T helper 17 (TH17) is a novel subset of T helper cells that has recently been identified in the hepatocellular carcinoma (HCC) tumor environment. Its presence seems to be linked with HCC progression, possibly via facilitating angiogenesis. The origin of tumor-associated TH17 may be related to the gut, in which the differentiation of T cells, especially TH17 cells, is affected by microbiota. As TH17 may appear to be a new therapeutic target against tumor-promoting inflammation, strategies such as using probiotics to polarize the response away from TH17 may be beneficial to slow down tumor progression. This paper will attempt to discuss the potential linkage between HCC progression, TH17, and gut microbiota and the possible therapeutic implications of probiotics to modulate TH17-mediated response for tumor growth.
1. Introduction
Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and is characterized by poor prognosis [1]. Tumor progression has now been recognized as the product of crosstalk between cancer cells and stromal cells, including immune cells [2]. Immune status appears to be different in distinct sites of the tumor [3]. The intratumoral region is generally in an immunosuppressive state [3] it contains dysfunctional antigen presenting cells, altered proportion of effector to regulatory T cells, and an abundance of immunosuppressive molecules, forming a network to facilitate immune evasion [4]. In contrast, the peritumoral stroma is highly infiltrated with various immune cells that actively secrete high concentrations of inflammatory cytokines for enhancing cell growth, angiogenesis, and tissue remodelling [3]. Hence, inflammatory response has been suggested to be rerouted in a tumor-promoting direction. Recently, TH17 cells have come into research focus as they have been identified in a number of tumors including HCC. TH17, and its effector molecules interleukin-17 (IL-17) and IL-22, are potent inducers of tissue inflammation and have been associated with a number of inflammatory and autoimmune diseases [5, 6]. The role of TH17 is paradoxical, but now there is accumulating evidence to illustrate that TH17 has tumor promoting effects in some cancer such as HCC. Though the origin of tumor associated TH17 cells is not completely understood, it is possible that they are recruited from the periphery [7]. The gut is the natural site of TH17 generation and it has recently been found that microbes can affect T cell differentiation via regulating dendritic cells. Thus, there appears to be a complex relationship between HCC progression, TH17 and gut microbiota. In this paper, the potential linkage between these three factors and the possible therapeutic implications of probiotics to modulate TH17-mediated response for tumor growth will be discussed.
2. Relationship between IL-17-Producing Cells and HCC Progression
IL-17 is a proinflammatory cytokine produced primarily by a novel subset of CD4+T cells known as TH17. In addition to TH cells, this cytokine can also be secreted by CD8+T cells, γδ T cells, lymphoid tissue inducer (LTi) cells, natural killer (NK) cells, and granulocytes [8]. At present, the IL-17-producing cells in human HCC tissue are found to be from the adaptive arm of immunity. A majority of them were identified to be TH17, though a substantial amount of IL-17+CD8+T cells can also be found in tumor. In addition to IL-17, these cells may also secrete IL-22, which was recently found to be related to HCC as well, though its production is not limited to T cells [9–11].
The role of TH17 cells in tumor immunity has been controversial. However, several lines of evidence suggested that these cells play a protumor role in HCC. Increased levels of TH17 cells were found in tumor tissue [12] and in peripheral blood [13] of HCC patients, and their level is correlated with unfavorable disease outcomes [7, 12, 14]. Similar results have also been observed in animal models, whereby limiting tumor TH17 expansion reduced the growth of transplanted liver tumor in rodents [7].
Many functions of IL-17 in the tumor microenvironment contribute to tumor progression. Apart from a minor direct effect on the proliferation and survival of cancer cells in other systems [15], and the recent report on its role in immune evasion via mediating B7-H1 expression on monocytes to suppress cytotoxic T cell activity [13], the major protumor role of IL-17 in inflammation-associated cancer relies on fostering angiogenesis. Indeed, both animal and human HCC tissues revealed that their levels were positively correlated with microvessel density and that these cells were observed to be enriched predominately at the invading edge of tumor tissue, the site where angiogenesis is most active [12]. The proangiogenic effect of IL-17 could be linked to its interaction with various stromal cells such as fibroblasts, keratinocytes, epithelial and endothelial cells. IL-17 leads to the induction of IL-6, IL-8, prostaglandin (PG) E1, and PGE2 as well as enhancement of intercellular adhesion molecule-1 expression [16–19]. IL-17 also participates in mobilization and recruitment of neutrophils [20] as well as inducing the secretion of tumor necrosis factor-α (TNF-α) and IL-1β from macrophages [21]. The collective effect results in the release of an array of proangiogenic cytokines including vascular endothelial growth factor (VEGF), hepatocyte growth factor and keratinocyte-derived chemokine in the tumor microenvironment [22]. Thus, IL-17 inevitably shifts the local biologic balance toward a predominance of angiogenic factors to enhance the net angiogenic activity. Owing to the highly vascular nature of HCC, IL-17+ cells may play an important role in progression of this type of tumor.
In addition to IL-17, it is conceivable that TH17 cell promote HCC via IL-22 production as well. Though there were only a few reports on the role of IL-22 in tumors, the literature generally supported the tumor-promoting function of this cytokine. A recent report from Jiang et al. [10] illustrated the excessive expression of IL-22 in HCC microenvironment and its expression appears to be related to advanced cancer stages. Conversely, knockdown of IL-22 inhibited tumor progression in a xenograft model of other systems [23]. The tumor promoting effect of IL-22 is believed to be mediated by signal transducer and activator of transcription factor 3 (STAT3), an oncogenic transcription factor constitutively activated in various malignancies [24]. In human liver cancer cells, IL-22-induced STAT3 activation promoted at least three hallmarks of cancer (proliferation, survival and angiogenesis) via the upregulation of a variety of mitogenic (cyclin D1, c-myc, and Rb2), anti-apoptotic (Bcl-2 and Bcl-xL) [10, 25], and angiogenic (VEGF) [10] genes. IL-22 was also shown to have immunosuppressive functions in other cancer [26], though it was not well studied in HCC so far.
