JOURNAL OF INTERFERON & CYTOKINE RESEARCH Volume 34, Number 10, 2014 ª Mary Ann Liebert, Inc. DOI: 10.1089/jir.2014.0081

Transcriptional Regulation of Pattern Recognition Receptors by JAK/STAT Signaling, and the Implications for Disease Pathogenesis Brendan John Jenkins

Cytokines are well known for their pleiotropism, affecting a large number of cellular responses, including proliferation, survival, functional maturation, and immunomodulation. It is, therefore, not surprising that both the deregulated expression of cytokines and the subsequent activation of their downstream signaling pathways is a common feature of many cancers, as well as chronic inflammatory, autoimmune, metabolic, and cardiovascular diseases. In this regard, activation of the Janus kinase ( JAK)/signal transducer and activator of transcription (STAT) pathway is the predominant intracellular signaling event triggered by cytokines, with STAT1 and STAT3 having the greatest diversity of biological functions among the 7 known members of the STAT family of latent transcription factors. Notably, over recent years, it has emerged that STAT1 and STAT3 are employed by various cytokines to manipulate the signal output of heterologous receptors of the innate immune system, namely pattern recognition receptors (PRRs), with both immune and nonimmune (eg, oncogenic, metabolic) cellular processes being affected. This review highlights these pivotal advancements in our understanding of how a cross talk between cytokine and PRR signaling networks can impact on a variety of cellular responses during disease pathogenesis, and the potential therapeutic implications of targeting these networks.

Introduction

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t was not so long ago that our understanding of the role of the mammalian immune system was primarily restricted to the orchestration of complex host defense mechanisms to counteract viral, bacterial, and parasitic infections, as well as tissue injury to restore homeostasis. Furthermore, the deregulation of the host immune response in such scenarios underpinned the onset and maintenance of chronic systemic or organ-specific inflammation. More recently, however, we have developed a better appreciation of the greater diversity of both the innate and adaptive arms of the immune system and their contributing role to cardiovascular disease and an ever-increasing number of cancers, autoimmune diseases, and metabolic disorders. In this respect, we now know that chronic inflammation comprising both innate and adaptive immune cell lineages is a common feature of such diseases, and is furthermore likely to play a significant role in disease onset, progression, and maintenance (Hansson and Hermansson 2011; Cader and Kaser 2013; Elinav and others 2013; Fuentes and others 2013; Mansell and Jenkins 2013; WahrenHerlenius and Do¨rner 2013). Pattern recognition receptors (PRRs) comprise several families of innate immune receptors, including Toll-like

receptors (TLRs), NOD-like receptors (NLRs), and RIG-Ilike receptors (RLRs), and it is now widely acknowledged that they serve as critical sensors of microbial-derived pathogen-associated molecular patterns (PAMPs) and/or host-derived (ie, endogenous) danger-associated molecular patterns (DAMPs) to trigger the inflammatory response (Kawai and Akira 2010; Kersse and others 2011; Ramos and Gale 2011). Following PRR activation, a vast number of cytokines are released by both immune (eg, macrophages, T cells) and nonimmune (eg, epithelial, endothelial) cells. Collectively, these inflammatory mediators stimulate a complex array of inflammatory cellular processes, including the recruitment, maturation, and activation of immune cells, as well as having effects on nonimmune cells such as epithelial, endothelial, and fibroblast cell survival and proliferation, which are an intrinsic part of tissue remodeling. The plethora of cellular processes triggered by cytokines is facilitated by their interaction with membrane-spanning receptors, which leads to the activation of numerous signaling pathways, among which the Janus kinase ( JAK)/ signal transducer and activator of transcription (STAT) pathway is the best characterized (Stark and Darnell 2012). In this scheme described above, it has been generally accepted that the PRR-mediated transcriptional induction of

Centre for Innate Immunity and Infectious Diseases, MIMR-PHI Institute of Medical Research (formerly Monash Institute of Medical Research), Clayton, Victoria, Australia.

