Published online before print February 21, 2007
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,
,1
* Molecular Biology Institute,
Department of Microbiology, Immunology and Molecular Genetics,
Jonsson Comprehensive Cancer Center,
Medical Scientist Training Program, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA
1 Correspondence: University of California, Los Angeles, Dept. of Microbiology, Immunology and Molecular Genetics, 8-240 Factor Building, 10833 Le Conte Avenue, Los Angeles, CA 90095, USA. E-mail: genhongc{at}microbio.ucla.edu
ABSTRACT
The immune system modulates a number of biological processes to properly defend against pathogens. Here, we review how crosstalk between nuclear hormone receptors and the innate immune system may influence multiple biological functions during an immune response. Although nuclear hormone receptor repression of innate immune responses and inflammation has been well studied, a number of new studies have identified repression of nuclear hormone receptor signaling by various innate immune responses. IFN regulatory factor 3, a key transcription factor involved in the induction of antiviral genes, may play a role in mediating such crosstalk between the innate immune response and nuclear receptor-regulated metabolism. This crosstalk mechanism is now implicated in the pathogenesis of atherosclerosis and Reye’s syndrome and could provide an explanation for other pathogen-associated metabolic and developmental disorders.
Key Words: innate immunity • metabolism • IRF3 • RXR
INTRODUCTION
Mammalian host defense against infectious challenges uses multiple systems to mount an effective response. The endocrine system is not only affected profoundly during an infection but also plays a role in regulation of the immune response, as evidenced by altered blood concentrations of multiple hormones during infections [1 2 3 ] and modified expression levels of hormone signaling machinery [4 5 6 ]. A diverse array of nuclear hormone receptors has been implicated in modulating inflammatory responses [7 8 9 10 ]. Our insight into the molecular mechanisms of this interaction between the endocrine and immune systems has been refined recently, and in this review, we will focus on recent advances in the understanding of crosstalk between the antiviral immune response and nuclear hormone receptors. Emerging evidence suggests that this endocrine-immune crosstalk is significant because of its potential role in a number of pathological processes such as Reye’s syndrome and atherosclerosis.
MODULATION OF INNATE IMMUNITY BY NUCLEAR HORMONE RECEPTORS
A number of studies have identified a relationship between nuclear hormone receptors and innate immunity, primarily focusing on the mechanisms by which nuclear hormone receptor signaling influences innate immunity and inflammation. The repression of proinflammatory genes by glucocorticoid receptor (GR) is one such relationship, which has been characterized extensively. When activated by glucocorticoids, GR is capable of repressing proinflammatory genes via a number of mechanisms that appear to be specific to how individual genes are activated by transcription factors, NF-
B, or AP-1 [11
, 12
]. Studies of GR repression of TLR-induced genes, which are involved directly in the inflammatory response, have focused mostly on repression of NF-B. The NF-B family consists of five proteins (p50, p52, c-Rel, RelA/p65, and RelB), which form hetero- and homodimeric transcriptional complexes. Although all of these proteins can form dimers with each other to regulate NF-B target genes, the majority of NF-B target genes can be split into those activated by canonical or noncanonical pathways [13
]. Most studies of GR-mediated repression of NF-B target genes have focused on the canonical pathway, which consists primarily of p50/p65 heterodimers that are activated by the IB kinase phosporylation-dependent degradation of IB proteins, inhibitory proteins that promote cytoplasmic localization of p50/p65 [14
15
16
17
]. One suggested mechanism of NF-B repression by GR is GR-mediated induction of IkB, a member of the IB family of proteins, which sequester p50/p65 in the cytoplasm [18
, 19
]. IB contains a binding glucocorticoid response element in its promoter, and the induction of IB could promote cytoplasmic localization of p50/p65 complexes and repression of NF-B target genes. GR-mediated repression of NF-B appears to also result from direct association of GR with the NF-B subunit p65 [20
], which could result in inhibition of p65/p50 NF-B association with DNA [20
]. However, later studies have shown that GR can repress NF-B-induced, proinflammatory genes, even in the context of p65 binding to DNA, and GR prevents association of p65 with general transcriptional molecules, such as positive transcription elongation factor b (pTEFb), or coactivators, such as IFN regulatory factor 3 (IRF3) [7
, 21
].