Since TH17 cells may act to promote HCC pathogenesis via production of IL-17 and IL-22; if we can modulate the TH17 status in the body, it may be possible to affect tumor progression. In order to do this, we first need to know the origin of tumor-associated TH17 cells.
3. Potential Source of Tumor-Associated TH-17 Cells
Tumor-associated TH17 cells may either be induced in the tumor microenvironment and/or recruited from distal sites.
In situ induction occurs when memory T cells enter a site of inflammation and encounter activated antigen-presenting cells (APC). Though it has been suggested that tumor-associated-macrophage (TAM) may be responsible for TH17 development because it outnumbers dendritic cells (DC), the most efficient APC, in the tumor environment, it appears that tumor-activated monocytes, but not TAM may play a dominant role in TH17 expansion in the context of HCC. Kuang et al. [7] have shown that monocytes could be activated by liver cancer cells to secrete several cytokines including IL-1β, IL-6, IL-23, thereby creating a proinflammatory cytokine milieu that facilitates the in vitro expansion of memory T cells. While studies in other systems have also demonstrated a critical role of transforming growth factor-β (TGF-β) in the development of human TH17 [27, 28], Kuang and his colleagues failed to find a correlation between the expression of this cytokine and TH17 cell density, implicating that the role of TGF-β in expanding TH17 cells remains to be elucidated in the local tumor environment of HCC. It is interesting to note that TH17 cells generated in this cytokine milieu can also produce interferon-γ (IFN-γ), which is the signature cytokine of TH1 cells. Thus there are two subsets of TH cells in HCC tissue: TH17 (IL-17+ IFN-γ−) and TH17/TH1 (IL-17+ IFN-γ+). How TH17/TH1 cells are generated is not yet known but it is possible that the tumor environment induces this phenotype, as most of the circulating TH17 cells in HCC patients did not express IFN-γ. IFN-γ from TH17/TH1 is suggested to promote further recruitment of TH17 by inducing CCL20 expression. CCL20 is the ligand for CCR6, which is a receptor highly expressed in the majority of TH17 cells [7, 29]. A positive feedback cycle may be formed in the tissue environment: CCR6+ memory TH17 is homed to tumor site by high levels of CCL20 [12]. It is then converted to TH17/TH1, which releases IFN-γ to recruit more CCR6+ memory TH17 from the periphery pool by the virtue of CCL20.
So where would the potential source for TH17 cells be? TH17 cells are preferentially enriched in the intestinal lamina propria of ileum and colon, while very low frequencies of these cells are present in extraintestinal sites at a steady state [30–32]. Polarization of naïve T cells is influenced by diverse signals produced by APC to develop into distinct effector (TH1, TH2, and TH17) or regulatory (Treg) lineages (Figure 1). It is now recognized that IL-12 and IFN-γ are needed for TH1 induction, whereas TH2 differentiation requires IL-4, and Treg requires TGF-β [33]. For TH17 differentiation, in vitro studies show that it requires multiple cytokines including TGF-β, IL-6, IL-21, IL-23, and IL-1β [8, 34–38]. TGF-β induces the expression of the retinoic acid-related orphan receptor RORγt, which is the master transcription factor for the TH17 effector cell lineage [30]. However, TGF-β alone is unable to initiate TH17 differentiation, as this cytokine also induces forkhead box p3 (Foxp3), which is a transcription factor essential for the differentiation of Tregs. Foxp3 would bind to RORγt and thereby inhibit RORγt-directed IL-17 expression [39], and hence excess TGF-β can inhibit expression and function of RORγt. In the presence of proinflammatory cytokines such as IL-6 or IL-21, this inhibitory effect would be relived, as these cytokines activate STAT3 and suppress the expression of Foxp3. As a result, the relative levels of RORγt are increased and TH17 cell differentiation is promoted. Once TH17 cells have developed, IL-23 is needed for stabilization and further expansion of these cells, as illustrated by studies with IL-23 receptor-deficient mice [40].
Polarization of T helper (TH) cell subsets. Naïve CD4+ T cells develop into different lineages (TH1, TH2, TH17, and Treg) in response to cytokine cues produced from antigen presenting cells. IL: interleukin; interferon γ: IFN-γ; FOXP3: forkhead box P3; RORγt: retinoic acid-related orphan receptor γt; STAT: signal transducer and activator of transcription; β: TGF-β transforming growth factor.
4. The Role of Microbiota in TH17 Immunity
Since IL-23 is required for developing productive and sustained TH17 responses, the signals that induce the production of this cytokine might be critical in determining whether TH17 cells dominated T cell response. Given that IL-23 is mainly produced by innate immune cells, including DCs and macrophages in the gut, it is not surprising to find that signals from commensal bacteria is necessary for induction of TH17 cells. This notion is supported by observation where TH17 cells were absent in the sterile gut of newborn mice but steadily increased from birth to post-weaning as symbiotic bacteria gradually colonized the intestine [41]. More importantly, it is not general bacterial colonization but the composition of bacteria that influence the makeup of the lamina propria T lymphocyte subsets. Ivanov et al. [32] has found that mice purchased from different vendors had shown marked differences in the number of TH17 cells in the gut. By sequencing microbiota of these animals, it was found that TH17 cell responses appear to be induced by specific classes of bacteria known as segmented filamentous bacteria (SFB), a Gram-positive bacteria belonging to the Firmicutes phylum and most closely related to the Clostridium genus [42]. Prominent TH17 responses may also be seen upon infection of pathogenic Mycobacterium [43], Klebsiella [44], and Citrobacter [36] or upon colonization with a complex microbial community [45]. Since multiple chronic liver diseases including HCC are often associated with intestinal dysbiosis and reduced species diversity [46–48], it seems that gut-derived microbial signals and intestinal immune network may be a factor to potentially reprogram systemic immune response towards a tumor-promoting direction.
