RESUMEN
Various gut bacteria, including Lactobacillus plantarum, possess several enzymes that produce hydroxy fatty acids (FAs), oxo FAs, conjugated FAs, and partially saturated FAs from polyunsaturated FAs as secondary metabolites. Among these derivatives, we identified 10-oxo-cis-6,trans-11-octadecadienoic acid (γKetoC), a γ-linolenic acid (GLA)-derived enon FA, as the most effective immunomodulator, which inhibited the antigen-induced immunoactivation and LPS-induced production of inflammatory cytokines. The treatment with γKetoC significantly suppressed proliferation of CD4+ T cells, LPS-induced activation of bone marrow-derived dendritic cells (BMDCs), and LPS-induced IL-6 release from peritoneal cells, splenocytes, and CD11c+ cells isolated from the spleen. γKetoC also inhibited the release of inflammatory cytokines from BMDCs stimulated with poly-I:C, R-848, or CpG. Further in vitro experiments using an agonist of GPR40/120 suggested the involvement of these GPCRs in the effects of γKetoC on DCs. We also found that γKetoC stimulated the NRF2 pathway in DCs, and the suppressive effects of γKetoC and agonist of GPR40/120 on the release of IL-6 and IL-12 were reduced in Nrf2-/- BMDCs. We evaluated the role of NRF2 in the anti-inflammatory effects of γKetoC in a dextran sodium sulfate-induced colitis model. The oral administration of γKetoC significantly reduced body weight loss, improved stool scores, and attenuated atrophy of the colon, in wild-type C57BL/6 and Nrf2+/- mice with colitis. In contrast, the pathology of colitis was deteriorated in Nrf2-/- mice even with the administration of γKetoC. Collectively, the present results demonstrated the involvement of the NRF2 pathway and GPCRs in γKetoC-mediated anti-inflammatory responses.
Asunto(s)
Microbioma Gastrointestinal , Enfermedades Inflamatorias del Intestino , Factor 2 Relacionado con NF-E2 , Receptores Acoplados a Proteínas G , Transducción de Señal , Animales , Masculino , Ratones , Colitis/metabolismo , Colitis/inducido químicamente , Colitis/tratamiento farmacológico , Citocinas/metabolismo , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Células Dendríticas/efectos de los fármacos , Modelos Animales de Enfermedad , Microbioma Gastrointestinal/efectos de los fármacos , Enfermedades Inflamatorias del Intestino/metabolismo , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Enfermedades Inflamatorias del Intestino/inmunología , Lactobacillus plantarum , Ratones Endogámicos C57BL , Ratones Noqueados , Factor 2 Relacionado con NF-E2/metabolismo , Ácidos Oléicos/farmacología , Receptores Acoplados a Proteínas G/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
Our newly developed menthyl esters of valine and isoleucine exhibit anti-inflammatory properties beyond those of the well-known menthol in macrophages stimulated by lipopolysaccharide (LPS) and in a mouse model of colitis induced by sodium dextran sulfate. Unlike menthol, which acts primarily through the cold-sensitive TRPM8 channel, these menthyl esters displayed unique mechanisms that operate independently of this receptor. They readily penetrated target cells and efficiently suppressed LPS-stimulated tumour necrosis factor-alpha (Tnf) expression mediated by liver X receptor (LXR), a key nuclear receptor that regulates intracellular cholesterol and lipid balance. The menthyl esters showed affinity for LXR and enhanced the transcriptional activity through their non-competitive and potentially synergistic agonistic effect. This effect can be attributed to the crucial involvement of SCD1, an enzyme regulated by LXR, which is central to lipid metabolism and plays a key role in the anti-inflammatory response. In addition, we discovered that the menthyl esters showed remarkable efficacy in suppressing adipogenesis in 3T3-L1 adipocytes at the mitotic clonal expansion stage in an LXR-independent manner as well as in mice subjected to diet-induced obesity. These multiple capabilities of our compounds establish them as formidable allies in the fight against inflammation and obesity, paving the way for a range of potential therapeutic applications.