Nissen and Yamamoto [22] found that GR activation prevented phosphorylation of serine 2 (Ser2) of the carboxy-terminal domain of RNA polymerase II when bound to NF-B target genes induced by the inflammatory cytokine TNF-. It was later determined that prevention of Ser2 phosphorylation was a direct result of GR binding to DNA-bound p65 and blocking NF-B recruitment of pTEFb [21
]. Blocking pTEFb recruitment appears not to result in the repression of transcriptional initiation of the proinflammatory gene Il-8 but rather, represses transcription of Il-8 mRNA at a postinitiation step. An additional mechanism for GR repression of proinflammatory genes has been shown to require IRF3 and NF-B recruitment to the promoter of inflammatory genes [7
].
Ogawa et al. [7] first identified the connection among NF-B, IRF3, and GR by finding that a number of LPS-induced genes repressed by GR activation also appeared to require IRF3 for maximal induction. It was shown that IRF3 and p65 are recruited to the IFN-stimulated response element (ISRE)-binding site in the promoters of some proinflammatory genes, such as Ifit1, in response to LPS stimulation. Furthermore, ligand-bound GR association with p65 appeared to inhibit p65 recruitment to Ifit1, suggesting that GR inhibited LPS-mediated induction of certain proinflammatory genes by preventing p65 recruitment to ISREs where IRF3 is bound. At other genes, such as Scyb9 and Clic4, IRF3 appears to be recruited to B-binding sites as a coactivator of NF-B. In this case, GR association with p65 appears to inhibit IRF3 recruitment to these genes [7
].
A number of other nuclear hormone receptors have been implicated in proinflammatory gene repression, including estrogen receptors (ERs), peroxisome proliferator-activated receptors (PPARs), vitamin D receptors (VDRs), and liver X receptors (LXRs) [8
9
10
, 23
24
25
26
]. Initial work by Pascual et al. [27] suggested that sumoylation of PPAR
can result in PPAR-mediated recruitment of the nuclear corepressor histone deacetylase-3 (HDAC3) complex to the promoters of proinflammatory genes, resulting in histone deactylation and transcriptional repression. Further work is required to fully elucidate the mechanisms by which many of these nuclear hormone receptors repress proinflammatory genes. In addition to nuclear hormone receptor repression of inflammatory mediators, nuclear hormone receptors are capable of modulating innate immunity in a positive manner. Vitamin D activation of VDR results in the induction of antimicrobial peptides, including cathelicidin antimicrobial peptide and defensin β2, as well as the TLR4 coreceptor CD14 [28
]. Liu et al. [29] found that TLRs use VDR antimicrobial activity in response to Mycobacterium tuberculosis through the up-regulation of VDR and vitamin D-1-hydroxylase genes. Thus, there is evidence that nuclear hormone receptors may regulate innate immune responses to bacteria and viral infections through positive and negative regulatory mechanisms.