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PATTERN RECOGNITION RECEPTOR REGULATION BY JAK/STAT

FIG. 1. Schematic diagram of bi-directional transcription regulation of cytokines and pattern recognition receptors (PRRs). Upon binding of pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs) ligands to their cognate PRR, numerous PRRdriven signaling cascades are activated, including the archetypical nuclear factor-kappaB (NF-kB) transcriptional complex, which leads to the induction of cytokine gene expression (eg, interleukin-6 family cytokines). Cytokines are then secreted from the cell and bind to their specific cytokine receptor (CR) in an autocrine (shown) or paracrine manner, leading to activation of the Janus kinase ( JAK)/ signal transducer and activator of transcription (STAT) pathway, which can then feedback and transcriptionally upregulate PRRs (eg, Toll-like receptors, NOD-like receptors). Green and black arrows depict PRR- and cytokinerelated events, respectively.

cytokines ultimately leads to the activation of such downstream cytokine signaling pathways which facilitate the actions of these inflammatory mediators. However, as will be discussed later in this review, it is now emerging that the JAK/STAT pathway in particular can feedback and modulate the transcriptional induction of PRRs, thus providing an intriguing bi-directional feedback regulatory loop between cytokines and PRRs (Fig. 1).

Cytokines and Their Predominant Usage of the JAK/STAT Pathway Cytokines are a class of small glycosylated regulatory proteins that are secreted into the microenvironment to control a wide range of cellular processes such as differentiation, proliferation, survival, functional maturation, and apoptosis. The 3-dimensional structure of cytokines and the

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receptors they bind to largely dictates their status as either type I or type II, and collectively these include many interleukins (ILs), colony-stimulating factors, and interferons (IFNs) (Krause and Pestka 2005; Wang and others 2009). The complex biological actions of cytokines often encompass both functional pleiotropy (multiple biological actions) and redundancy (shared biological actions), and are elicited through the activation of numerous intracellular signaling pathways following the interaction of a cytokine with its specific cell surface receptor. Ever since its discovery some 2 decades ago, the JAK/ STAT pathway has been the most characterized signal transduction cascade underpinning the broad-ranging biological activities of cytokines (Stark and Darnell 2012). The tyrosine phosphorylation of receptors by their bound JAKs ( JAK1–3, TYK2) leads to the recruitment of 1 or more of the 7 members of the STAT family of latent transcription factors, which upon their tyrosine phosphorylation-mediated release from receptors translocate to the nucleus where they modulate diverse gene transcriptional programs (Stark and Darnell 2012). Collectively, the transcriptional activity and subsequent biological actions of STATs are influenced by a multitude of posttranslational modifications, including tyrosine phosphorylation, serine phosphorylation, acetylation, methylation, sumoylation, and ubiquitination (Decker and Kovarik 2000; Ungureanu and others 2005; Wei and others 2012; Wieczorek and others 2012; Kim and others 2013a). Together with the fact that nonphosphorylated versions of STAT1 and STAT3 can direct the transcription of different target genes compared with their phosphorylated counterparts (Yang and Stark 2008), STATs have at their disposal an impressive repertoire of modifications by which to transcriptionally regulate genes involved in most cytokine-driven cellular responses. Considering the diverse nature of biological actions attributed to the JAK/STAT pathway, it is of no surprise that the hyperactivation of this pathway has been linked to the pathogenesis of many disease states, especially chronic inflammation, autoimmune diseases, and cancer (Yu and others 2009; O’Shea and Plenge 2012). It is also for this reason that many years’ worth of intense research efforts has been directed at understanding the molecular mechanisms, which modulate JAK/STAT signaling, with the suppressor of cytokine signaling (SOCS) family of proteins having emerged as the most crucial negative regulators of the JAK/STAT cascade (Linossi and others 2013). Despite the widely acknowledged dominance of the JAK/STAT pathway in underpinning cytokine biology, it is noteworthy that the broad-ranging cellular activities of cytokines, in particular cell proliferation and survival, are further enhanced by their utilization of additional pathways (not discussed in this review), namely extracellular signal-regulated kinase/mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)/Akt cascades (Chang and Karin 2001; Woodgett 2005).