Asunto(s)
Antiinflamatorios , Fármacos Antiobesidad , Receptores X del Hígado , Obesidad , Animales , Ratones , Obesidad/tratamiento farmacológico , Obesidad/metabolismo , Receptores X del Hígado/metabolismo , Receptores X del Hígado/agonistas , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Fármacos Antiobesidad/farmacología , Fármacos Antiobesidad/uso terapéutico , Adipogénesis/efectos de los fármacos , Ésteres/química , Colitis/tratamiento farmacológico , Colitis/inducido químicamente , Colitis/metabolismo , Humanos , Mentol/farmacología , Ratones Endogámicos C57BL , Lipopolisacáridos , Factor de Necrosis Tumoral alfa/metabolismo , Células 3T3-L1 , Sulfato de Dextran , Adipocitos/metabolismo , Adipocitos/efectos de los fármacos , Macrófagos/inmunología , Macrófagos/metabolismo , Macrófagos/efectos de los fármacos , Canales Catiónicos TRPM/metabolismoRESUMEN
Short-chain fatty acids (SCFAs) are produced by the intestinal microbiota during the fermentation of dietary fibers as secondary metabolites. Several recent studies reported that SCFAs modulate the development and function of immune-related cells. However, the molecular mechanisms by which SCFAs regulate mast cells (MCs) remain unclear. In the current study, we analyzed the function and gene expression of mouse MCs in the presence of SCFAs in vitro and in vivo. We found that the oral administration of valerate or butyrate ameliorated passive systemic anaphylaxis and passive cutaneous anaphylaxis in mice. The majority of SCFAs, particularly propionate, butyrate, valerate, and isovalerate, suppressed the IgE-mediated degranulation of bone marrow-derived MCs, which were eliminated by the Gi protein inhibitor pertussis toxin and by the knockdown of Gpr109a. A treatment with the HDAC inhibitor trichostatin A also suppressed IgE-mediated MC activation and reduced the surface expression level of FcεRI on MCs. Acetylsalicylic acid and indomethacin attenuated the suppressive effects of SCFAs on degranulation. The degranulation degree was significantly reduced by PGE2 but not by PGD2. Furthermore, SCFAs enhanced PGE2 release from stimulated MCs. The SCFA-mediated amelioration of anaphylaxis was exacerbated by COX inhibitors and an EP3 antagonist, but not by an EP4 antagonist. The administration of niacin, a ligand of GPR109A, alleviated the symptoms of passive cutaneous anaphylaxis, which was inhibited by cyclooxygenase inhibitors and the EP3 antagonist. We conclude that SCFAs suppress IgE-mediated activation of MCs in vivo and in vitro involving GPR109A, PGE2, and epigenetic regulation.
Asunto(s)
Anafilaxia , Niacina , Ratones , Animales , Anafilaxia/tratamiento farmacológico , Anafilaxia/metabolismo , Niacina/farmacología , Niacina/metabolismo , Dinoprostona/metabolismo , Butiratos/farmacología , Butiratos/metabolismo , Valeratos/metabolismo , Mastocitos/metabolismo , Epigénesis Genética , Inmunoglobulina E/metabolismo , Degranulación de la CélulaRESUMEN
Liver fibrosis results from chronic liver injury triggered by factors such as viral infection, excess alcohol intake, and lipid accumulation. However, the mechanisms underlying liver fibrosis are not fully understood. Here, we demonstrate that the expression of fibroblast growth factor 18 (Fgf18) is elevated in mouse livers following the induction of chronic liver fibrosis models. Deletion of Fgf18 in hepatocytes attenuates liver fibrosis; conversely, overexpression of Fgf18 promotes liver fibrosis. Single-cell RNA sequencing reveals that overexpression of Fgf18 in hepatocytes results in an increase in the number of Lrat+ hepatic stellate cells (HSCs), thereby inducing fibrosis. Mechanistically, FGF18 stimulates the proliferation of HSCs by inducing the expression of Ccnd1. Moreover, the expression of FGF18 is correlated with the expression of profibrotic genes, such as COL1A1 and ACTA2, in human liver biopsy samples. Thus, FGF18 promotes liver fibrosis and could serve as a therapeutic target to treat liver fibrosis.
