Constitutive type I interferon modulates homeostatic balance through tonic signaling (original) (raw)

. Author manuscript; available in PMC: 2013 Feb 24.

Abstract

Interferons (IFNs) were discovered nearly 60 years ago as a family of cytokines induced during and protecting from viral infection. They have been documented to play essential roles in numerous physiological processes beyond innate antiviral defense, including immunomodulation, regulation of the cell cycle, cell survival and differentiation, and the host response to microbial pathogens. Recent data have also uncovered a potentially darker side to the functions of IFN, including roles in autoimmunity and diabetes. Many IFN effects occur in the absence of acute viral infection, highlighting a physiologic role for constitutively produced IFN. Type I IFNs are constitutively produced at vanishingly low quantities and yet exert profound effects, mediated at least in part through modulation of signaling intermediates required for diverse cytokine response pathways. We review evidence for a yin-yang of IFN function through its role in modulating crosstalk between multiple cytokines by both feed-forward and feed-back regulation of common signaling intermediates and postulate that a similar mechanism underlies a homeostatic role for IFN through tonic signaling in the absence of acute infection.

Three types of interferon (IFN) have been identified in mammals. The type I IFN family encodes 7 subtypes, including 13 IFNα isoforms, IFN-ε, IFN-κ, IFN-ω and IFNβ. There is also a single type II IFN (IFNγ) and the type III IFNs comprised of IFNλ 1, 2 and 3 (also named IL29, IL28a, and IL28b, respectively) (Levy et al., 2011; Li et al., 2009; Pestka et al., 2004). Type I IFNs are secreted in abundance in response to viral infection, acting early during the immune response to potentiate antiviral responses and prime and maintain adaptive immunity (Durbin et al., 2000; Huber and Farrar, 2011; Muller et al., 1994). Interestingly, low amounts of IFNβ accumulate in the tissue milieu in the absence of infection. Until recently, the purpose of this constitutive IFNβ has been unclear, in part because the quantities of constitutive IFN are close to the threshold of detection of even the most sensitive assays (Hamilton et al., 1996; Vogel and Fertsch, 1984). It has been proposed that small quantities of IFNβ prime cells for an efficient subsequent response to other cytokines, and are also necessary for immune homeostasis, maintenance of bone density and antiviral and anti-tumor immunity. Similarly, constitutive IFN may play detrimental roles, particularly when improperly regulated, by augmenting an autoimmune-prone condition or by enhancing potentially debilitating inflammation that could lead to cancer (de Visser et al., 2006). It is important to build an understanding of the molecular events that underpin constitutive IFN production and action and how defects in this process impact disease.

Constitutive type I IFN secretion

In the early 1980s, Velio Bocci proposed a biological role for constitutive IFN signaling based on observations that uninfected tissue preparations produced an antiviral activity akin to IFN. It was proposed that IFN was induced by ongoing low-grade exposure of the mucosa to external pathogens, tissue remodeling or damage (Bocci, 1980). Whilst the constitutive production of type I IFN has not been addressed under germ free conditions to assess a potential role for commensal microorganisms, type I IFN mRNA and protein have subsequently been detected in tissues of healthy mice maintained in specific pathogen free environments (Gresser, 1990; Tovey et al., 1987; Viti et al., 1985; Yaar et al., 1986). The generation of neutralizing type I IFN antibodies and later animals lacking the type I IFN receptor (Ifnar) or the Ifnβ gene provided essential tools to further substantiate the existence and importance of constitutive type I IFN. It is now clear that constitutive IFNβ occurs in healthy animals and is necessary for a diverse array of biological effects, including maintenance of the hematopoietic stem cell (HSC) niche, immune cell function and bone remodeling. Moreover, perturbations of IFN contribute to the pathology of autoimmune disease, antiviral immunity and cancer.