The mechanisms of how intestinal bacteria prime DC for TH17 development is not yet fully understood, but it is likely to involve several microbial-derived molecules such as the toll-like receptor (TLR) ligands, adenosine 5′-triphosphate (ATP), and serum amyloid A (SAA) that result in IL-23 production. TLRs are a class of pattern-recognition receptors (PRRs) that play a key role in the innate immune system for recognizing various microbes and/or its products, collectively known as pathogen-associated molecular patterns (PAMPs) [49]. The nature of cytokines secreted by DC is dependent on PAMPs that DC encountered in the peripheral tissues during its immature phase. While stimulation of TLR4 by LPS gives both IL-23 and IL-12, stimulation of TLR2 by peptidoglycan generally induces large amounts of IL-23 from DC, though the quantity may vary depending on the structure of peptidoglycan [50]. TLR9 and TLR5 signaling may also be necessary, as illustrated by in vivo [51] and in vitro [52] studies, respectively. Apart from PAMPs, the binding of extracellular ATP could also elicit the release of IL-23 in addition to other IL-17 inducing proinflammatory cytokines such as IL-6 and IL-1β from DC [31, 53, 54] as a result of activating the membrane ion channel and G protein receptors such as ionotropic and metabotropic purinergic receptors [55, 56]. The importance of the ATP signaling pathway was demonstrated in vitro, whereby the differentiation program of TH17 became severely inhibited upon addition of ATP degrading enzyme apyrase [31]. Commensal bacteria have been shown to generate copious amount of extracellular ATP [57] and thereby important in IL-23 production. Transient production of IL-23 by lamina propria DCs can also be induce by SAA, an acute phase protein found to be upregulated in the ileum by TH17 inducing bacteria. However, the signaling pathways induced by SAA are currently unknown [58]. Collectively, these findings illustrate that microbiota played an important role in sustaining TH17 responses via IL-23 induction, which may involve signaling mediated by the TLR ligand, ATP, and SAA. This mechanism establishes a TH17 cell-inducing cytokine environment (Figure 2).
A simplified diagram showing the possible mechanisms of intestinal bacteria in influencing the polarization of TH17 cells in the lamina propria. Activation of dendritic cells by intestinal microbes results in secretion of proinflammatory cytokines such as IL-12, L-23, IL-27. TH17-inducing bacteria may promote TH17 immunity via IL-23 induction, which may involve signaling mediated by the TLR ligands (a), extracellular ATP (b), and SAA (c). Meanwhile, some probiotic strains may skew immunity away from TH17 via IL-12 and IL-27 induction as a result of activating TLR and dectin receptors (a′). These cytokines can inhibit TH17 development while facilitate TH1 differentiation. Probiotic may also work by controlling the growth and colonization of TH17-inducing bacteria (d). IL: interleukin; P2X: ionotropic receptors; P2Y: metabotropic receptors; PAMPs: pathogen-associated molecular patterns; SAA: serum amyloid A; TLR: toll-like receptor.
5. Modulation of Extraintestinal TH17 Response by Commensal Bacteria
Notably, the influence of commensal bacteria on the balance of T cell subsets is not only confined to the gut, but can also be extended to extraintestinal sites. This notion may be supported by several studies of autoimmune disease whose development is TH17-dependent. It was found that introduction of SFBs into the sterile gut of healthy mice was able to induce arthritis and encephalomyelitis [59, 60]. The aggravation of disease appeared to be the consequence of an increase in the number of TH17 cells that traffic out of the gut to the extraintestinal site, as Lee et al. [59] has revealed an increase in TH17 cell responses in spinal cords of SFB monocolonized mice in a model of encephalomyelitis. These findings may have significant implications for regulating systemic pathogenic TH17 by modulating the composition of intestinal bacteria, and probiotics have been suggested to exhibit this potential.
6. Potential Immunomodulatory Capacity of Probiotics
Probiotics are live microorganisms that confer health benefit to host when administered in adequate amounts [61]. The established probiotics are generally Lactobacillus and Bifidobacterium species, though Lactococcus, Enterococcus, and Streptococcus species, as well as some nonpathogenic strains of Escherichia coli that can also be found [62]. Administration of Lactobacillus and Bifidobacterium species orally has been shown to protect against the development of various TH17-mediated diseases [63–72], possibly via reprogramming TH cell response or by controlling growth of TH17-inducing bacteria. Due to strain or species-specific molecular characteristics of probiotic bacteria, the immunomodulatory effect exhibited may depend strongly on the choice of the probiotic strain.