Asunto(s)
Células Estrelladas Hepáticas , Cirrosis Hepática , Ratones , Animales , Humanos , Células Estrelladas Hepáticas/metabolismo , Cirrosis Hepática/patología , Hígado/metabolismo , Fibrosis , Proliferación CelularRESUMEN
In the present study, we evaluated the effects of kaempferol on bone marrow-derived mast cells (BMMCs). Kaempferol treatment significantly and dose-dependently inhibited IgE-induced degranulation, and cytokine production of BMMCs under the condition that cell viability was maintained. Kaempferol downregulated the surface expression levels of FcεRI on BMMCs, but the mRNA levels of FcεRIα, ß, and γ-chains were not changed by kaempferol treatment. Furthermore, the kaempferol-mediated downregulation of surface FcεRI on BMMCs was still observed when protein synthesis or protein transporter was inhibited. We also found that kaempferol inhibited both LPS- and IL-33-induced IL-6 production from BMMCs, without affecting the expression levels of their receptors, TLR4 and ST2. Although kaempferol treatment increased the protein amount of NF-E2-related factor 2 (NRF2)-a master transcription factor of antioxidant stress-in BMMCs, the inhibition of NRF2 did not alter the suppressive effect of kaempferol on degranulation. Finally, we found that kaempferol treatment increased the levels of mRNA and protein of a phosphatase SHIP1 in BMMCs. The kaempferol-induced upregulation of SHIP1 was also observed in peritoneal MCs. The knockdown of SHIP1 by siRNA significantly enhanced IgE-induced degranulation of BMMCs. A Western blotting analysis showed that IgE-induced phosphorylation of PLCγ was suppressed in kaempferol-treated BMMCs. These results indicate that kaempferol inhibited the IgE-induced activation of BMMCs by downregulating FcεRI and upregulating SHIP1, and the SHIP1 increase is involved in the suppression of various signaling-mediated stimulations of BMMCs, such as those associated with TLR4 and ST2.
Asunto(s)
Mastocitos , Receptores de IgE , Degranulación de la Célula , Inmunoglobulina E/metabolismo , Proteína 1 Similar al Receptor de Interleucina-1/metabolismo , Quempferoles/farmacología , Quempferoles/metabolismo , Mastocitos/metabolismo , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , Receptores de IgE/genética , Receptores de IgE/metabolismo , ARN Mensajero/metabolismo , Receptor Toll-Like 4/genética , Receptor Toll-Like 4/metabolismoRESUMEN
Dendritic cells (DCs), which are typical antigen-presenting cells, localize to various sites in the body, particularly the front line of infection as sentinels, and are involved in innate and adaptive immune responses. Although the functions of DCs, such as pathogen-induced cytokine production and antigen-specific T cell activation, are important for host defenses against infection and tumorigenesis, the hyper- and/or extended activation of DCs leads to inflammatory and autoimmune diseases. In the present study, ß-damascone, a major ingredient of rose fragrance, was selected from an aroma library as a candidate compound that suppresses antigen-induced immune responses. ß-Damascone inhibited the functions of DCs, including the antigen-dependent proliferation of T cells, DC-induced Th1 development, and the TLR ligand-induced production of inflammatory cytokines by DCs. The ß-damascone treatment also increased the protein level of the transcription factor NF-E2-related factor 2 (NRF2), which plays key roles in antioxidant responses, and the transcription of Hmox1 and Nqo1, target genes of NRF2, in DCs. Nrf2 -/ - DCs induced Th1-development and produced large amount of IL-12p40 even in the presence of ß-damascone, whereas these functions by Nrf2 +/- DCs were inhibited by ß-damascone under the same conditions. The intake of ß-damascone suppressed ear swelling in contact hypersensitivity (CHS) model mice, but not in CHS-induced Nrf2 -/ - mice. Collectively, the present results indicate the potential of the rose aroma compound ß-damascone, which suppresses DC-mediated immune responses by activating the NRF2 pathway in DCs, for the prevention and/or attenuation of immune-mediated diseases.
RESUMEN
Mast cells (MCs) play key roles in IgE-mediated immunoresponses, including in the protection against parasitic infections and the onset and/or symptoms of allergic diseases. IgE-mediated activation induces MCs to release mediators, including histamine and leukotriene, as an early response, and to produce cytokines as a late phase response. Attempts have been made to identify novel antiallergic compounds from natural materials such as Chinese medicines and food ingredients. We herein screened approximately 60 compounds and identified salicylaldehyde, an aromatic aldehyde isolated from plant essential oils, as an inhibitor of the IgE-mediated activation of MCs. A degranulation assay, flow cytometric analyses, and enzyme-linked immunosorbent assays revealed that salicylaldehyde inhibited the IgE-mediated degranulation and cytokine expression of bone-marrow-derived MCs (BMMCs). The salicylaldehyde treatment reduced the surface expression level of FcεRI, the high affinity receptor for IgE, on BMMCs, and suppressed the IgE-induced phosphorylation of tyrosine residues in intercellular proteins, possibly Lyn, Syk, and Fyn, in BMMCs. We also examined the effects of salicylaldehyde in vivo using passive anaphylaxis mouse models and found that salicylaldehyde administration significantly enhanced the recovery of a reduced body temperature due to systemic anaphylaxis and markedly suppressed ear swelling, footpad swelling, and vascular permeability in cutaneous anaphylaxis.