Mechanism of constitutive type I IFN production

Although type I IFNs are encoded by multiple genes, they are co-regulated in a complex fashion involving a positive feed-forward regulatory loop (Marie et al., 1998; Sato et al., 1998). In the absence of priming amounts of IFNβ, mouse embryo fibroblasts (MEFs) do not produce other type I IFNs, suggesting that IFNβ is a master regulator and highlighting the importance of IFNβ secretion in regulating all type I IFN activities and presumably those mediated by type III IFN (Erlandsson et al., 1998; Takaoka et al., 2000). IFNβ mRNA expression increases dramatically in response to viral infection; in this context the occupancy of the IFNβ promoter and enhancer has been extensively characterized. The IFNβ promoter contains four positive regulatory domains (PRDI-IV), which are occupied by overlapping transcription factor complexes. Interferon regulatory factor (IRF)-3 and IRF7 bind PRDI and III; the AP-1 heterodimer of ATF-2 and c-Jun binds PRDIV; and the NF-κB p50-RelA heterodimer binds PRDII (Fig. 1a). In addition, roles for the architectural protein HMGA1 and for a positioned nucleosome have been defined (Ford and Thanos, 2010; Maniatis et al., 1998). The binding of each of these components in the correct orientation and location results in activation of the IFNβ promoter in response to viral infection. For virus induced IFNβ expression, IRF3 and IRF7 appear to be essential (Hata et al., 2001; Sato et al., 2000).

Figure 1. Transcription factors for inducible and constitutive IFNβ promoter activity.

Figure 1

The _IFN_β promoter contains four positive regulatory domains (PRDI-IV). (Upper) Stimulation-dependent induction of IFNβ expression requires cooperative recruitment of a number of transcription factor complexes to its promoter: IRF-3 and/or IRF-7, ATF-2 and c-Jun, p50 and RelA, and the architectural protein HMGA1 (not pictured). The binding of these factors to their specific regions (IRF-3 and IRF-7 bind PRDI and III; ATF-2 and c-Jun bind PRDIV; p50 and RelA bind PRDII) leads to rapid and robust induction of IFNβ expression. (Lower) In the absence of stimulation the IFNβ promoter is occupied by c-Jun at PRDIV and RelA at PRDII, which promote basal IFNβ expression; and IRF-2 at PRDI and p50 homodimers at PRDI, PRDII and III, which negatively regulate IFNβ production. Involvement of additional transcription factors, particularly partners for c-Jun and RelA in unstimulated cells, remain to be identified.

Less is known regarding the transcriptional regulation of constitutive IFNβ. The most notable distinction from acutely induced IFN expression is a switch from dependency on IRF3 and IRF7 to c-Jun and NF-κB components (Fig. 1b). In contrast to pathogen-induced IFNβ production, deletion of IRF3 does not prevent constitutive IFNβ expression (Hata et al., 2001). In addition, deletion of IRF9 resulting in undetectable amounts of IRF7 has no impact on constitutive IFNβ (Hata et al., 2001). However, AP-1 and NF-κB components appear essential. AP-1 and NF-κB are dimeric transcription factors, activated by a diverse array of cytokines and growth factors. AP-1 is comprised of Jun, Fos or ATF proteins; NF-κB is comprised of a dimer of p50, p52, p65 (RelA), RelB or c-Rel. Although AP-1 and NF-κB play important but non-essential roles in viral induction of IFNβ (Balachandran and Beg, 2011), both are essential for constitutive IFNβ production. c-Jun occupies PRDIV on the IFNβ promoter in uninfected cells, and its deletion decreases constitutive IFNβ expression by half (Gough et al., 2010). It is likely that the NF-κB subunit RelA also maintains constitutive expression of IFNβ, since RelA is bound to PRDII in unstimluated cells and loss of RelA causes gene expression defects in unstimulated cells resembling loss of IFN (Basagoudanavar et al., 2011; Wang et al., 2010). However, constitutive IFNβ expression by _Rela_−/− MEFs has not been directly measured.