The JAK/STAT Pathway in Disease The pathological consequences of deregulated JAK/STAT signaling have been widely documented in many animal models of chronic inflammatory and autoimmune diseases, and cancers. For instance, genetic and therapeutic targeting of the JAK/STAT signaling axis in experimentally induced autoimmune disease models for type 1 diabetes, multiple

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sclerosis [experimental autoimmune encephalomyelitis (EAE)], and rheumatoid arthritis (RA), as well as chronic inflammation models such as inflammatory bowel disease (IBD) and atherosclerosis, substantially ameliorate the disease which is associated invariably with dampening the net STAT3 signaling output from numerous proinflammatory, disease-associated cytokines including IL-6, IFN-g, IL-12, and IL-23 (Bright and others 1999; Gharavi and others 2007; Liu and others 2008a, 2014; Oyamada and others 2009; Durant and others 2010; Stump and others 2011; Davoodi-Semiromi and others 2012; Yu and others 2012). In a similar vein, the selective interference of JAK1, JAK2, or STAT3 activity has been shown to effectively suppress inflammation-associated tumorigenesis in a range of mouse cancer models characterized by hyperactivation of STAT3 in organs such as colon, stomach, and pancreas ( Jenkins and others 2005; Ernst and others 2008; Grivennikov and others 2009; Lesina and others 2011; Stuart and others 2014). The link between alterations in JAK/STAT signaling and human diseases related to immune deficiency or inflammation has also gained some momentum by way of identification of polymorphisms in genes for JAK and STAT family members that are associated with increased susceptibility to IBD and microbial infections (Barrett and others 2008; Minegishi and Karasuyama 2009; Franke and others 2010). In addition, constitutively activating somatic mutations in the STAT3 gene have been linked to the pathogenesis of human inflammatory hepatocellular adenomas (Pilati and others 2011), thus adding further weight to the notion that this pathway is a likely target for therapeutic intervention in human cancer. Moreover, although still in its relative infancy, the causal role assigned to JAK/STAT signaling in the pathogenesis of experimental animal disease models has translated to the clinic thus far, with encouraging results obtained for RA and IBD patients treated with the JAK inhibitor Tofacitinib (Sandborn and others 2012; van Vollenhoven and others 2012). Considering the wealth of other JAK (and STAT) inhibitors that are currently in the preclinical development and early phase clinical trials (O’Shea and Plenge 2012), it will be of great interest over the coming years to ascertain the effectiveness of these inhibitors in an increasing number of human disease settings.

PRRs and Their Role in Disease It is now widely accepted that innate immune responses triggered by PAMP or DAMP signals depend on PRRs, which collectively comprise members of the TLR, NLR, and RLR families (Stutz and others 2009; Kawai and others 2010). Following recognition of their ligands, PRRs activate the prototypical nuclear factor-kappaB (NF-kB) transcriptional complex, which leads to the induction of a plethora of genes comprising of cytokines, chemokines, growth and angiogenic factors, as well as positive and negative regulators of apoptosis and the cell cycle, which collectively promote both inflammatory and oncogenic cellular processes (Rakoff-Nahoum and Medzhitov 2009; Stutz and others 2009; Tye and others 2012; Tye and Jenkins 2013). In addition, members of the TLR family, in particular, have been reported to utilize numerous well-documented cytokine signaling cascades, including MAPK, PI3K/Akt and, more recently, JAK/STAT, to promote their biological activities (Rhee and others 2003; Cario and others 2007;