Asunto(s)
Anafilaxia , Mastocitos , Aldehídos/metabolismo , Anafilaxia/tratamiento farmacológico , Anafilaxia/metabolismo , Animales , Degranulación de la Célula , Citocinas/metabolismo , Inmunoglobulina E/metabolismo , Mastocitos/metabolismo , Ratones , Receptores de IgE/metabolismo , Transducción de SeñalRESUMEN
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a cytotoxic cytokine that induces cancer cell death by binding to TRAIL receptors. Because of its selective cytotoxicity toward cancer cells, TRAIL therapeutics, such as recombinant TRAIL and agonistic antibodies targeting TRAIL receptors, have garnered attention as promising cancer treatment agents. However, many cancer cells acquire resistance to TRAIL-induced cell death. To overcome this issue, we searched for agents to sensitize cancer cells to TRAIL-induced cell death by screening a small-molecule chemical library consisting of diverse compounds. We identified a cardiac glycoside, proscillaridin A, as the most effective TRAIL sensitizer in colon cancer cells. Proscillaridin A synergistically enhanced TRAIL-induced cell death in TRAIL-sensitive and -resistant colon cancer cells. Additionally, proscillaridin A enhanced cell death in cells treated with TRAIL and TRAIL sensitizer, the second mitochondria-derived activator of caspase mimetic. Proscillaridin A upregulated TRAIL receptor expression, while downregulating the levels of the anti-cell death molecules, cellular FADD-like IL-1ß converting enzyme-like inhibitor protein and Mcl1, in a cell type-dependent manner. Furthermore, proscillaridin A enhanced TRAIL-induced cell death partly via O-glycosylation. Taken together, our findings suggest that proscillaridin A is a promising agent that enhances the anti-cancer efficacy of TRAIL therapeutics.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias del Colon , Proscilaridina , Ligando Inductor de Apoptosis Relacionado con TNF , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Apoptosis/efectos de los fármacos , Caspasas/metabolismo , Línea Celular Tumoral , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/metabolismo , Neoplasias del Colon/patología , Sinergismo Farmacológico , Humanos , Proscilaridina/administración & dosificación , Proscilaridina/farmacología , Receptores del Ligando Inductor de Apoptosis Relacionado con TNF/metabolismo , Ligando Inductor de Apoptosis Relacionado con TNF/administración & dosificación , Ligando Inductor de Apoptosis Relacionado con TNF/farmacologíaRESUMEN
The nonexpressor of pathogenesis-related (NPR) gene family is well known to play a crucial role in transactivation of TGA transcription factors for salicylic acid (SA)-responsive genes, including pathogenesis-related protein 1 (PR1), during plants' immune response after pathogen attack in the model dicot Arabidopsis thaliana. However, little is known about NPR gene functions in monocots. We therefore explored the functions of NPRs in SA signaling in the model monocot Brachypodium distachyon. BdNPR1 and BdNPR2/3 share structural similarities with A. thaliana AtNPR1/2 and AtNPR3/4 subfamilies, respectively. The transcript level of BdNPR2 but not BdNPR1/3 appeared to be positively regulated in leaves in response to methyl salicylate. Reporter assays in protoplasts showed that BdNPR2 positively regulated BdTGA1-mediated activation of PR1. This transactivation occurred in an SA-dependent manner through SA binding at Arg468 of BdNPR2. In contrast, BdNPR1 functioned as a suppressor of BdNPR2/BdTGA1-mediated transcription of PR1. Collectively, our findings reveal that the TGA-promoted transcription of SA-inducible PR1 is orchestrated by the activator BdNPR2 and the repressor BdNPR1, which function competitively in B. distachyon.