Threshold expression of IFNβ in unstimulated cells is governed by IRF2 and p50 homodimers, both of which are constitutively expressed and bind the IFNβ promoter as repressors (Fig. 1b) (Cheng et al., 2011; Senger et al., 2000; Thanos and Maniatis, 1995); Harada et al., 1989). IRF2-deficient cells have heightened expression of IFNα and β and IFN target genes and _Irf2_−/− mice develop a psoriasis-like skin disease that is ameliorated by removing IFN signaling, such as ablation of IFNAR1 (Arakura et al., 2007; Honda et al., 2003). The abundance of constitutive IFNβ following loss of p50 has not been measured; however p50-deficient animals are developmentally normal with no signs of the skin disease caused by IRF2 loss, suggesting a lesser role for p50 as a repressor of constitutive IFNβ (Sha et al., 1995). Together, these reports document that the IFNβ promoter is occupied by both activators (c-Jun and RelA) and suppressors (IRF2 and p50 homodimers), the balance of which maintain tight control of constitutive IFNβ in absence of overt stimuli.

Regulation of cytokine signal transduction by constitutive IFNβ secretion

Binding of type I IFNs to IFNAR (Pestka et al., 2004) activates receptor-associated Janus kinases (JAKs) (Bach et al., 1997), which phosphorylate the receptor and activate latent Signal Transducers and Activators of Transcription (STATs) by receptor recruitment and phosphorylation on a caboxy-terminal tyrosine residue (Levy and Darnell, 2002; Stark et al., 1998). Activated STATs form higher order transcription factor complexes (Schroder et al., 2004), which translocate to the nucleus and bind to promoter elements to induce target gene expression (Fig. 2). These transcription factor complexes include STAT1 homodimers and a heterotrimer of STAT1, STAT2 and IRF9, known as ISGF3 (Levy et al., 1988). STATs 3, 4, 5 and 6 can also be phosphorylated in response to type I IFNs, forming both homodimers and heterodimers (Platanias, 2005).

Figure 2. Constitutive IFNβ signaling sets the balance of signaling intermediaries.

Figure 2

In a healthy organism, low amounts of IFNβ are constitutively secreted, which maintains appropriate expression of IFN-inducible signaling intermediaries, including the transcription factors STAT1, STAT2, IRF5, IRF7, and IRF9 (center). Appropriate expression allows a balance between STAT1 or ISGF3 signaling and signaling through other STAT proteins (e.g., STAT4). Diminished constitutive IFNβ secretion (left) results in decreased expression of ISGF3 subunit proteins, altering the balance of signaling (e.g., between ISGF3 and STAT4) and culminating in susceptibility to infection and cancer, inefficient hematopoietic stem cell (HSC) mobilization, and increased bone resorption. Excessive expression of IFNβ (right) drives over-expression of ISGF3 proteins, initiating an inflammatory environment that can result in autoimmunity and exhaustion of the HSC niche.

Somewhat paradoxically, loss of constitutive IFNβ or loss of IFN responsiveness (e.g., as observed in Ifnar1−/− animals) attenuates cellular responses not only to type I IFNs but also to unrelated cytokines, such as IFNγ and IL-6. Several hypotheses have been advanced to explain this phenomenon. In one model, IFN augments other cytokine responses by direct interaction of heterologous receptors, allowing co-recruitment of downstream effector molecules. To date there have been two such hybrid receptors proposed; the association of IFNAR1 with IFNγR2 (Takaoka et al., 2000) and the association of IFNAR1 with the common gp130 chain of the IL-6 receptor (Mitani et al., 2001). It was proposed that constitutive IFNβ secretion leads to the assembly of these multimeric receptors, and cytokine-dependent receptor crosstalk augments tyrosine phosphorylation of IFNAR1, providing a docking site for latent STAT1 or STAT3, transcription factors necessary for IFNγ and IL-6 responses. This model could account for cooperation between type I and II IFN and IL-6; however, this model would also suggest far greater overlap in the transcriptional response and biological outcome to stimulation with these cytokines than has actually been observed (Der et al., 1998; Weihua et al., 2000).