Probiotic may prime DC for the development of other TH subsets. For example, activation of TLR or dectin receptors would trigger DC to produce IL-12p70, IL-23, or IL-27, which are important in skewing TH1 or TH17 immunity. While IL-23 sustains TH17 response, IL-12 and IL-27 drive TH1 differentiation by activating STAT1 and inducing the expression of T box transcription factor (T-bet), the key transcriptional regulator of TH1 cells [5]. IL-27 and IFN-γ derived from TH1 cells could downregulate RORγt in a STAT1-dependent manner and thereby dampen development of TH17 cells, whereas IL-17 from TH17 did not similarly suppress TH1 polarization [73]. IL-12 and IFN-γ would further increase T-bet expression in DC to drive TH1 differentiation [74]. Hence, probiotic strain that favors IL-12 and IL-27 is likely to skew immune response away from TH17 to TH1 (Figure 2). Several strains of Lactobacillus (e.g., L. acidophilus [75], L. gasseri [72], and L. rhamnosus [76]) and Bifidobacterium (e.g., B. lactis, B. breve and B. bifidum [77, 78]) may possess this capacity. TH1 cytokines such as IL-12 and IFN-γ are known to have potent antitumor immunity as they could activate cytotoxic T cells and NK cells to kill cancer cells. Deficiency of T-bet in DC leads to exaggerated TNF production and contributes to creating a chronic inflammatory state that modulates the composition of microbiota and eventually leads to cancer development [79, 80]. Therefore, promoting TH1 differentiation by probiotics may possibly shift pathogenic TH17 inflammation to antitumor TH1 response.
Apart from regulating T cell polarization, probiotic may also work by controlling the growth of TH17-inducing bacteria such as SFB. Indeed, administration of L. plantarum almost completely depleted the SFB present in the ileum [81]. Although the underlying mechanisms have not yet been investigated in that study, it is tempting to speculate that probiotic may adversely affect SFB colonization and survival by competing for the use of nutrients and other external metabolites. In accordance to the highly reduced genome, SFBs lack a number of enzymes for basic metabolic pathways that are important for growth and survival, including biosynthesis of amino acids and cofactors. To compensate for these auxotrophies, SFB expressed a large array of transporters to acquire sugars, many cofactors, and nearly all amino acids and from the environment [82]. Lactobacillus may serve as a competitor for the uptake of amino acids, as genome sequencing has revealed a considerable degree of auxotrophy for amino acids in these bacteria. There may also be competition for the internalization and utilization of sugar, as Bifidobacterium and Lactobacillus situated in intestinal niche generally encode a large capacity for carbohydrate transport and metabolism [83–87]. Bifidobacterium have excellent carbohydrate sequestering capacity as they use a “docking station” to capture carbohydrate to their cell surface to avoid losing the molecules to nearby competitors [88–90]. In addition to amino acids and sugar utilization, the metabolism of some Lactobacillus strains, including L. paracasei or L. rhamnosus, could also lead to major changes to levels of a number of metabolites, including methylamines and short-chain fatty acids [91, 92]. Together, the metabolisms and activities of these commensal bacteria may create an unfavorable environment for functionality of SFB in vivo. Other strategies for probiotics to limit pathogenic bacterial growth may include production of antimicrobial compounds, competition for specific adhesion sites and maintaining intestinal tight junction [81], but these mechanisms will not be discussed here in detail. All these mechanisms may directly or indirectly change the composition and diversity of the intestinal microbiota and modulate DC-mediated immunity as mentioned above.
All in all, commensal bacteria of Bifidobacterium and Lactobacillus genera are associated with balancing TH response locally and systemically. Hence, establishing a balanced microbiota in favor of these protective probiotic bacteria may be a good strategy to maintain immune homeostasis via DC priming and that may possibly modulate tumorigenic proinflammatory milieu at sites distant from the gut.
7. Conclusion
In conclusion, TH17 has recently been found in HCC tumor and its presence has been linked to disease progression, possibly involving angiogenesis. Gut TH17 seems to be a potential source for tumor-associated TH17, where it could be homed to the tumor environment via CCR6/CCL20 axis and expand locally. Commensal bacteria are necessary for development of gut TH17 by IL-23 induction in DC. Probiotics may affect cytokine profile of DC by activating different PRRs and controlling the growth of some potent TH17 inducers such as SFB. This potential linkage of HCC environment, TH17 cells, and microbiota may implicate for novel targets for therapeutic intervention in HCC progression.
