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.
Highlights
Macrophages are a heterogeneous population of immune cells that play diverse roles, such as regulating inflammation and contributing to tissue remodeling in both innate and adaptive immune responses[1]
By q-PCR and western blot analyses, we showed that levels of Interleukin 4-induced gene-1 (IL4I1) mRNA and protein expression increased ~10-fold as the freshly isolated BM cells differentiated into macrophages; BM cells exhibited the lowest expression levels on day 0 (Fig 1A and 1B)
We examined the expression of IL4I1 in primary monocytes and macrophages, respectively
Summary
Macrophages are a heterogeneous population of immune cells that play diverse roles, such as regulating inflammation and contributing to tissue remodeling in both innate and adaptive immune responses[1]. Macrophages exhibit remarkable plasticity and can undergo changes in response to environmental cues. They can differentiate into two distinct subsets in different culture environments: classically-activated (M1) and alternatively-activated (M2) macrophages[2,3,4]. Alternatively-activated macrophages induced by Th2 cytokines, such as IL-4 or IL-13 (to yield M2a macrophages), immune complexes in combination with IL-1β or LPS (to yield M2b macrophages), or IL-10, TGFβ or glucocorticoids (to yield M2c macrophages), can contribute to wound-healing and immune regulation, as well as tumor progression[2,6,7,8,9,10]. IL-10, and TGF-β that are produced by TAMs (tumor-associated macrophages, a type of polarized M2 macrophage) are known to be immunosuppressive mediators produced by these macrophages, the possible presence of other mediators has not yet been fully addressed[11]
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