An alternative model posits regulation of signaling intermediaries by priming amounts of IFNβ, rather than direct receptor crosstalk. In this model, low level IFNβ signaling is required to maintain adequate expression of STAT1 and 2, and likely a host of other signaling components, all of which are STAT target genes. In the absence of constitutive IFNβ or its receptor, basal STAT expression is diminished, compromising STAT-dependent biological responses, such as those induced by IFNγ and IL6 (Fig. 2). Cells with defects in IFNβ signaling have decreased basal expression of STAT1 and STAT2 compared to wild type cells (Fleetwood et al., 2009; Gough et al., 2010). Furthermore, gene expression studies demonstrated that basal expression of other signaling molecules is affected by loss of constitutive IFNβ signaling, including reduced IRF1, IRF7 and possibly STAT3 (Fleetwood et al., 2009; Gough et al., 2010; Thomas et al., 2006). STAT6 is also IFN- responsive and therefore is likely diminished in the absence of constitutive IFNβ (de Veer et al., 2001). Given the many intermediary cytokine signaling molecules that are themselves induced by JAK-STAT activation, loss of basal signaling likely leads to a paucity of intermediary proteins required for an array of diverse responses. This model would explain the attenuated signaling and biological activity of other cytokines that engage the STAT pathways, such as reduced IFNγ, IL-6 and CSF-1 signaling observed in Ifnar1−/− cells (Gough et al., 2010; Karaghiosoff et al., 2000; Park et al., 2000; Thomas et al., 2006). This hypothesis of a direct priming role for constitutive IFN would also account for the observation that treatment of Ifnar1−/− macrophages with sub-threshold expression of IFNγ increases both basal STAT1 expression and subsequent IFNγ-induced STAT1 phosphorylation (Hu et al., 2002). If reduced responsiveness is due to limited STAT1 abundance, increasing STAT1 expression can rescue signaling, regardless of the receptor complex involved. However, recovery of IFNγ responsiveness by IFNγ priming in the absence of IFNAR would not be predicted by a receptor cross-talk model.

An extension to the IFN priming hypothesis is that the ratio of specific STAT proteins shapes the biological response to a stimulus. In the case of Ifnar1−/− or _Ifnb1_−/− cells, STAT1 and STAT2 expression is diminished providing a stoichiometric advantage to other STAT proteins for receptor binding. An example of the biological relevance of STAT protein ratios is the IL-6 to IFNγ switch caused by reduced STAT3 expression. IL-6 signaling in the absence of STAT3 exhibits a transcriptional and biological profile similar to that of IFNγ by preferentially engaging STAT1 (Costa-Pereira et al., 2002). The inverse happens in response to IFN, leading to enhanced antiviral signaling due to absence of the tonic effect of STAT1-STAT3 competition (Wang et al., 2011). Because constitutive IFNβ is a critical regulator of STAT protein expression, it is capable of sculpting subsequent responses to diverse stimuli of the JAK-STAT pathway by shifting the ratio of available STATs. Taken together, these findings suggest that the precise set-point of STAT and other signaling protein abundance, maintained by basal IFN signaling, is a critical regulator of the quantity and quality of subsequent responses.

Biological significance of constitutive IFN secretion

Constitutive type I IFN is important for the maintenance and mobilization of the hematopoietic stem cell niche (Essers et al., 2009; Sato et al., 2009). Treatment of mice with poly(I:C), a strong inducer of type I IFNs, or with IFNα itself, causes HSC exit from G0 and temporarily induces proliferation of dormant HSCs (Essers et al., 2009; Sato et al., 2009). Mice lacking IFNAR1 are refractory to type I IFN and therefore their HSC compartment remains quiescent in response to either poly(I:C) or IFNα treatment (Essers et al., 2009; Sato et al., 2009). These studies documented a role for induced IFN in the regulation of hematopoietic expansion, but analysis of the bone marrow of un-manipulated _Ifnar1_−/− animals revealed a role for constitutive IFN in HSC homeostasis. _Ifnar_−/− mice display a reduction in the total number of HSCs compared to wild type animals (Essers et al., 2009), suggesting that tonic IFN signaling maintains the HSC compartment. Because bone marrow from _Ifnar1_−/− mice is capable of reconstituting the hematopoietic compartment of lethally irradiated wild-type hosts (Diamond et al., 2011; Dunn et al., 2005), some of the tonic effects of IFN likely act on the bone marrow stroma in the HSC niche. Mice lacking STAT1 have a defective response to poly(I:C) similar to Ifnar1−/− suggesting that IFNα induced HSC proliferation is STAT1 dependent (Essers et al., 2009).

