeted to lysosomes, an important subcellular compartment involved in Ag processing [1].
• Murine eotaxin: an eosinophil chemoattractant inducible in endothelial cells and in interleukin 4-induced tumor suppression [16].

Associations of Il4i1 with chemical compounds

• This subtractive amplification technique allowed us to use small amounts of RNA from lipopolysaccharide +/- IL-4-stimulated normal B cells to obtain IL-4-induced genes from these cells [15].
• The Fig1 cDNA sequence encodes a predicted 70-kDa flavoprotein with best homology to the monoamine oxidases, particularly in domains responsible for FAD binding [15].
• In support of this selectivity, IL4I1 is inhibited by aromatic competitors (benzoic acid and para-aminobenzoic acid), but not by nonaromatic LAAO inhibitors [1].
• TNF-alpha also blocked IL-4-induced tyrosine phosphorylation of IRS-2, but not of STAT6 [17].
• Molecular mechanisms underlying IL-4-induced leukocyte recruitment in vivo: a critical role for the alpha 4 integrin [18].

Physical interactions of Il4i1

• Mutation of the flanking TT and CC in this motif blocked IL-4 responsiveness and binding of the IL-4-induced mannose receptor binding protein [19].

Regulatory relationships of Il4i1

• A murine interleukin-4 antagonistic mutant protein completely inhibits interleukin-4-induced cell proliferation, differentiation, and signal transduction [20].
• IL-4-induced STAT6 suppresses IFN-gamma-stimulated STAT1-dependent transcription in mouse macrophages [21].
• In contrast, LNC.4 T cells showed a substantial IL 4-induced proliferative response which was on the one hand synergistically enhanced by minimal amounts of IL 2 and, on the other hand, strongly inhibited by interferon-gamma [22].
• Moreover, IL-21 inhibited IL-4-induced germ line C(epsilon) transcription in B cells without the inhibition of signal transducer and activator of transcription 6 (Stat6) activation [11].
• In the course of examining macrophage fusion factors (MFF) present in Con A-CM, we found that IL-4 induced fusion of alveolar macrophages with a time course similar to that induced by Con A-CM [23].

Other interactions of Il4i1

• One unknown gene (designated Fig1 for IL-Four Induced Gene 1) and one gene with homology to the human transcription factor E4BP4 were confirmed by Northern blot analysis to be induced 10-20-fold by IL-4 treatment [24].
• In this report, we show that the impaired IL-4-induced proliferative response of Stat6-deficient lymphocytes is not due to an inability to activate alternate signaling pathways, such as those involving insulin receptor substrates, or to a failure to upregulate IL-4 receptor levels [25].
• Although it is well established that interleukin 4 (IL-4) is a potent anti-apoptotic cytokine for B lymphocytes, little is known about the IL-4-induced molecular events regulating cell survival [26].
• Interferon-gamma is produced by activated immature mouse thymocytes and inhibits the interleukin 4-induced proliferation of immature thymocytes [27].
• The IL-4-induced generation of peripheral Tregs was independent of the presence of TGF-beta or IL-10, but was dependent on Ag-specific stimulation and B7 costimulation [28].

Analytical, diagnostic and therapeutic context of Il4i1

• The fact that ICOS ligation of wild-type T cells significantly enhanced IL-4-induced Stat6 phosphorylation and primary GATA-3 induction, but not IL-4 transcription, of naive CD4+ T cells was consistent with the results obtained from ICOS-/- T cell experiments [29].
• Similar to IL-2, IL-4 induced blastogenesis and the generation of large granular lymphocytes, all LAK activity observed was exclusively associated with the large granular lymphocyte fraction, and the cytolytic effector cells were heterogeneous in regards to cell surface phenotype [30].
• The latter also inhibited IL-4 induced over-expression of MCP-1 mRNA measured by classical and real time RT-PCR [31].
• PCR analysis of gamma 1 germline transcript expression in clonal B cell cultures or single pre-activated B cells, shows that the IL-4 induced increase in the frequency of cells expressing gamma 1 germline transcripts directly correlates with the increased frequency of cells switching from IgM to IgG1 production [32].
• A cell surface ELISA to detect interleukin-4-induced class II MHC expression on murine B cells [33].

References