Asunto(s)
Arabidopsis , Brachypodium , Arabidopsis/genética , Arabidopsis/metabolismo , Brachypodium/genética , Brachypodium/metabolismo , Regulación de la Expresión Génica de las Plantas/genética , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Ácido Salicílico/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Activación Transcripcional/genéticaRESUMEN
Rodent mast cells are classified into two major subsets, mucosal mast cells (MMCs) and connective tissue mast cells. MMCs arise from mast cell progenitors that are mobilized from the bone marrow to mucosal tissues in response to allergic inflammation or helminth infection. TGF-ß is known as an inducer of MMC differentiation in mucosal tissues, but we have previously found that Notch receptor-mediated signaling also leads to the differentiation. Here, we examined the relationship between Notch and TGF-ß signaling in MMC differentiation using mouse bone marrow-derived mast cells (BMMCs). We found that the coexistence of Notch and TGF-ß signaling markedly upregulates the expression of MMC markers, mouse mast cell protease (mMCP)-1, mMCP-2, and αE integrin/CD103, more than Notch or TGF-ß signaling alone, and that their signals act interdependently to induce these marker expressions. Notch and TGF-ß-mediated transcription of MMC marker genes were both dependent on the TGF-ß signaling transducer SMAD4. In addition, we also found that Notch signaling markedly upregulated mMCP-1 and mMCP-2 expression levels through epigenetic deregulation of the promoter regions of these genes, but did not affect the promoter of the CD103-encoding gene. Moreover, forced expression of the constitutively active Notch2 intracellular domain in BMMCs showed that Notch signaling promotes the nuclear localization of SMADs 3 and 4 and causes SMAD4-dependent gene transcription. These findings indicate that Notch and TGF-ß signaling play interdependent roles in inducing the differentiation and maturation of MMCs. These roles may contribute to the rapid expansion of the number of MMCs during allergic mucosal inflammation.
Asunto(s)
Mastocitos , Factor de Crecimiento Transformador beta , Animales , Expresión Génica , Inflamación/metabolismo , Mastocitos/metabolismo , Ratones , Membrana Mucosa , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
The opioid receptors play important roles in the regulation of sense and emotions. Although it is recently revealed that opioid receptors are also expressed in various cells, but not restricted in the central nervous system, the effects of opioids on peripheral immune cells are largely unknown. In the current study, we evaluated the effect of opioids on immune system by using selective agonists for δ opioid receptor. Systemic administration of KNT-127 or intraperitoneal injection of YNT-2715 (a KNT-127-related compound that cannot pass through the blood-brain barrier) significantly alleviated the pathology of dextran sodium sulfate-induced colitis. In KNT-127-treated mice, the levels of an inflammatory cytokine IL-6 in the serum, and macrophages in the mesenteric lymph nodes (MLNs) were decreased in the progression stage, and those of regulatory T cells (Tregs) in the MLN were increased in the recovery stage. In vitro experiments revealed that KNT-127 inhibited the release of IL-6 and another inflammatory cytokine TNF-α from macrophages and accelerated the development of Tregs. Our study suggests that δ opioid agonists act directly on immune cells to improve the pathology of the colitis and can be candidates of immunomodulatory drugs.
Asunto(s)
Analgésicos Opioides/farmacología , Antiinflamatorios/farmacología , Colitis/prevención & control , Colon/efectos de los fármacos , Morfinanos/farmacología , Receptores Opioides delta/agonistas , Animales , Colitis/inducido químicamente , Colitis/inmunología , Colitis/metabolismo , Colon/inmunología , Colon/metabolismo , Sulfato de Dextran , Modelos Animales de Enfermedad , Femenino , Interleucina-6/metabolismo , Ganglios Linfáticos/efectos de los fármacos , Ganglios Linfáticos/inmunología , Ganglios Linfáticos/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Macrófagos/metabolismo , Ratones Endogámicos C57BL , Receptores Opioides delta/metabolismo , Transducción de Señal , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Mast cells (MCs) play critical roles in Th2 immune responses, including the defense against parasitic infections and the initiation of type I allergic reactions. In addition, MCs are involved in several immune-related responses, including those in bacterial infections, autoimmune diseases, inflammatory bowel diseases, cancers, allograft rejections, and lifestyle diseases. Whereas antigen-specific IgE is a well-known activator of MCs, which express FcεRI on the cell surface, other receptors for cytokines, growth factors, pathogen-associated molecular patterns, and damage-associated molecular patterns also function as triggers of MC stimulation, resulting in the release of chemical mediators, eicosanoids, and various cytokines. In this review, we focus on the role of interleukin (IL)-10, an anti-inflammatory cytokine, in MC-mediated immune responses, in which MCs play roles not only as initiators of the immune response but also as suppressors of excessive inflammation. IL-10 exhibits diverse effects on the proliferation, differentiation, survival, and activation of MCs in vivo and in vitro. Furthermore, IL-10 derived from MCs exerts beneficial and detrimental effects on the maintenance of tissue homeostasis and in several immune-related diseases including contact hypersensitivity, auto-immune diseases, and infections. This review introduces the effects of IL-10 on various events in MCs, and the roles of MCs in IL-10-related immune responses and as a source of IL-10.