IRF2, as a negative regulator of IFNβ expression, modulates the concentration of constitutively secreted IFNβ (Arakura et al., 2007; Honda et al., 2003; Senger et al., 2000). Increased IFNβ secretion in _Irf2_−/− mice leads to the exhaustion of the HSC niche, similar to that observed following prolonged IFN treatment. This depletion of HSCs can be averted by ablation of Ifnar1 (Sato et al., 2009). These data can be explained by positing that constitutive type I IFN is normally at a concentration below the threshold necessary to mobilize HSCs but at a level sufficient to maintain the HSC niche. Therefore, either the absence of constitutive IFN or prolonged elevated IFN depletes the HSC niche, although due to opposing underlying mechanisms.

Immune cell homeostasis and activity

The importance of constitutive IFNβ in maintaining immune homeostasis has been revealed by studies examining the aberrant phenotype of mice lacking type I IFN receptors. IFNAR-deficient mice have decreased splenic NK cells and B220 positive B lymphocytes and increased Gr1+CD11c+ myeloid cells (Hwang et al., 1995; Swann et al., 2007). In the absence of constitutive IFNβ signaling, murine hematopoietic cells exhibit enhanced proliferative responses to low doses of CSF-1 and increased expression of the activation markers CD11c and CD11b (Hamilton et al., 1996; Honda et al., 2003; Hwang et al., 1995; Teige et al., 2003).

Constitutive IFNβ augments myeloid cell function and macrophage homeostasis, as shown by analysis of macrophages from C3H-HeJ mice, which are incapable of inducing IFN in response to LPS due to a defect in the Tlr4 gene (Poltorak et al., 1998). Culturing C3H-HeJ macrophages with supernatants from wildtype C3H-HeN macrophages that express constitutive IFNβ enhanced their phagocytic potential. A similar effect was obtained by adding low ‘priming’ concentrations of IFN to C3H-HeJ macrophages (Vogel and Fertsch, 1984). Conversely, phagocytic potential was attenuated when C3H/HeN macrophages were incubated with IFNα and IFNβ neutralizing antibodies (Vogel and Fertsch, 1984), documenting the requirement for constitutive IFN in maintaining macrophage function. The physiologic consequence of the importance of constitutive IFN for macrophage function may be reflected by the influence of the gut microbiota on hematopoietic homeostasis through basal TLR signaling (Musso et al., 2011).

Given the role of constitutive IFNβ in regulating macrophage activity, effects on other myeloid lineages could be expected. For instance, osteoclasts are required for bone remodeling and therefore critical for maintaining bone homeostasis. Constitutive IFNβ impairs bone marrow-derived macrophage differentiation into osteoclasts, resulting in reduced bone resorption. This is seen most clearly in vivo by comparing wild type, Ifnβ −/− and _Ifnar1_−/− mice; the mutant strains exhibit decreased bone density and increased numbers of osteoclasts (Takayanagi et al., 2002). Therefore constitutive IFNβ probably maintains the entire myeloid lineage at correct homeostatic numbers, which has implications for both the regulation of the innate immune system and maintenance of the skeletal system.