El-SeragH. B.RudolphK. L.Hepatocellular carcinoma: epidemiology and molecular carcinogenesis20071327255725762-s2.0-3425002020110.1053/j.gastro.2007.04.061MuellerM. M.FusenigN. E.Friends or foes—bipolar effects of the tumour stroma in cancer20044118398492-s2.0-814422895210.1038/nrc1477WuY.ZhengL.Dynamic education of macrophages in different areas of human tumors201253195201AhmedF.SteeleJ. C.HerbertJ. M. J.StevenN. M.BicknellR.Tumor stroma as a target in cancer2008864474532-s2.0-5134909293710.2174/156800908785699360KornT.BettelliE.OukkaM.KuchrooV. K.IL-17 and Th17 cells200927485517ZenewiczL. A.FlavellR. A.Recent advances in IL-22 biology20112331591632-s2.0-7995258436810.1093/intimm/dxr001KuangD. M.PengC.ZhaoQ.WuY.ChenM. S.ZhengL.Activated monocytes in peritumoral stroma of hepatocellular carcinoma promote expansion of memory T helper 17 cells20105111541642-s2.0-7344911192510.1002/hep.23291WeaverC. T.HattonR. D.ManganP. R.HarringtonL. E.IL-17 family cytokines and the expanding diversity of effector T cell lineages2007258218522-s2.0-3384720696910.1146/annurev.immunol.25.022106.141557KuangD. M.PengC.ZhaoQ.WuY.ZhuL. Y.WangJ.YinX. Y.LiL.ZhengL.Tumor-activated monocytes promote expansion of IL-17-producing CD8+ T cells in hepatocellular carcinoma patients20101853154415492-s2.0-7795639709810.4049/jimmunol.0904094JiangR.TanZ.DengL.ChenY.XiaY.GaoY.WangX.SunB.Interleukin-22 promotes human hepatocellular carcinoma by activation of STAT320115439009092-s2.0-7996111776910.1002/hep.24486ZenewiczL. A.FlavellR. A.IL-22 and inflammation: Leukin' through a glass onion20083812326532682-s2.0-5974909560310.1002/eji.200838655ZhangJ. P.YanJ.XuJ.PangX. H.ChenM. S.LiL.WuC.LiS. P.ZhengL.Increased intratumoral IL-17-producing cells correlate with poor survival in hepatocellular carcinoma patients20095059809892-s2.0-6454910846210.1016/j.jhep.2008.12.033ZhaoF.HoechstB.GamrekelashviliJ.Human CCR4+ CCR6+ Th17 cells suppress autologous CD8+ T cell responses20121881260556062WangW. W.WangZ. M.LiuY. Y.QinY. H.ShenQ.Increased level of Th17 cells in peripheral blood correlates with the development of hepatocellular carcinoma20103210757761ZhangB.RongG.WeiH.The prevalence of Th17 cells in patients with gastric cancer20083743533537FossiezF.DjossouO.ChomaratP.Flores-RomoL.Ait-YahiaS.MaatC.PinJ. J.GarroneP.GarciaE.SaelandS.BlanchardD.GaillardC.Das MahapatraB.RouvierE.GolsteinP.BanchereauJ.LebecqueS.T cell interleukin-17 induces stromal cells to produce proinflammatory and hematopoietic cytokines19961836259326032-s2.0-1584440215510.1084/jem.183.6.2593YaoZ.PainterS. L.FanslowW. C.UlrichD.MacduffB. M.SpriggsM. K.ArmitageR. J.Human IL-17: a novel cytokine derived from T cells199515512548354862-s2.0-0028858556NumasakiM.FukushiJ. I.OnoM.NarulaS. K.ZavodnyP. J.KudoT.RobbinsP. D.TaharaH.LotzeM. T.Interleukin-17 promotes angiogenesis and tumor growth20031017262026272-s2.0-003784991510.1182/blood-2002-05-1461NumasakiM.LotzeM. T.SasakiH.Interleukin-17 augments tumor necrosis factor-α-induced elaboration of proangiogenic factors from fibroblasts200493139432-s2.0-234246871910.1016/j.imlet.2004.01.014NiessJ. H.LeithäuserF.AdlerG.ReimannJ.Commensal gut flora drives the expansion of proinflammatory CD4 T cells in the colonic lamina propria under normal and inflammatory conditions200818015595682-s2.0-40449091849JovanovicD. V.Di BattistaJ. A.Martel-PelletierJ.JolicoeurF. C.HeY.ZhangM.MineauF.PelletierJ. P.IL-17 stimulates the production and expression of proinflammatory cytokines, IL-β and TNF-α, by human macrophages19981607351335212-s2.0-0032055597NumasakiM.WatanabeM.SuzukiT.TakahashiH.NakamuraA.McAllisterF.HishinumaT.GotoJ.LotzeM. T.KollsJ.SasakiH.IL-17 enhances the net angiogenic activity and in vivo growth of human non-small cell lung cancer in SCID mice through promoting CXCR-2-dependent angiogenesis20051759617761892-s2.0-27144449330ZhangW.ChenY.WeiH.ZhengC.SunR.ZhangJ.TianZ.Antiapoptotic activity of autocrine interleukin-22 and therapeutic effects of interleukin-22-small interfering RNA on human lung cancer xenografts20081420643264392-s2.0-5814918323510.1158/1078-0432.CCR-07-4401YuH.JoveR.The stats of cancer—new molecular targets come of age200442971052-s2.0-1042302005RadaevaS.SunR.PanH. N.HongF.GaoB.Interleukin 22 (IL-22) plays a protective role in T cell-mediated murine hepatitis: IL-22 is a survival factor for hepatocytes via STAT3 activation2004395133213422-s2.0-234246246010.1002/hep.20184CurdL.FavorsS.GreggR.Pro-tumour activity of interleukin-22 in HPAFII human pancreatic cancer cells20121682192199VolpeE.ServantN.ZollingerR.BogiatziS. I.HupéP.BarillotE.SoumelisV.A