MODULATION OF METABOLIC FUNCTION BY INNATE IMMUNITY
The contribution of viral infections to the pathogenesis of various metabolic diseases has been implicated in a number of studies [1
, 3
, 30
31
32
33
34
]. Recently, the mechanisms by which the immune response to viral infections may modulate nuclear hormone receptor-mediated gene regulation and metabolic functions have been described. Studies focusing on bacterial and viral infections have demonstrated that infection with these pathogens results in repression of nuclear receptor target genes in multiple cell types, including macrophages and hepatocytes. In macrophages, nuclear receptor target genes such as ATP-binding cassette (ABC) transporter A1 (ABCA1), ABCG1, apolipoprotein E (apoE), and cellular retinol-binding protein type II are significantly repressed by the innate immune response [35
, 36
]. A number of nuclear receptor target genes in hepatocytes are also repressed by innate immune and acute-phase responses, including CYP3A4, UGT1A6, CYP24, SREBP-1c, Mdr3, KNG1, and L-FABP [4
, 5
, 36
37
38
]. These genes control a wide range of metabolic and developmental functions and are regulated by the retinoid X receptor (RXR)-related family of nuclear hormone receptors. This family of nuclear receptors consists of RXRs in a heterodimeric complex with many different nuclear receptors, including PPARs, LXR, farnesoid X receptor, VDR, thyroid receptor, pregnane X receptor (PXR), and constitutive adrostane receptor [39
40
41
42
43
44
45
46
47
48
]. The repression of RXR-related metabolic genes during an immune response is not uniform, as LXR/RXR, PXR/RXR, VDR/RXR, retinoic acid receptor/RXR, and some PPAR/RXR target genes are repressed, but other PPAR/RXR target genes, such as CD36 and adipose differentiation-related protein (ADRP), are relatively unaffected [35
]. Further studies examining the requirement of RXR for transcriptional regulation of these genes could provide more insight into why some nuclear receptor target genes are repressed, and others are not. In addition, the effect of pathogen infection on transcription regulation of other nuclear hormone receptor target genes remains to be studied.
Although repression of nuclear hormone receptor-regulated genes by inflammatory mediators has long been established, research into the molecular mechanisms by which innate immune responses and inflammation inhibit nuclear receptor function has only emerged recently. The NF-B p65 subunit is capable of repressing nuclear hormone receptor transcription in vitro, as shown in a study using overexpression of p65 in GR, androgen receptor, progesterone, and ER chloramphenicol acetyltransferase transcription assays [49
]. Furthermore, p65 has been shown to interact with the DNA-binding domain of RXR in GST-pull-down assays [50
]. This association with RXR was suggested as the mechanism by which NF-B activation disrupted PXR/RXR binding to the proximal promoter of CYP3A4 and mediated repression of PXR target genes [50
]. In addition, inflammatory cytokines, such as TNF- and IL-1β, which activate NF-B, have been documented to repress expression of nuclear hormone receptors such as LXR and RXR, as well as nuclear hormone receptor target genes in hepatic cells and kidney cells [37
, 51
]. Further studies are needed, however, to determine the exact molecular mechanisms by which these cytokines mediate nuclear hormone receptor repression and if other inflammatory cytokines exhibit similar properties.
IRF3 REPRESSION OF NUCLEAR RECEPTOR TARGET GENES
In addition to these other suggested mechanisms, recent studies have found a potential role for IRF3 in repression of nuclear receptor signaling and in the potentiation of metabolic diseases by viral infections [36
]. IRF3 is one of nine members of the IRF family of transcription factors, as defined by the structural similarity of their DNA-binding motifs (reviewed by Taniguchi et al. [52
]). In response to a viral infection, the constitutively expressed IRF3 is phosphorylated and subsequently dimerizes and translocates to the nucleus, where it aids in the transactivation of a number of genes, the most well-characterized of which is IFN-β [53
54
55
]. IRF3 binds cooperatively with NF-B and AP-1 at the IFN-β promoter and seems to be critical for initiation of proper nucleosome remodeling of the promoter [56
57
58
59
]. The activating phosphorylation of IRF3 appears to be mediated by TNF receptor (TNFR)-associated factor family member-associated NF-B activator-binding kinase 1 (TBK1), which itself is activated via the intracellular RNA helicases retinoic acid-inducible protein I (RIG-I) or melanoma differentiation-associated gene 5 (MDA-5), which sense dsRNA produced during viral replication or by extracellularly derived ligands acting through TLRs [60
61
62
63
]. Processing of dsRNA by RIG-I or MDA-5 results in interaction with the adaptor protein Cardif through homotypic interactions via common caspase activation and recruitment domains [64
65
66
]. Although it is not known precisely how signaling is ultimately transmitted from Cardif to TBK1, studies have shown that TNFR-associated factor-3 (TRAF3)-deficient mouse embryonic fibroblasts are defective in IFN production in response to vesicular stomatitis virus infection and that TRAF3 interacts with Cardif, suggesting that TRAF3 may act as an adaptor molecule [67
, 68
]. Ligand binding by TLR3 and TLR4 also results in TBK1 activation and subsequent IRF3 phosphorylation via recruitment of the adaptor Toll/IL-1 receptor (TIR) domain-containing adaptor-inducing IFN-β (TRIF) to cytoplasmic TIR domains of TLR3 and TLR4 [69
]. Similar to the intracellular pathway, it is unclear what the final bridge from TRIF to TBK1 might be, although TRAF3 has again been implicated in this role along with neutrophil-activating peptide 1 [68
, 70
]. The intracellular receptors and TLR pathways also activate a number of other inflammatory transcription factors including NF-B and AP-1 through different sets of adaptor molecules. This is important, as many antiviral gene promoters, such as IFN-β, require cooperative recruitment of several transcription factors for robust transactivation.