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Schroder and others 2007; Yang and others 2009; Bode and others 2012; Tye and others 2012). At least in the case of TLR signaling, activation of MAPK and PI3K/Akt pathways occurs directly through the TLR adaptors myeloid differentiation primary response gene 88 (MyD88) and MyD88adapter-like/TIR-domain-containing adaptor protein (Mal/ TIRAP) (Akira and others 2006; Cario and others 2007; Santos-Sierra and others 2009). With respect to the JAK/ STAT pathway, while initial findings assumed that its activation downstream of TLRs was most likely indirect through the TLR-mediated upregulation of JAK/STATactivating cytokines such as IL-6 and IL-10 (Yang and others 2009), other studies suggest alternate and possibly more direct, cytokine-independent mechanisms by which TLRs can activate the JAK/STAT signaling cascade (Rhee and others 2003; Jabara and others 2012; Lee and others 2012). The TLR family has attracted much attention as a key player in the onset and progression of numerous inflammatory and immune-related disorders, largely due to their being the first identified family of PRRs and, therefore, the most widely studied. Numerous autoimmune disease mouse models for EAE, RA, and type 1 diabetes coupled to mice deficient in specific TLRs, or analyzed through the exogenous administration of TLR ligands, have implicated several TLRs including TLR2, TLR4, and TLR9 in disease pathogenesis (Kim and others 2007; Mills 2011). In a similar vein, studies largely using mice deficient in TLR2, TLR4, or the MyD88 adaptor have revealed that TLR signals promote disease pathogenesis in a range of models for chronic inflammatory disorders such as IBD and atherosclerosis, as well as inflammation-associated cancers of the stomach or colon (Fukata and others 2007; Liu and others 2008b; Rakoff-Nahoum and Medzhitov 2009; Higashimori and others 2011; Hoshi and others 2012; Tye and others 2012; Kennedy and others 2014). The validity of such experimental findings to human disease has been supported by the link between genetic polymorphisms and/or aberrant expression among TLR family members (again primarily TLR2 and TLR4) and increased risk of human inflammatory diseases such as IBD, atherosclerosis, and RA among others (Corr and O’Neill 2009; Cario 2010), as well as cancers of the colon and stomach (Tye and others 2012; Tye and Jenkins 2013; Marusawa and Jenkins 2014). Among PRRs, much interest has also arisen over recent years in certain intracellular receptors of the NLR family, namely NLR pyrin domain containing 1 (NLRP1), NLRP3, NLRP6, NLR caspase activation and recruitment domain (CARD) containing 4 (NLRC4), NLRC5, and NLR apoptosis inhibitory protein (NAIP) (Stutz and others 2009; Davis and others 2011; Janowski and others 2013). A key unifying function of these NLR family members, along with the cytosolic DNA sensor Absent in melanoma 2 (AIM2) (Hornung and others 2009), is their ability to mediate the assembly of multiprotein inflammasome complexes, which are necessary for the release of mature and cleaved forms of the potent proinflammatory cytokines IL-1b and IL-18 (Stutz and others 2009; Davis and others 2011; Janowski and others 2013). Indeed, the strong association between deregulated IL-1b and IL-18 production and a range of autoimmune and chronic inflammatory disorders has placed further emphasis on understanding the mechanisms responsible for inflammasome activity, and thus the production of these cytokines, in human disease (Sedimbi and others

PATTERN RECOGNITION RECEPTOR REGULATION BY JAK/STAT

2013; Zhao and others 2013). In this regard, the assembly of active, multiprotein inflammasome complexes involves a 2stage process, the first of which is a priming step involving the induction of pro-IL-1b and pro-IL-18 transcripts and biologically inactive precursor proteins in response to proinflammatory stimuli transduced through PRRs or cytokine receptors. In the second stage, ligand sensing by each NLR or AIM2 leads to the recruitment and activation of caspase-1 in a manner that is either dependent (eg, NLRP3) or independent (eg, NLRC4) of interactions with the adaptor protein apoptosis-related speck-like protein containing a CARD (ASC), which in turn catalyses the cleavage of proIL-1b and pro-IL-18 into their active and mature forms that are secreted from the cell (Stutz and others 2009). The importance of inflammasomes to disease pathogenesis is strongly evidenced by inflammatory and autoimmune diseases such as IBD, atherosclerosis, diabetes, gout, and Muckle–Wells syndrome, which have been linked invariably to inflammasome-mediated augmented IL-1b production through NLRP3 (Agostini and others 2004; Martinon and others 2006; Bauer and others 2010; Wen and others 2012), which is the most widely investigated NLRP family member and responds to a large range of microbial and hostderived stimuli (Kersse and others 2011). By contrast to the relatively consistent role for inflammasomes in driving inflammatory diseases, the role of inflammasomes in cancer appears more complex and is most likely influenced by the cell type and tissue-specific contexts, as well as differences in the activities of the IL-1b and IL-18 effector cytokines. For instance, studies involving mice deficient in the ASC inflammasome adaptor, or specific NLRs (NLRP3, NLRP6, NLRC4) have revealed a protective role for these NLRs against inflammation-associated intestinal tumorigenesis irrespective of the targeted cell type (epithelial/tumor versus immune/inflammatory), and point to a bias towards IL-18 in maintaining homeostasis and protecting against inflammation-associated carcinogenesis in the intestine (Allen and others 2010; Hu and others 2010; Chen and others 2011; Zaki and others 2011). By contrast to the overt protective role assigned to inflammasomes in intestinal tumorigenesis, the use of genetically-modified mice deficient in specific inflammasome components has revealed opposing roles for inflammasome activation in diverse tumor models. Such divergent roles for specific inflammasomes is best illustrated with NLRP3, whereby depending on the immune cell subset in which it is activated during tumorigenesis, it can promote (dendritic cells, natural killer cell) or suppress (myeloidderived suppressor cells) antitumor immune responses (Ghiringhelli and others 2009; Chow and others 2012; Bruchard and others 2013). Similarly, exposure of ASC-deficient mice to experimentally induced inflammation-driven skin carcinogenesis indicates a differential oncogenic role for ASC when expressed in myeloid cells versus a tumor-suppressive role when expressed in keratinocytes (Chow and others 2012; Drexler and others 2012).