critical function for transforming growth factor-β, interleukin 23 and proinflammatory cytokines in driving and modulating human TH-17 responses2008966506572-s2.0-4404910272410.1038/ni.1613ManelN.UnutmazD.LittmanD. R.The differentiation of human TH-17 cells requires transforming growth factor-β and induction of the nuclear receptor RORγt2008966416492-s2.0-4404910456410.1038/ni.1610NistalaK.AdamsS.CambrookH.UrsuS.OlivitoB.De JagerW.EvansJ. G.CimazR.Bajaj-ElliottM.WedderburnL. R.Th17 plasticity in human autoimmune arthritis is driven by the inflammatory environment20101073314751147562-s2.0-7795703299410.1073/pnas.1003852107IvanovI. I.McKenzieB. S.ZhouL.TadokoroC. E.LepelleyA.LafailleJ. J.CuaD. J.LittmanD. R.The orphan nuclear receptor RORγt directs the differentiation program of proinflammatory IL-17+ T helper cells20061266112111332-s2.0-3374858842310.1016/j.cell.2006.07.035AtarashiK.NishimuraJ.ShimaT.UmesakiY.YamamotoM.OnoueM.YagitaH.IshiiN.EvansR.HondaK.TakedaK.ATP drives lamina propria TH17 cell differentiation200845572148088122-s2.0-5364910067510.1038/nature07240IvanovI. I.FrutosR. D. L.ManelN.YoshinagaK.RifkinD. B.SartorR. B.FinlayB. B.LittmanD. R.Specific microbiota direct the differentiation of IL-17-producing T-helper cells in the mucosa of the small intestine2008443373492-s2.0-5334917307010.1016/j.chom.2008.09.009DeenickE. K.TangyeS. G.Autoimmunity: IL-21: a new player in Th17-cell differentiation20078575035052-s2.0-3494889053510.1038/sj.icb.7100114BettelliE.KornT.OukkaM.KuchrooV. K.Induction and effector functions of TH17 cells20084537198105110572-s2.0-4574910172710.1038/nature07036VeldhoenM.HockingR. J.AtkinsC. J.LocksleyR. M.StockingerB.TGFβ in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells20062421791892-s2.0-3224444256210.1016/j.immuni.2006.01.001ManganP. R.HarringtonL. E.O'QuinnD. B.HelmsW. S.BullardD. C.ElsonC. O.HattonR. D.WahlS. M.SchoebT. R.WeaverC. T.Transforming growth factor-β induces development of the T H17 lineage200644170902312342-s2.0-3364656095010.1038/nature04754BettelliE.CarrierY.GaoW.KornT.StromT. B.OukkaM.WeinerH. L.KuchrooV. K.Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells200644170902352382-s2.0-3364657746610.1038/nature04753ChungY.ChangS. H.MartinezG. J.YangX. O.NurievaR.KangH. S.MaL.WatowichS. S.JettenA. M.TianQ.DongC.Critical regulation of early Th17 cell differentiation by interleukin-1 signaling20093045765872-s2.0-6404908979810.1016/j.immuni.2009.02.007ZhouL.LopesJ. E.ChongM. M. W.IvanovI. I.MinR.VictoraG. D.ShenY.DuJ.RubtsovY. P.RudenskyA. Y.ZieglerS. F.LittmanD. R.TGF-beta-induced Foxp3 inhibits TH17 cell differentiation by antagonizing RORgammat function200845371922362402-s2.0-4344913530510.1038/nature06878MurphyK. M.ReinerS. L.The lineage decisions of helper T cells20022129339442-s2.0-003688506710.1038/nri954PalmerC.BikE. M.DiGiulioD. B.RelmanD. A.BrownP. O.Development of the human infant intestinal microbiota200757, article e1772-s2.0-3454762440410.1371/journal.pbio.0050177SnelJ.HeinenP. P.BlokH. J.CarmanR. J.DuncanA. J.AllenP. C.CollinsM. D.Comparison of 16S rRNA sequences of segmented filamentous bacteria isolated from mice, rats, and chickens and proposal of 'Candidatus Arthromitus'19954547807822-s2.0-0028800208CruzA.KhaderS. A.TorradoE.FragaA.PearlJ. E.PedrosaJ.CooperA. M.CastroA. G.Cutting edge: IFN-γ regulates the induction and expansion of IL-17-producing CD4 T cells during mycobacterial infection20061773141614202-s2.0-33746215298HappelK. I.ZhengM.YoungE.QuintonL. J.LockhartE.RamsayA. J.ShellitoJ. E.SchurrJ. R.BagbyG. J.NelsonS.KollsJ. K.Cutting edge: roles of toll-like receptor 4 and IL-23 in IL-17 expression in response to Klebsiella pneumoniae infection20031709443244362-s2.0-0242584872NiessJ. H.LeithäuserF.AdlerG.ReimannJ.Commensal gut flora drives the expansion of proinflammatory CD4 T cells in the colonic lamina propria under normal and inflammatory conditions200818015595682-s2.0-40449091849DapitoD. H.MencinA.GwakG.Promotion of hepatocellular carcinoma by the intestinal microbiota and TLR42012214504516FoxJ. G.FengY.TheveE. J.RaczynskiA. R.FialaJ. L. A.DoernteA. L.WilliamsM.McFalineJ. L.EssigmannJ. M.SchauerD. B.TannenbaumS. R.DedonP. C.WeinmanS. A.LemonS. M.FryR. C.RogersA. B.Gut microbes define liver cancer risk in mice exposed to chemical and viral transgenic hepatocarcinogens201059188972-s2.0-7344914320710.1136/gut.2009.183749CesaroC.TisoA.Del PreteA.CarielloR.TuccilloC.CotticelliG.Del Vecchio BlancoC.LoguercioC.Gut microbiota and probiotics in chronic liver diseases20114364314382-s2.0-7995592343110.1016/j.dld.2010.10.015SmitsH. H.EngeringA.Van