IRF3 may have other functions beyond the induction of IFN-β. A number of other target genes can be induced directly by IRF3, including RANTES and ISG56 [71 72 73 ]. In addition to its role in activating antiviral genes, IRF3 appears to have inhibitory gene regulation functions. Studies with dominant-negative IRF3 mutants and IRF3-deficient macrophages demonstrate that antiviral responses use IRF3 to repress nuclear receptor target genes [36 ]. Studies done in Type I IFN receptor-deficient cells demonstrate that this requirement for IRF3 is independent of Type I IFN induction [36 ]. Additional studies will clarify further the role of IRF3 in metabolic regulation outside of its known function in Type I IFN and antiviral gene induction.
Studies examining IRF3 inhibition of nuclear hormone receptor target genes implicate the transcriptional and functional repression of RXR, a key heterodimeric partner for a number of nuclear receptors. The importance of RXR as a heterodimeric partner to other nuclear receptors in the transcriptional activation of their target genes is demonstrated clearly by the fact that RXR-deficient mice are embryonic-lethal [74
, 75
]. Furthermore, tissue-specific RXR mutations demonstrate a significant role for RXR in the gene regulation of nuclear hormone receptor target genes required for a number of metabolic functions [76
77
78
]. Activation of IRF3 by TLR3 ligand polyinosinic-polycytidylic acid (polyI:C) in bone marrow-derived macrophages results in significant transcriptional repression of RXR mRNA [36
]. Furthermore, this repression involves the recruitment of the transcriptional repressor Hes1 to the promoter of RXR. Hes1 functions by recruiting Groucho/transducin-like enhancer-of-split tetramers to the RXR promoter, which in turn, recruit HDACs upon hyperphosphorylation by casein kinase 2 [79
]. It is interesting that treatment with polyI:C, in combination with nuclear receptor agonists, leads to greater loss of RXR protein than by either factor alone as a result of combinatorial repression of RXR mRNA by IRF3 and activation of 26S-proteosome complexes by nuclear receptor agonists [36
].
IRF3 AND CHOLESTEROL EFFLUX: IMPLICATIONS IN ATHEROSCLEROSIS
The role of nuclear hormone receptor signaling in atherosclerosis has been demonstrated through the use of nuclear receptor ligand administration and hematopoietic nuclear receptor deficiency in the context of mouse models of atherosclerosis. These studies point to the PPAR and LXR subfamilies of nuclear receptors as important players in the development of atherosclerosis. The PPAR subfamily consists of three proteins, PPAR, PPAR, and PPAR
, whose physiological ligands appear to be polyunsaturated fatty acids and eicosanoids [80
, 81
]. PPAR ligand administration leads to a reduction in atherosclerosis, and reconstitution of low-density lipoprotein receptor (LDLR)-deficient mice with PPAR-deficient bone marrow results in increased atherosclerosis [82
, 83
]. Reduced pathogenesis of atherosclerosis is also seen in apoE-deficient mice treated with PPAR ligand and in mice deficient in PPAR and apoE [84
, 85
]. Finally, reconstitution of LDLR-deficient mice with PPAR-deficient bone marrow results in reduced atherosclerosis, although treatment with cognate ligand did not affect progression of the disease [84
, 86
]. The mechanisms by which PPARs affect atherosclerotic progression are numerous and include modulation of blood lipid levels, cellular lipid uptake, efflux, and metabolism and regulation of inflammation (reviewed by Li and Palinski [87
]). It is important that some studies have suggested that these effects may be in part a result of PPAR-mediated transactivation of LXRs [83
, 88
].