JAK/STAT-Mediated Transcriptional Regulation of TLRs In many of the inflammation-associated disease states, as previously discussed in this study, the often concurrent upregulated expression of cytokines and PRRs, along with their respective signaling pathways (primarily JAK/STAT

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and NF-kB, respectively) suggests that both cytokines and PRRs may synergize to drive disease outcomes. In this respect, the notion that cytokines (through the JAK/STAT pathway) can modulate the biological response of PRRs has recently been demonstrated in vivo using mouse models characterized by deregulated expression of members of the IL-6 cytokine family and the consequent hyperactivation of STAT3. As its name implies, IL-6 is the archetypal member of the IL-6 family of cytokines, which includes other welldocumented family members such as IL-11, IL-27, IL-31, leukemia inhibitory factor, and Oncostatin-M among others, and demonstrates vast functional pleiotropism, including potent oncogenic and proinflammatory properties (Silver and Hunter 2010; Mihara and others 2012; Mansell and Jenkins 2013). In a study, our laboratory utilized the gp130F/F mouse model engineered to carry a knock-in mutation, which disrupts the SOCS3 binding site in the cytoplasmic domain of gp130 itself, the essential signal-transducing receptor b subunit for IL-6 family cytokines ( Jenkins and others 2005), thus leading to impaired negative regulation of gp130/JAK/STAT signaling. Specifically, we demonstrated that lipopolysaccharide (LPS)/TLR4-induced lethality was exacerbated in gp130F/F mice and characterized by increased IL-6 production and STAT3 activation, which in turn augmented TLR4 signaling in nonimmune cells (Greenhill and others 2011a, 2011b). In support of the ability of IL-6 to modulate TLR4driven inflammatory responses in vivo, transgenic overexpression of IL-6 (and associated STAT3 hyperactivation) in mice also leads to LPS hypersensitivity characterized by augmented production of numerous proinflammatory mediators and impaired survival rates (Strippoli and others 2012). Although precise mechanism(s) by which IL-6 influenced TLR4-induced inflammatory responses in these mouse models remains to be formally elucidated, the related IL-27 cytokine has been shown to enhance LPS-induced proinflammatory cytokine production in human monocytes by upregulating TLR4 expression in a STAT3-dependent manner, suggesting that the IL-6/STAT3 signaling axis may similarly regulate the transcriptional activity of the TLR4 gene (Guzzo and others 2012). Whereas the above studies largely focus on TLR4-mediated proinflammatory responses occurring during bacterial infections (mimicked by the use of LPS), the broader implications for the regulation of TLR4 by STAT3 are demonstrated by a report on skeletal muscle biopsies from patients with impaired glucose tolerance, in which TLR4 gene expression was upregulated by IL-6-induced STAT3 activation (Kim and others 2013b). Moreover, IL-6/STAT3-mediated upregulation of TLR4 is linked to the ensuing inflammation and underlying insulin resistance common in such patients, and as such it is tempting to speculate that STAT3 may provide a molecular bridge linking IL-6 (and potentially other family members) and TLR4 inflammatory responses with metabolic syndrome and its associated increased risk of cardiovascular disease and diabetes (Fessler and others 2009; Kim and others 2009; White and Stephens 2011). The ability of IL-6 family cytokines, through the JAK/ STAT pathway, to regulate the gene expression of TLR family members is not restricted to TLR4, as exemplified by our recent observation that the IL-11/STAT3 signaling axis upregulated the gene expression of TLR2 in the gastric epithelium of gp130F/F mice, which in turn promoted the proliferation and survival of gastric epithelial (tumor) cells

