title: IL4I1 Is a Novel Regulator of M2 Macrophage Polarization That Can Inhibit T Cell Activation via L-Tryptophan and Arginine Depletion and IL-10 Production.
abstract: Interleukin 4-induced gene-1 (IL4I1) was initially described as an early IL-4-inducible gene in B cells. IL4I1 protein can inhibit T cell proliferation by releasing its enzymatic catabolite, H2O2, and this effect is associated with transient down-regulation of T cell CD3 receptor-zeta (TCRζ) expression. Herein, we show that IL4I1 contributes to the regulation of macrophage programming. We found that expression of IL4I1 increased during bone marrow-derived macrophage (BMDM) differentiation, expression of IL4I1 is much higher in primary macrophages than monocytes, and IL4I1 expression in BMDMs could be induced by Th1 and Th2 cytokines in two different patterns. Gene expression analysis revealed that overexpression of IL4I1 drove the expression of M2 markers (Fizz1, Arg1, YM-1, MR) and inhibited the expression of M1-associated cytokines. Conversely, knockdown of IL4I1 by siRNA resulted in opposite effects, and also attenuated STAT-3 and STAT-6 phosphorylation. Furthermore, IL4I1 produced by macrophages catalyzed L-tryptophan degradation, while levo-1-methyl-tryptophan (L-1-MT), but not dextro-1-methyl-tryptophan, partially rescued IL4I1-dependent inhibition of T cell activation. Other inhibitors, such as diphenylene iodonium (DPI), an anti-IL-10Rα blocking antibody, and a nitric oxide synthase inhibitor, NG-monomethyl-L-arginine, also had this effect. Overall, our findings indicate that IL4I1 promotes an enhanced M2 functional phenotype, which is most likely associated with the phosphorylation of STAT-6 and STAT-3. Moreover, DPI, L-1-MT, NG-monomethyl-L-arginine, and anti-IL-10Rα blocking antibody were all found to be effective IL4I1 inhibitors in vitro.
authors.affiliation: Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, P. R. China.
authors.forename: Yinpu
authors.initials: Y
authors.lastname: Yue
authors.affiliation: Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, P. R. China.
authors.forename: Wei
authors.initials: W
authors.lastname: Huang
authors.affiliation: Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, P. R. China.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Liang
authors.affiliation: Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, P. R. China.
authors.forename: Jing
authors.initials: J
authors.lastname: Guo
authors.affiliation: College of Animal Sciences, Key Laboratory of Animal Molecular Nutrition of the Ministry of Education, Zhejiang University, Hangzhou, P. R. China.
authors.forename: Jian
authors.initials: J
authors.lastname: Ji
authors.affiliation: Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, P. R. China.|Department of Microbiology and Immunology, Medical School of Huzhou Teachers College, Huzhou, P. R. China.
authors.forename: Yunliang
authors.initials: Y
authors.lastname: Yao
authors.affiliation: Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, P. R. China.
authors.forename: Mingzhu
authors.initials: M
authors.lastname: Zheng
authors.affiliation: Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, P. R. China.
authors.forename: Zhijian
authors.initials: Z
authors.lastname: Cai
authors.affiliation: Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, P. R. China.|Program in Molecular and Cellular Biology, Zhejiang University School of Medicine, Hangzhou, P. R. China.
authors.forename: Linrong
authors.initials: L
authors.lastname: Lu
authors.affiliation: Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, P. R. China.
authors.forename: Jianli
authors.initials: J
authors.lastname: Wang
mesh_terms: D000818:Animals; D001120:Arginine / Q000276:immunology / Q000378:metabolism; D016764:Cell Polarity; D049109:Cell Proliferation; D016207:Cytokines / Q000096:biosynthesis* / Q000276:immunology; D005420:Flavoproteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D005786:Gene Expression Regulation; D016753:Interleukin-10 / Q000096:biosynthesis* / Q000276:immunology; D050830:L-Amino Acid Oxidase; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D014364:Tryptophan / Q000276:immunology / Q000378:metabolism; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000276:immunology / Q000378:metabolism
chemical_list: D016207:Cytokines; D005420:Flavoproteins; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7; D016753:Interleukin-10; D014364:Tryptophan; D001120:Arginine; C484538:Il4i1 protein, mouse; D050830:L-Amino Acid Oxidase