The LXR subfamily contains two members, LXR and LXRβ, whose natural ligands are thought to be certain modified forms of cholesterol known as oxysterols [89
, 90
]. Activation of LXRs in macrophages leads to up-regulation of multiple gene products critical for cellular cholesterol efflux including a number of ABC cholesterol transporters such as ABCA1, ABCG1, ABCG5, and ABCG8 [91
92
93
]. Consistent with these observations, LXR ligand administration leads to decreased atherosclerotic development. Loss of LXR/β in the bone marrow of apoE-deficient or LDLR-deficient mice leads to increased atherosclerosis [94
, 95
]. Given the critical roles of these nuclear receptors in macrophage lipid homeostasis and atherosclerosis, it is possible to speculate that their modulation by pattern recognition receptor (PRR)-mediated signaling might lead to enhanced atherosclerotic potential.
Our expanding knowledge of atherosclerosis reveals an endocrine and immunological component to its pathogenesis. Dyslipidemia, an aberration in the levels of plasma lipids, has long been known to be associated with development of atherosclerosis and is now recognized as a causative factor [96 , 97 ]. Furthermore, beginning nearly two decades ago, immunohistochemical studies of atherosclerotic plaques implicated immune responses in atherosclerosis etiology. These investigations demonstrated the presence of a number of immune cells, including macrophages, T cells, and mast cells, in atherosclerotic plaques [98 99 100 ]. Although much focus has been placed on the role of endogeneously produced, oxidized lipids in generating an inflammatory reaction, studies by Saikku et al. [101] first drew attention to the possibility for an infectious etiology to the disease. Since then, several pathogens have been linked to atherosclerotic disease with much focus on the role of Chlamydia pneumoniae and CMV. Evidence has mounted from a variety of angles: Epidemiologically, the presence of a high level of antibodies to C. pneumoniae or CMV has been associated with cardiovascular disease [102 103 104 ]. Furthermore, CMV and C. pneumoniae have been found in atherosclerotic plaques using a number of techniques including immunohistochemical staining, in situ hybridization, and PCR-based approaches [105 106 107 108 109 ]. Although some have questioned the conclusions from the above human studies [110 , 111 ], animal models have provided a more rigorous experimental backdrop for investigating the role of these pathogens in atherosclerosis. CMV and C. pneumoniae inoculation have been found to accelerate lesion formation in hypercholesterolemic mice [112 , 113 ], and successful prevention of cardiovascular pathology in certain C. pneumoniae animal models by antibiotic treatment has inspired a number of clinical trials, although the results so far have been mixed [114 115 116 ]. Although there is growing evidence of a role for pathogens in the development of atherosclerosis, the molecular details of how the immune response to pathogens contributes to the pathogenesis of atherosclerotic diseases has not been fully investigated.
Castrillo et al. [35] first linked IRF3 activation to the development of atherosclerosis. In addition to identifying a critical role for IRF3 in the repression of nuclear receptor target genes such as ABCG1 and ABCA1, they demonstrated that this gene repression mechanism results in defects in nuclear hormone receptor function in macrophages. The effect of the innate immune response on nuclear receptor gene regulation and function appears to diminish cholesterol efflux in macrophages following polyI:C treatment in a manner requiring IRF3 [35 ]. This IRF3-mediated defect in cholesterol clearance could contribute to macrophage foam cell formation and the progression of atherosclerosis, a mechanism that should be taken into account when devising therapeutics for treatment of this disease.