Type I IFN has complex effects on T cells. It is a potent suppressor of proliferation in most cell types, but it enhances the survival and proliferation of CD8+ blasts (Marrack and Kappler, 2004). Unexpectedly, _Ifnar1_- and _Ifnb_-deficient animals do not have altered CD8+ T cell numbers; however, following peptide or DNA-based immunization these mice accumulate twice the number of antigen specific CD8+ T cells compared to wild type (Dikopoulos et al., 2005). One explanation for this apparent contradiction is the relative ratios of STAT proteins expressed. IFNAR-deficient cells express lower amounts of STAT1, enabling JAK-STAT signaling to favor STAT4 over STAT1 (Fig. 2). STAT4 stimulates T-cell proliferation, production of the Th1 subset of CD4+ cells, and is a master regulator of IFNγ secretion from NK cells. In contrast STAT1 activation is typically growth inhibitory and impedes IFNγ secretion from NK cells (Miyagi et al., 2007; Nguyen et al., 2002). In addition, CD8+ T cells have a less robust induction of STAT1 expression than CD4+ T cells (Gil et al., 2006), which would compound the STAT1 to STAT4 switch and lead to reduction in IL-10 producing CD4+ T regulatory cells (Dikopoulos et al., 2005).

Constitutive type I IFN is involved in the maintenance of NK cell biology at several levels. The primary cytokine necessary for NK cell proliferation is IL-15, which is a type I IFN-regulated gene (Fehniger et al., 2001; Kennedy et al., 2000; Lodolce et al., 1998; Montoya et al., 2002). Although IL-2 can equivalently support STAT1-deficient NK cell growth, IL-15 is able not only to support growth but also to restore cytotoxicity to _Stat1_−/− NK cells (Lee et al., 2000). Due to the inability of _Ifnar1_−/− or _Ifnar2_−/− mice to respond to constitutively secreted IFNβ, it was unsurprising to find that the number of NK cells in these animals was lower than wild type animals and that these mice were highly susceptible to the outgrowth of NK-targeted tumor cells (Swann et al., 2007). Again, these effects occur in the absence of an overt pathogenic stimulation, suggesting that the mutant animal phenotype is caused by loss of tonic IFN signaling. In addition to a proliferative defect, NK cells derived from _Ifnar2_−/− mice are defective in IL-2 mediated killing of RMAS cells in vitro, although the cytotoxicity of naïve IFNAR-deficient NK cells to some targets is not affected (Lee et al., 2000; Swann et al., 2007). In contrast, complete absence rather than just reduced expression of STAT1 results in a profound defect in NK cell cytotoxicity (Lee et al., 2000). Interestingly, the dichotomy of STAT1 and STAT4 expression also influences the activity of NK cells. Basal expression of STAT4 is higher than that of STAT1 in NK cells (Mack et al., 2011), where it drives IFNγ production (Mack et al., 2011; Miyagi et al., 2007). IFN generated during infection increases STAT1 expression in NK cells, which displaces STAT4 on IFNAR leading to suppression of IFNγ production (Mack et al., 2011; Miyagi et al., 2007). NK cells from _Ifnar1_−/− animals have attenuated STAT1 expression (Miyagi et al., 2007). Abundant STAT1 and STAT2 leads to stimulation of NK cell mediated cytotoxicity, whereas reduced STAT1 but abundant STAT4 stimulates cytokine secretion at the expense of cytotoxicity (Nguyen et al., 2002). Because the ratios of STAT proteins are set by tonic IFN signaling, constitutive IFN is critical for modulating subsequent cellular responses.

These observations highlight another important consequence of constitutive IFN, to modulate relative expression of STAT proteins. STAT1, STAT2, and STAT6 are all IFN responsive genes and as such constitutive IFN governs their abundance (de Veer et al., 2001). We have recently confirmed that absence of constitutive IFN signaling, either due to genetic ablation of Ifnar1 or by treatment with blocking antibodies, markedly reduced STAT1 and STAT2 expression in a range of primary tissues, including dendritic cells, splenocytes, fibroblasts, heart, large intestine, small intestine, liver, lung and pancreas (Gough et al., 2010). This observation suggests that the ratio between STAT1 and other STATs is governed by constitutive IFNβ, establishing homeostatic regulation of multiple lineages. Taken together, these observations demonstrate that basal levels of STATs and other proteins is maintained through tonic IFN signaling