Asunto(s)
Antiinflamatorios/metabolismo , Inflamación/metabolismo , Interleucina-10/metabolismo , Mastocitos/metabolismo , Animales , Humanos , Enfermedades del Sistema Inmune/patología , Mastocitos/citología , Modelos BiológicosRESUMEN
NLRP3 inflammasomes play crucial roles in the initiation of host defense by converting pro-Caspase-1 to mature Caspase-1, which in turn processes immature IL-1ß and IL-18 into their biologically active forms. Although NLRP3 expression is restricted to monocytic lineages such as monocytes, macrophages, and dendritic cells, the mechanisms determining the lineage-specific expression of NLRP3 remain largely unknown. In this study, we investigated the transcription factors involved in cell-type-specific transcription of NLRP3. We found that a distal, rather than a proximal, promoter of human NLRP3 was predominantly used in the human monocytic cell lines and macrophages. Reporter analysis showed that an Ets/IRF composite element (EICE) at -309/-300 and an Ets motif at +5/+8 were critical for transcriptional activity of the distal promoter. Electrophoretic mobility shift assays and chromatin immunoprecipitation assays demonstrated that two transcription factors, PU.1 and IRF8, both of which play essential roles in development and gene expression of the monocytic lineage, were bound to the EICE site, whereas PU.1 alone was bound to the Ets site. Knockdown of PU.1 and/or IRF8 mediated by small interfering RNA downregulated expression of NLRP3 and related molecules and markedly diminished the LPS-induced release of IL-1ß in THP-1, suggesting that activity of the NLRP3 inflammasome was suppressed by knockdown of PU.1 and IRF8. Taken together, these results indicate that PU.1 and IRF8 are involved in the monocytic lineage-specific expression of NLRP3 by binding to regulatory elements within its promoter and that PU.1 and IRF8 are potential targets for regulating the activity of the NLRP3 inflammasome.
Asunto(s)
Inflamasomas/genética , Factores Reguladores del Interferón/metabolismo , Macrófagos/inmunología , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Proteínas Proto-Oncogénicas/metabolismo , Transactivadores/metabolismo , Animales , Regulación de la Expresión Génica/inmunología , Técnicas de Silenciamiento del Gen , Humanos , Inflamasomas/inmunología , Inflamasomas/metabolismo , Factores Reguladores del Interferón/genética , Macrófagos/metabolismo , Ratones , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Regiones Promotoras Genéticas , Proteínas Proto-Oncogénicas/genética , Especificidad de la Especie , Células THP-1 , Transactivadores/genética , Células U937RESUMEN
Interleukin (IL)-11 is a member of the IL-6 family of cytokines and is involved in multiple cellular responses, including tumor development. However, the origin and functions of IL-11-producing (IL-11+) cells are not fully understood. To characterize IL-11+ cells in vivo, we generate Il11 reporter mice. IL-11+ cells appear in the colon in murine tumor and acute colitis models. Il11ra1 or Il11 deletion attenuates the development of colitis-associated colorectal cancer. IL-11+ cells express fibroblast markers and genes associated with cell proliferation and tissue repair. IL-11 induces the activation of colonic fibroblasts and epithelial cells through phosphorylation of STAT3. Human cancer database analysis reveals that the expression of genes enriched in IL-11+ fibroblasts is elevated in human colorectal cancer and correlated with reduced recurrence-free survival. IL-11+ fibroblasts activate both tumor cells and fibroblasts via secretion of IL-11, thereby constituting a feed-forward loop between tumor cells and fibroblasts in the tumor microenvironment.