Der KleijD.De JongE. C.SchipperK.Van CapelT. M. M.ZaatB. A. J.YazdanbakhshM.WierengaE. A.Van KooykY.KapsenbergM. L.Selective probiotic bacteria induce IL-10-producing regulatory T cells in vitro by modulating dendritic cell function through dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin20051156126012672-s2.0-2044450373710.1016/j.jaci.2005.03.036ReF.StromingerJ. L.Toll-like receptor 2 (TLR2) and TLR4 differentially activate human dendritic cells20012764037692376992-s2.0-003581315710.1074/jbc.M105927200HallJ. A.BouladouxN.SunC. M.WohlfertE. A.BlankR. B.ZhuQ.GriggM. E.BerzofskyJ. A.BelkaidY.Commensal DNA limits regulatory T cell conversion and is a natural adjuvant of intestinal immune responses20082946376492-s2.0-5334916420010.1016/j.immuni.2008.08.009UematsuS.FujimotoK.JangM. H.YangB. G.JungY. J.NishiyamaM.SatoS.TsujimuraT.YamamotoM.YokotaY.KiyonoH.MiyasakaM.IshiiK. J.AkiraS.Regulation of humoral and cellular gut immunity by lamina propria dendritic cells expressing Toll-like receptor 52008977697762-s2.0-4554909942910.1038/ni.1622ChowJ.MazmanianS. K.Getting the bugs out of the immune system: do bacterial microbiota “fix” intestinal T cell responses?2009518122-s2.0-5824909218910.1016/j.chom.2008.12.006SchnurrM.ToyT.ShinA.WagnerM.CebonJ.MaraskovskyE.Extracellular nucleotide signaling by P2 receptors inhibits IL-12 and enhances IL-23 expression in human dendritic cells: a novel role for the cAMP pathway20051054158215892-s2.0-1354425138910.1182/blood-2004-05-1718KhakhB. S.NorthR. A.P2X receptors as cell-surface ATP sensors in health and disease200644271025275322-s2.0-3374670138010.1038/nature04886AtarashiK.TanoueT.HondaK.Induction of lamina propria Th17 cells by intestinal commensal bacteria20102850803680382-s2.0-7865025100410.1016/j.vaccine.2010.09.026IvanovaE. P.AlexeevaY. V.PhamD. K.WrightJ. P.NicolauD. V.ATP level variations in heterotrophic bacteria during attachment on hydrophilic and hydrophobic surfaces20069137462-s2.0-33646419536IvanovI. I.AtarashiK.ManelN.BrodieE. L.ShimaT.KaraozU.WeiD.GoldfarbK. C.SanteeC. A.LynchS. V.TanoueT.ImaokaA.ItohK.TakedaK.UmesakiY.HondaK.LittmanD. R.Induction of intestinal Th17 cells by segmented filamentous bacteria200913934854982-s2.0-7035034354410.1016/j.cell.2009.09.033LeeY. K.MenezesJ. S.UmesakiY.MazmanianS. K.Proinflammatory T-cell responses to gut microbiota promote experimental autoimmune encephalomyelitis2011108supplement 1461546222-s2.0-7995274867410.1073/pnas.1000082107WuH. J.IvanovI. I.DarceJ.HattoriK.ShimaT.UmesakiY.LittmanD. R.BenoistC.MathisD.Gut-residing segmented filamentous bacteria drive autoimmune arthritis via T helper 17 cells20103268158272-s2.0-7795391358610.1016/j.immuni.2010.06.001ReidG.SandersM. E.GaskinsH. R.New scientific paradigms for probiotics and prebiotics2003372105118BorchersA. T.SelmiC.MeyersF. J.KeenC. L.GershwinM. E.Probiotics and immunity200944126462-s2.0-5904908699210.1007/s00535-008-2296-0MatsuzakiT.NagataY.KadoS.UchidaK.KatoI.HashimotoS.YokokuraT.Prevention of onset in an insulin-dependent diabetes mellitus model, NOD mice, by oral feeding of Lactobacillus casei199710586436492-s2.0-0030801225CalcinaroF.DionisiS.MarinaroM.CandeloroP.BonatoV.MarzottiS.CorneliR. B.FerrettiE.GulinoA.GrassoF.De SimoneC.Di MarioU.FalorniA.BoirivantM.DottaF.Oral probiotic administration induces interleukin-10 production and prevents spontaneous autoimmune diabetes in the non-obese diabetic mouse2005488156515752-s2.0-2384449380910.1007/s00125-005-1831-2LavasaniS.DzhambazovB.NouriM.FåkF.BuskeS.MolinG.ThorlaciusH.AlenfallJ.JeppssonB.WeströmB.A novel probiotic mixture exerts a therapeutic effect on experimental autoimmune encephalomyelitis mediated by IL-10 producing regulatory T cells201052, article e90092-s2.0-7774932238910.1371/journal.pone.0009009KatoI.Endo-TanakaK.YokokuraT.Suppressive effects of the oral administration of Lactobacillus casei on type ii collagen-induced arthritis in DBA/1 mice19986386356442-s2.0-003254086710.1016/S0024-3205(98)00315-4BaharavE.MorF.HalpernM.WeinbergerA.Lactobacillus GG bacteria ameliorate arthritis in Lewis rats20041348196419692-s2.0-3543088024SoJ. S.KwonH. K.LeeC. G.YiH. J.ParkJ. A.LimS. Y.HwangK. C.JeonY. H.ImS. H.Lactobacillus casei suppresses experimental arthritis by down-regulating T helper 1 effector functions2008459269026992-s2.0-4084908559410.1016/j.molimm.2007.12.010Di GiacintoC.MarinaroM.SanchezM.StroberW.BoirivantM.Probiotics ameliorate recurrent Th1-mediated murine colitis by inducing IL-10 and IL-10-dependent TGF-β-bearing regulatory