Antiviral and anti-tumor effects

Type I and type II IFNs bind to distinct receptors and therefore it was assumed that loss of IFNAR would have no effect on IFNγ signaling. Surprisingly, it was found that IFNγ dependent antiviral responses are compromised in the absence of IFNAR1 (Gough et al., 2010; Muller et al., 1994; Takaoka et al., 2000). The importance of constitutive IFNβ secretion in maintaining IFNγ-dependent antiviral activities has been highlighted in a number of experimental observations. Priming IFNβ-deficient MEFs with low dose IFNβ restored IFNγ-mediated antiviral responses and increased resistance to influenza virus by promoting activation of DCs (Phipps-Yonas et al., 2008; Takaoka et al., 2000). Since maintenance of STAT1 expression in MEFs is dependent on constitutive IFNβ, absence of IFN responsiveness (e.g., _Ifnar1_−/− or _Ifnb1_−/− mice) attenuated IFNγ-mediated antiviral responses. Ectopic restoration of STAT1 to physiologic expression in IFNAR-deficient cells rescued IFNγ-mediated antiviral protection without altering the response to type I IFN (Gough et al., 2010). Positive correlation between the abundance of constitutive IFNβ and subsequent antiviral responses has also been observed in physiologic situations. For example, cardiac myocytes have higher constitutive IFNβ expression than cardiac fibroblasts, and myocytes show increased resistance to viral infection (Zurney et al., 2007).

Type I IFN is used as a treatment for viral infection (hepatitis B and C) and cancer (including chronic myeloid leukemia and melanoma) and its efficacy is affected by constitutive IFN. Melanoma is often refractory to IFNα and IFNβ treatment relative to normal tissue. This loss of IFN responsiveness is associated with reduced STAT1 expression (Landolfo et al., 2000; Sun et al., 1998; Wong et al., 1997) and restoration of STAT1 expression to amounts seen in normal tissue via transduction or priming with IFNγ regained responsiveness to type I IFN treatment (Wong et al., 1998; Wong et al., 1997). Other studies have shown that low amounts of IFNβ repress tumor growth by preventing production of pro-angiogenic cytokines by tumor infiltrating neutrophils (Jablonska et al., 2010). Defects in type I IFN secretion and/or signaling have also been seen in other human malignancies, including the deletion of IFN genes in acute leukemia cells (Colamonici et al., 1992) and malignant T-cells (Heyman et al., 1994); down-regulation of IFNAR in hairy cell leukemia (Billard et al., 1986), gastric cancer (Chen et al., 2009) and lymphoblastoid cells (Pfeffer and Donner, 1990); loss of JAK1 in lung carcinoma (Kaplan et al., 1998); down regulation of IFN signaling components in melanoma (Wong et al., 1997) and chronic myeloid leukemia (Landolfo et al., 2000); and overexpression of negative regulatory SOCS proteins in cancer (Lesinski et al., 2010; Li et al., 2004). The number and variety of malignancies with mutations that prevent production of or alter responsiveness to IFN suggests that aberrations in IFN sensitivity and production provide a survival advantage for tumor cells and thus a potential target for therapeutic intervention.

Autoimmunity

The development and progression of autoimmune diseases is multifactorial; however, increased secretion of type I IFN or an IFN-stimulated gene signature is typical in patients with a number of diseases, such as systemic lupus erythematosus (SLE), Sjögren’s Syndrome or type I diabetes mellitus (DM), correlating with increased disease severity (Crow, 2010; Kirou et al., 2005; Lu et al., 2007). A subset of patients receiving IFN treatment for hepatitis C develop DM, arthritis or multiple sclerosis (MS) (Passos de Souza et al., 2001; Yamazaki et al., 2010), despite the fact that IFNβ is commonly used to treat MS (Buttmann and Rieckmann, 2007; Tak, 2004). Similarly, there is a subset of MS patients that do not respond to IFNβ treatment. Non-responders present with high circulating amounts of IFNβ, suggesting that a precise setpoint of IFNβ concentration must be maintained; both higher or lower amounts result in pathologic consequences (Comabella et al., 2009).