ROLE OF IRF3 IN VIRAL-INDUCED REPRESSION OF LIVER METABOLISM
From even a purely clinical standpoint, Reye’s syndrome appears a prototypical example for how crosstalk between endocrine and immune systems may lead to a pathological condition. The syndrome is typified by an acute, febrile illness leading to encephalopathy and fatty degeneration of the liver with characteristic, ultrastructural damage to mitochondria. Metabolic derangement of the liver ensues, leading to rising ammonia levels and elevated liver enzyme levels indicative of injury to the organ [117 ]. A number of reports have correlated the syndrome with administration of acetylsalicylic acid (ASA; aspirin) during infection with viruses, including chickenpox, influenza A or B, adenoviruses, hepatitis A viruses, paramyxovirus, picornaviruses, reoviruses, herpesviruses, measles, and varicella-zoster viruses, indicating a possible etiological role for these factors [98 , 118 119 120 121 122 123 124 ]. As a result, a sizeable public health campaign was organized in the United States during the 1980s, warning physicians and the public of the dangers of aspirin use in children during viral infections. This campaign may have led to the subsequent fall in reported cases of Reye’s syndrome since then, although cases still occur in less-developed countries [117 ]. It is important to note that this etiological hypothesis for Reye’s syndrome has remained controversial. Some have questioned the validity of the studies originally linking aspirin administration to the metabolic disorder, citing the fact that the original pediatric cases studied possessed not only a heterogeneous patient population but also a varied symptomology. Furthermore, the use of antiemetics was also correlated with the syndrome in these studies, calling into question the sole focus on aspirin as the contributing factor to Reye’s syndrome. Finally, the very ontological basis of the disorder has been called into doubt, as many now consider Reye’s syndrome to be a heterogenous group of related metabolic disorders rather than a specific clinico-pathological entity [125 126 127 ]. Nevertheless, the findings of the original studies have gained widespread acceptance, and administration of aspirin in the context of viral illness is now considered poor clinical practice. In spite of these studies, a mechanistic understanding of how viral illness concomitant with aspirin administration could lead to Reye’s syndrome has been lacking.
Recent knowledge of repression of nuclear hormone receptor gene regulation and function by the antiviral response has shed new light on the molecular pathogenesis of Reye’s syndrome [35
, 36
]. In addition to repressing nuclear hormone receptor target genes involved in cholesterol metabolism, IRF3 activation and subsequent repression of RXR result in a significant decrease in nuclear hormone receptor target genes involvedin hepatic metabolism, including CYP3A4/CYP3A11 and UGT1A6, amongst others [36
]. Although nuclear receptors such as PXR and RXR have not been implicated specifically in human Reye’s syndrome, their target genes, such as CYP3A4, CYP2C9, and UGT1A6, have been identified as major mediators of ASA metabolism [128
129
130
131
132
133
]. It appears that activation of IRF3, in response to virus, may play a key role in the pathogenesis of Reye’s syndrome through the repression of ASA metabolic enzymes regulated by nuclear receptors. Failure to convert the ASA-metabolic intermediate, salicylic acid, into more hydrophilic forms results in impaired excretion of ASA metabolic products. Build-up of salicylic acid can in turn disrupt mitochondrial function, leading to hepatotoxicity [134
135
136
137
]. IRF3-mediated repression of CYP3A11 and UGT1A6 appears to result in similar effects, with hepatotoxicity and increased levels of serum ammonia [36
]. This work is significant, as most prior work about Reye’s syndrome has focused on mechanisms of ASA metabolism or has failed to identify key innate immunity mediators that would contribute to the pathogenesis of Reye’s syndrome. This current work now points to potential molecular mechanisms of pathogenesis of Reye’s syndrome, which like atherosclerosis, result from improper activation of an innate immune response and IRF3 (Fig. 1
).