cells20051746323732462-s2.0-14844349149O'MahonyC.ScullyP.O'MahonyD.MurphyS.O'BrienF.LyonsA.SherlockG.MacSharryJ.KielyB.ShanahanF.O'MahonyL.Commensal-induced regulatory T cells mediate protection against pathogen-stimulated NF-κB activation2008482-s2.0-5084911909710.1371/journal.ppat.1000112e1000112LivingstonM.LoachD.WilsonM.TannockG. W.BairdM.Gut commensal Lactobacillus reuteri 100-23 stimulates an immunoregulatory response2010881991022-s2.0-7424908814610.1038/icb.2009.71JanR. L.YehK. C.HsiehM. H.Lactobacillus gasseri suppresses Th17 pro-inflammatory response and attenuates allergen-induced airway inflammation in a mouse model of allergic asthma20121081130139ZhouL.ChongM. M. W.LittmanD. R.Plasticity of CD4+ T cell lineage differentiation20093056466552-s2.0-6554911586210.1016/j.immuni.2009.05.001LazarevicV.GlimcherL. H.T-bet in disease20111275976062-s2.0-7995947313410.1038/ni.2059ChenC. C.ChiuC. H.LinT. Y.ShiH. N.WalkerW. A.Effect of probiotics Lactobacillus acidophilus on Citrobacter rodentium colitis: the role of dendritic cells20096521691752-s2.0-6044909228510.1203/PDR.0b013e31818d5a06VeckmanV.MiettinenM.PirhonenJ.SirénJ.MatikainenS.JulkunenI.Streptococcus pyogenes and Lactobacillus rhamnosus differentially induce maturation and production of Th1-type cytokines and chemokines in human monocyte-derived dendritic cells20047557647712-s2.0-234261485510.1189/jlb.1003461LópezP.González-RodríguezI.GueimondeM.Immune response to Bifidobacterium bifidum strains support Treg/Th17 plasticity201169, article e24776JeonS. G.KayamaH.UedaY.Probiotic Bifidobacterium breve induces IL-10-producing Tr1 cells in the colon201285, article e1002714MolloyM. J.BouladouxN.BelkaidY.2011ElsevierGarrettW. S.PunitS.GalliniC. A.MichaudM.ZhangD.SigristK. S.LordG. M.GlickmanJ. N.GlimcherL. H.Colitis-associated colorectal cancer driven by T-bet deficiency in dendritic cells20091632082192-s2.0-6924923254910.1016/j.ccr.2009.07.015FuentesS.EgertM.Jimenez-ValeraM.Monteoliva-SanchezM.Ruiz-BravoA.SmidtH.A strain of Lactobacillus plantarum affects segmented filamentous bacteria in the intestine of immunosuppressed mice200863165722-s2.0-3684906207910.1111/j.1574-6941.2007.00411.xPrakashT.OshimaK.MoritaH.Complete genome sequences of rat and mouse segmented filamentous bacteria, a potent inducer of th17 cell differentiation2011103273284KleerebezemM.VaughanE. E.Probiotic and gut lactobacilli and bifidobacteria: molecular approaches to study diversity and activity2009632692902-s2.0-7034954415310.1146/annurev.micro.091208.073341KimJ. F.JeongH.YuD. S.ChoiS. H.HurC. G.ParkM. S.YoonS. H.KimD. W.JiG. E.ParkH. S.OhT. K.Genome sequence of the probiotic bacterium Bifidobacterium animalis subsp. lactis AD011200919126786792-s2.0-6414910724810.1128/JB.00044-09RyanS. M.FitzgeraldG. F.Van SinderenD.Transcriptional regulation and characterization of a novel β-fructofuranosidase-encoding gene from Bifidobacterium breve UCC20032005717347534822-s2.0-2214445609510.1128/AEM.71.7.3475-3482.2005SchellM. A.KarmirantzouM.SnelB.VilanovaD.BergerB.PessiG.ZwahlenM. C.DesiereF.BorkP.DellevM.PridmoreR. D.ArisoniF.The genome sequence of Bifidobacterium longum reflects its adaptation to the human gastrointestinal tract2002992214422144272-s2.0-21544443432SelaD. A.ChapmanJ.AdeuyaA.KimJ. H.ChenF.WhiteheadT. R.LapidusA.RokhsarD. S.LebrillaC. B.GermanJ. B.PriceN. P.RichardsonP. M.MillsD. A.The genome sequence of Bifidobacterium longum subsp. infantis reveals adaptations for milk utilization within the infant microbiome20081054818964189692-s2.0-5774911320110.1073/pnas.0809584105Van Den BroekL. A. M.HinzS. W. A.BeldmanG.VinckenJ. P.VoragenA. G. J.Bifidobacterium carbohydrases-their role in breakdown and synthesis of (potential) prebiotics20085211461632-s2.0-3894913146910.1002/mnfr.200700121HinzS. W. A.VerhoefR.ScholsH. A.VinckenJ. P.VoragenA. G. J.Type I arabinogalactan contains β-D-Galp-(1→3)-β-D-Galp structural elements200534013213521432-s2.0-2374444908010.1016/j.carres.2005.07.003VenturaM.O'FlahertyS.ClaessonM. J.TurroniF.KlaenhammerT. R.van SinderenD.O'TooleP. W.Genome-scale analyses of health-promoting bacteria: probiogenomics20097161712-s2.0-5764918447410.1038/nrmicro2047MartinF. P. J.WangY.SprengerN.YapI. K. S.LundstedtT.LekP.RezziS.RamadanZ.Van BladerenP.FayL. B.KochharS.LindonJ. C.HolmesE.NicholsonJ. K.Probiotic modulation of symbiotic gut microbial-host metabolic interactions in a humanized microbiome mouse model20084, article 1572-s2.0-3834907877210.1038/msb4100190VenturaM.O'FlahertyS.ClaessonM. J.TurroniF.KlaenhammerT. R.van SinderenD.O'TooleP. W.Genome-scale analyses of health-promoting bacteria: probiogenomics20097161712-s2.0-5764918447410.1038/nrmicro2047