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during gastric tumorigenesis (Tye and others 2012). The clinical significance of such a finding is underscored by the correlation between augmented STAT3 activation and TLR2 expression in human gastric cancer, which serves as a prognostic indicator for low patient survival (McCormack and others 2012; Tye and others 2012; Tye and Jenkins 2013). Notably, the transcriptional regulation of the TLR2 gene by STAT3 in the gastric epithelium was specific, since the gastric epithelial gene expression of other TLR family members, for instance TLR4, was not affected in gp130F/F mice. Further, chromatin immunoprecipitation experiments in human gastric cancer cell lines confirmed the IL-11induced STAT3 (tyrosine phosphorylated) binding to a single site in the TLR2 promoter, which matched the 5¢TTCCCGGA-3¢ consensus DNA binding motif for STAT3 (Kidder and others 2008; Tye and others 2012). In this respect, our bioinformatic analysis and experimental data did not reveal any STAT3 binding motif in the human/mouse TLR4 gene promoters (unpublished observations), which appears at face value to contradict reports that STAT3 can modulate the gene expression of TLR4 (Guzzo and others 2012; Kim and others 2013b). A possible explanation for this discrepancy could be that tyrosine-phosphorylated STAT3 may not bind to the TLR4 promoter, which was not examined in the above-mentioned reports. In such a scenario, it is conceivable that STAT3 may have an indirect transcriptional effect on TLR4 promoter activity in its unphosphorylated state through the interaction with a binding partner such as the transcription factor NF-kB (Yang and others 2007), which was also shown to regulate TLR4 gene expression along with STAT3 (Guzzo and others 2012). Notably, IL-6 has also been shown to upregulate TLR2 expression in human bronchial epithelial cells through JAK2/STAT3 signaling (Melkamu and others 2013), suggesting that STAT3-mediated regulation of TLR2 is not just restricted to the gastric epithelium and therefore may have broader consequences for pathophysiological responses in multiple organs. Although investigations into the role of JAK/STAT signaling in promoting the gene expression of TLRs is still in its relative infancy, it will be of interest to see whether other STAT family members apart from STAT3 also possess the ability to transcriptionally activate TLR gene promoters, and thus modulate TLR-induced molecular and cellular processes. In this regard, STAT1 activation in response to IFN-g treatment of alveolar macrophages can increase both TLR2 and TLR4 gene expression leading to augmented production of LPS-induced proinflammatory cytokines (Southworth and others 2012). Considering the robust activation of STAT1 during inflammatory responses initiated by a wide variety of TLRs (often as a downstream effector of TLR-induced IFNa, -b, or -g production), it may almost be expected that STAT1 will promote the expression of other TLRs as part of its proinflammatory arsenal, in a manner analogous to its ability to mediate Myd88 gene expression for optimal TLRinduced proinflammatory cytokine production (Serezani and others 2011).

Other PRRs as Transcriptional Targets of JAK/STAT Signaling Compared to the discovery of TLRs over 2 decades ago, the more recent identification of other PRRs such as AIM2, as well as members of the NLR family, has meant that there

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is a paucity of information concerning the gene regulation of these PRRs. Nonetheless, the possibility that cytokines can employ the JAK/STAT pathways to transcriptionally regulate genes for PRRs other than TLRs is supported by a handful of studies that have emerged over recent years examining cross talk between cytokine signaling pathways and inflammasome activation. In a study, IFN-a, -b, or -g were reported to induce AIM2 gene expression in human prostate cancer cell lines, which as expected, correlated with increased IFN-induced STAT1 activation (Ponomareva and others 2013). Although the authors did not formally demonstrate that STAT1 was directly responsible for IFNinduced AIM2 gene expression, it might be assumed to be the case since STAT1 activation is the primary signaling event that is common to both type I (a, b) and II (g) IFNs. With respect to NLR family members, the use of JAK2 inhibitors on LPS-stimulated macrophages has very recently implicated the JAK2/STAT3 pathway in promoting NLRC5 expression at the mRNA and protein levels (Li and others 2014). Although it was unclear from this study how JAK2/ STAT3 signaling was activated downstream of the LPS/ TLR4 interaction, it could be presumed from the observed concomitant LPS-induced IL-6 production that an indirect mechanism is responsible, whereby IL-6 would activate the JAK2/STAT3 signaling cascade. In contrast to the wealth of studies revealing positive regulatory roles for JAK/STAT signaling in the transcriptional induction of TLR and NLR family members (and AIM2), a study indicates that type I IFN signaling can also suppress activation of NLRP1 and NLRP3 inflammasomes by 2 alternate mechanisms, albeit independent of any direct effect of STAT1 or STAT3 on the transcriptional activity of the promoters for these NLR genes (Guarda and others 2011). Rather, type I IFN-induced activation of STAT1 blocked the processing capability of caspase-1 by an as yet unclear mechanism. Furthermore, in parallel, type I IFN/STAT1 signaling induced the production of the anti-inflammatory cytokine IL-10, which through STAT3 then inhibits the expression of pro-IL-1a and -IL-1b precursor proteins. Considering the wide variety of extrinsic stimuli of viral, bacterial, or fungal origin, which can trigger type I IFNs, it remains to be seen how broadly applicable such regulation of inflammasomes will be in infectious and inflammatory diseases characterized by aberrant production of IL-1 family cytokines.