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Figure 1. Current model of IRF3-mediated repression of RXR and nuclear receptor target genes and function. (A) PRRs such as TLR3 and RIG-I recognize foreign pathogens (virus, etc.) and activate IRF3. (B) IRF3 activation results in Hes1/HDAC1-mediated transcriptional repression of RXR. In combination with 26S proteosome-mediated degradation of RXR, RXR target genes are repressed, including those that regulate cholesterol metabolism and those involved in xenobiotic metabolism. NR, Nuclear receptor. (C) Repression of LXR/RXR target genes, such as ABCA1, results in impaired cholesterol efflux with implications in atherosclerosis. (D) Repression of PXR/RXR target genes, such as CYP3A4 and UGT1A6, results in impaired acetylsalicylic acid metabolism with implications in Reye’s syndrome.
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In addition to atherosclerosis and Reye’s syndrome, there are other metabolic diseases that may be affected by crosstalk between nuclear hormone receptors and the innate immune system. Steatosis associated with viral infection is a frequent pathological occurrence during hepatitis C virus (HCV) infection, and multiple reports have found a correlation between increased HCV-induced steatosis and more severe liver fibrosis [138
139
140
141
142
]. Although the HCV infection rate approaches nearly 1% worldwide, only 30% of infected patients develop liver fibrosis substantial enough to be considered cirrhotic within 20 years. These fibrotic complications of HCV infection ultimately lead to the need for liver transplantation and death [143
]. Although it remains unclear how HCV infection could cause a steatotic pathology, viral-induced repression of RXR and defective bile acid metabolism may prove to be an attractive mechanism for the pathogenesis of steatosis.
Bone metabolism disorders, such as Paget’s disease, have also been linked to chronic viral infections [31 , 34 ]. In addition, there have been several lines of evidence that patients with HCV or HIV infections may be more susceptible to defects in bone metabolism [144 145 146 147 ]. As VDR/RXR target genes play a key role in bone metabolism and calcium homeostasis [148 , 149 ], it will be interesting to determine if IRF3 may play a key role in the development of such bone diseases. It is possible that chronic activation of IRF3 may result in similar effects as those seen in VDR-deficient mice, such as bone metabolism defects and hypocalcaemia [150 ], as activation of IRF3 does result in significant repression of VDR/RXR target genes.
Another area of interest will be how IRF3 and an antiviral innate immune response in developing fetuses may affect development during a maternal viral infection. Maternal viral infections have been shown to impair child development as a result of an antiviral response rather than through the mechanisms of viral infections themselves [151
]. Given that RXR-deficient mice are embryonic-lethal, IRF3-mediated repression of RXR could have severe effects on embryonic development during a maternal viral infection. Future studies analyzing the possible connection between IRF3 and nuclear receptors in maternal viral infections could yield interesting answers about the effect of innate immune response on embryonic development. In addition to repression of RXR, IRF3 may play other roles in repressing nuclear receptor target genes. Further study in this field will likely yield other potential mechanisms of repression that will shed more light on the role of IRF3 in nuclear receptor gene regulation. It is clear from the initial work done in this field that IRF3 is an attractive, therapeutic target in regulating metabolic disorders such as atherosclerosis and Reye’s syndrome. Future work in this field will provide new insight into the significance of metabolism and immune system crosstalk and will provide novel, therapeutic targets for other metabolic and immune disorders.
Received December 20, 2006; revised January 30, 2007; accepted February 1, 2007.
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  T. Flatt, A. Heyland, F. Rus, E. Porpiglia, C. Sherlock, R. Yamamoto, A. Garbuzov, S. R. Palli, M. Tatar, and N. Silverman Hormonal regulation of the humoral innate immune response in Drosophila melanogaster J. Exp. Biol., August 15, 2008; 211(16): 2712 - 2724. [Abstract] [Full Text] [PDF]
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