Interleukin (IL)-15 and IL-2 Reciprocally Regulate Expression of the Chemokine Receptor CX3CR1 through Selective NFAT1- and NFAT2-dependent Mechanisms

Molecular Signaling Section, Laboratory of Host Defenses, NIAID, National Institutes of Health, Bethesda, Maryland 20892, USA.
Journal of Biological Chemistry (Impact Factor: 4.57). 12/2004; 279(47):48520-34. DOI: 10.1074/jbc.M406978200
Source: PubMed


We have recently reported that interleukin (IL)-15 and IL-2, which signal through IL-2Rβγ, oppositely regulate expression
of the proinflammatory chemokine receptor CX3CR1. Here we delineate molecular mechanisms responsible for this paradox. By
using a luciferase reporter plasmid, we identified a 433-bp region spanning the major transcriptional start point of human
CX3CR1 that, when expressed in human peripheral blood mononuclear cells (PBMCs), possessed strong constitutive promoter activity.
IL-2 and IL-15 treatment increased and abolished this activity, respectively, mimicking their effects on endogenous CX3CR1. IL-2 and IL-15 have been reported to also have opposite effects on the immunoregulatory transcription factor NFAT (nuclear
factor of activated T cells), and the 433-bp region contains a κB-like NFAT site. The effects of IL-15 and IL-2 on both CX3CR1 reporter activity and endogenous CX3CR1 transcription in PBMCs were abolished by the NFAT inhibitors cyclosporin A and VIVIT. Moreover, mutation of the κB-like NFAT
sequence markedly attenuated IL-2 and IL-15 modulation of CX3CR1 promoter-reporter activity in PBMCs. Furthermore, chromatin immunoprecipitation revealed that IL-15 promoted specific recruitment
of NFAT1 but not NFAT2 to the CX3CR1 promoter, whereas IL-2 had the converse effect. This appears to be relevant in vivo because mouse CX3CR1 mRNA was expressed in both PBMCs and splenocytes from NFAT1–/– mice injected with recombinant IL-15 but was undetectable in cells from IL-15-injected NFAT1+/+ BALB/c mice; as predicted, IL-2 up-regulated cx3cr1 in both mouse strains to a similar extent. Thus, by pharmacologic, genetic, and biochemical criteria in vitro and in vivo, our results suggest that IL-15 and IL-2 oppositely regulate CX3CR1 gene expression by differentially recruiting NFAT1 and NFAT2 to a κB-like NFAT site within the CX3CR1 promoter. We propose that expression of CX3CR1 and possibly other immunoregulatory genes may be determined in part by the balance of NFAT1 and NFAT2 activity in leukocytes.

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    • "A positive feedback loop in which NK cells responding to IL-15 induce further expression of IL-15 by dendritic cells for the stimulation of CD8 T cells is an additional possibility [51]. Moreover, IL-15 has also been shown to modulate chemokine and chemokine receptor expression by NK cells and T cells [52], [53], [54]. As IL-15 deficiencies also cause reductions in CD8 T cell accumulation in the BAL [19], chemotactic potential of IL-15 for NK cells presented here provides a possible link between IL-15-mediated effects of both the innate and adaptive immune responses to influenza infection. "
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    • "Indeed, numerous experimental findings showed that, in activated T cells, induction of both the IL-2 promoter and the HIV-1 long terminal repeat (LTR) depend critically on the activity of NFAT (Chow et al., 1999; Cron et al., 2000; Fortin et al., 2001; Kinoshita et al., 1998). Of note, increased production of IL-2 can boost HIV-1 replication through autocrine mechanisms, for instance, by further stimulating NFAT (Barlic et al., 2004) and, in addition, can promote viral spread in bystander CD4 + T cells through their recruitment and activation. In HIV-infected quiescent T cells, the phosphorylation/activation of proximal TCR/CD3 and CD28 effectors (i.e., PLC-γ1, Vav, ZAP-70, Akt) occurred normally as in uninfected cells, suggesting that to induce NFAT activation Nef uses mechanisms that are downstream in the pathway. "
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    • "FASL, IL2RB, CX3CR1 (Figure 2B) and TGFB1 at 2 hours and IFNγ, p21 (CDKN1A) and TNF2 at 24 hours. A recent study showed that IL2 can induce CX3CR1 expression through NFAT2 (NFATC1) binding to its promoter, whereas IL15 represses it through induction of NFAT1 [34]. This observation indicates that NFAT1 (NFATC2) and NFAT2 (NFATC1) may have opposite roles in the expression of some genes in NK cells. "
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