Conclusions Over the last decade it has become widely acknowledged that PRRs are key regulators of immunity and the inflammatory response, and together with their increasing involvement in a range of autoimmune, infectious and inflammatory diseases, as well as cancers, there is a pressing global need to understand the complex molecular mechanisms that control their activation. As has been the focus of this review, one such regulatory mechanism involves the transcriptional induction of genes encoding PRRs by cytokine-induced JAK/ STAT signaling, which, therefore, also augments the ensuing PRR-triggered cellular responses. The mere fact that cytokines, which are induced following activation of upstream PRRs, can also feedback through JAK/STAT signaling to modulate PRR-mediated cellular responses further highlights the complexities underpinning the intricate balance of positive and negative regulation of the immune system.

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It should also be noted that investigations into the regulation of PRRs, whether it be at the transcriptional or translational levels, or through posttranslational modifications, and their relatedness to organ homeostasis and/or disease pathogenesis, are still in their infancy, which accounts for the general paucity of information currently available on this subject. Accordingly, there are many questions that remain unanswered regarding the regulation of specific PRRs, for instance: are cytokine-activated pathways independent of JAK/STAT (eg, MAPK, PI3K/Akt) involved; do other STAT family members, apart from STAT1 and STAT3, transcriptionally regulate PRRs; and does cell type specificity influence the ability of a cytokine to regulate a particular PRR? Given the worldwide research interest into the roles of cytokines and PRRs in disease, the vast array of advanced molecular and cellular biological tools available nowadays to researchers should yield answers to these and many other related questions expeditiously. Finally, the clear evidence for cross talk between cytokines and PRRs, together with the large number of diseases in which these families of innate immune regulators and their corresponding downstream signaling pathways are commonly deregulated, are likely to have clinical implications in the future, both regarding the development of bona fide diagnostic and predictive biomarkers (for patient stratification), as well as in selective use of therapies. This latter point is especially pertinent considering the recent advancements made in the clinic with JAK inhibitors against autoimmune and inflammatory diseases (O’Shea and Plenge 2012), and suggests that the blockade of JAK/STAT pathways with such inhibitors may also suppress immune-related responses driven by PRRs. Accordingly, it will be of great importance to understand in such disease states whether any coincidental suppression of PRR responses with JAK inhibitors will have further beneficial effects by dampening disease-associated inflammation responses, or whether it would be detrimental by inadvertently suppressing PRRmediated immunity.

Acknowledgments Dr. R. Smith (MIMR-PHI) is thanked for reviewing this article. This study was supported by grants from the Association for International Cancer Research, the Cancer Council of Victoria, and the Sylvia and Charles Viertel Charitable Foundation, as well as the Operational Infrastructure Support Program by the Victorian Government of Australia.

Author Disclosure Statement There are no financial conflicts of interest to declare.

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Address correspondence to: Prof. Brendan John Jenkins Centre for Innate Immunity and Infectious Diseases MIMR-PHI Institute of Medical Research (formerly Monash Institute of Medical Research) 27-31 Wright St. Clayton Victoria 3168 Australia E-mail: [email protected] Received 15 May 2014/Accepted 12 June 2014

STAT signaling, and the implications for disease pathogenesis.

Cytokines are well known for their pleiotropism, affecting a large number of cellular responses, including proliferation, survival, functional maturat...
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