Elevated IFNα expression in SLE patients may be responsible for the generation of autoimmune antibodies by inducing monocyte differentiation and potentiating activation of CD4+ T cells in response to self antigens (Blanco et al., 2001). The pathologic consequence of elevated IFN in SLE is revealed by disease amelioration in mice by IFNAR deficiency. Moreover, IFN neutralizing antibodies have shown promise in clinical trials in SLE (Nacionales et al., 2007; Yao et al., 2009).

As noted above, IRF-2 deficiency leads to psoriasis due to elevated IFN (Arakura et al., 2007). The AP-1 and NF-κB subunits c-Jun and RelA that drive constitutive IFNβ expression are elevated in psoriatic plaques (Lizzul et al., 2005; Mehic et al., 2005; van der Fits et al., 2003). No discrete pathogens have been implicated in disease causation, suggesting that altered tonic type I IFN signalling contributes to the pathogenesis of psoriasis.

These data support a unified concept of IFN-mediated homeostasis. Appropriate amounts of basal IFN maintain the abundance of a wide variety of signalling molecules important for both immunity and tissue homeostasis. Neither reduced nor enhanced levels of IFN can be tolerated without adverse consequences of either impaired hematopoietic homeostasis and reduced immune responses on the one hand or increased inflammation and autoimmunity on the other. It will be of great interest to understand the contribution of the microbiome to both the appropriate and the inappropriate regulation of tonic IFN (Musso et al., 2011).

Conclusions

IFNβ and other type I IFNs are constitutively secreted at low amounts by many tissues of the body as a means of maintaining homeostasis and priming cells to maintain a rapid and robust innate and adaptive immune response to subsequent challenge. It will be important to determine whether there are other similar biological processes whereby constitutive low level autocrine or paracrine cytokine signaling maintains homeostatic balance. The range of influences of constitutive IFNβ is due, in large part, to its role in maintaining the expression of STAT proteins and other signaling intermediates, although the full range of signaling proteins whose basal abundance is determined by tonic IFN signaling remains to be documented. The loss of priming concentrations of IFNβ leads to compromised expression of STAT and other regulatory proteins, resulting in impaired cross-talk between cytokine signaling networks and a host of additional phenotypes, such as aberrant immune cell function, bone remodeling and deregulation of HSC homeostasis. Documenting the extent of innate and adaptive immune pathways influenced by IFN priming will be an important area of further investigation. Modulation of the abundance of signaling intermediates by constitutive IFN regulates both the quantity and the quality of subsequent responses, due to competitive interactions among related proteins. This mechanism potentially explains many situations of cross-talk between diverse cytokine families that signal through overlapping components subject to feed-back and feed-forward regulatory networks. Increased research into the regulation and function of tonic IFN signaling and identification of the relevant IFN-stimulated genes that contribute to homeostasis could have major implications for our understanding of how a healthy immune system is maintained. Of importance will be development of a more complete picture of the sources of tonic IFN, in particular determining the contribution of environmental signals, such as influences from microbial flora.

Acknowledgments

D.J.G is supported by a Special Fellow award from the Leukemia and Lymphoma society. N.L.M is supported by a Cancer Research Institute Predoctoral Emphasis in Tumor Immunology Scholarship. R.W.J. is a Principal Research Fellow of the National Health and Medical Research Council of Australia (NHMRC) and supported by NHMRC Program and Project Grants, the Susan G. Komen Breast Cancer Foundation, the Prostate Cancer Foundation of Australia, Cancer Council Victoria, The Leukemia Foundation of Australia, Victorian Breast Cancer Research Consortium, Victorian Cancer Agency and the Australian Rotary Health Foundation. D.E.L acknowledges funding from the National Institutes of Health (R01AI28900, U54AI057158).

Footnotes

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