Asunto(s)
Adenoma/inmunología , Colitis/patología , Neoplasias Colorrectales/inmunología , Fibroblastos/inmunología , Interleucina-11/metabolismo , Recurrencia Local de Neoplasia/epidemiología , Adenoma/genética , Adenoma/mortalidad , Adenoma/cirugía , Anciano , Anciano de 80 o más Años , Animales , Línea Celular Tumoral , Colitis/inducido químicamente , Colitis/inmunología , Colon/citología , Colon/inmunología , Colon/patología , Colon/cirugía , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/mortalidad , Neoplasias Colorrectales/cirugía , Sulfato de Dextran/administración & dosificación , Sulfato de Dextran/toxicidad , Modelos Animales de Enfermedad , Supervivencia sin Enfermedad , Femenino , Fibroblastos/metabolismo , Regulación Neoplásica de la Expresión Génica/inmunología , Técnicas de Silenciamiento del Gen , Genes Reporteros , Proteínas Fluorescentes Verdes/genética , Humanos , Interleucina-11/genética , Subunidad alfa del Receptor de Interleucina-11/genética , Subunidad alfa del Receptor de Interleucina-11/metabolismo , Mucosa Intestinal/citología , Mucosa Intestinal/inmunología , Mucosa Intestinal/patología , Estimación de Kaplan-Meier , Masculino , Ratones , Ratones Noqueados , Ratones Transgénicos , Persona de Mediana Edad , Recurrencia Local de Neoplasia/inmunología , Organoides , Cultivo Primario de Células , Estudios Retrospectivos , Transcriptoma/inmunología , Microambiente Tumoral/inmunologíaRESUMEN
Dendritic cells (DCs) and T cells play important roles in immune regulation, and modulating their function is an approach for developing preventive or therapeutic strategies against immune disorders. Herein, the effect of pterostilbene (PSB) (3',5'-dimethoxy-resveratrol)-a resveratrol-related polyphenol found in blueberries-on immune regulation was evaluated. Using an in vitro co-culture system, PSB was found to exert the strongest inhibitory effect among all tested resveratrol derivatives on DC-mediated T cell proliferation; moreover, PSB treatment decreased the Th1 and Th17 populations and increased the regulatory T cell (Treg) population. Upon co-stimulation with anti-CD3 and anti-CD28 antibodies, PSB inhibited CD4+ T cell proliferation and differentiation into Th1 cells. Additionally, PSB acted on DCs to suppress the lipopolysaccharide-induced transactivation of genes encoding antigen presentation-related molecules and inflammatory cytokines by attenuating the DNA-binding ability of the transcription factor PU.1. Furthermore, PSB promoted DC-mediated Foxp3+ Treg differentiation, and PU.1 knockdown increased DC-induced Treg activity. Oral administration of PSB alleviated the symptoms of dextran sulfate sodium-induced colitis and decreased tumor necrosis factor-α expression in mice. Thus, PSB treatment ameliorates colonic inflammation.
Asunto(s)
Antiinflamatorios/farmacología , Colitis Ulcerosa/tratamiento farmacológico , Células Dendríticas/inmunología , Estilbenos/farmacología , Linfocitos T Reguladores/inmunología , Animales , Antiinflamatorios/uso terapéutico , Línea Celular , Proliferación Celular , Células Cultivadas , Colitis Ulcerosa/inmunología , Colon/efectos de los fármacos , Colon/inmunología , Citocinas/genética , Citocinas/metabolismo , Células Dendríticas/efectos de los fármacos , Factores de Transcripción Forkhead/metabolismo , Ratones , Ratones Endogámicos C57BL , Proteínas Proto-Oncogénicas/metabolismo , Estilbenos/uso terapéutico , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/fisiología , Células TH1/inmunología , Células TH1/fisiología , Células Th17/inmunología , Células Th17/fisiología , Transactivadores/metabolismoRESUMEN
Dendritic cell toll-like receptors (TLRs) and the high-affinity immunoglobulin E (IgE) receptor (FcεRI) may biologically interact with regard to atopic dermatitis (AD) development and, especially, severity. Our aim here was to test if such interaction can be detected on the genetic level. The combined effect of the TLR2 gene (TLR2) rs4696480 and the FcεRI α-chain gene (FCER1A) rs2252226 and rs2251746 polymorphisms on the AD severity as measured by SCORAD was assessed. The FCER1A rs2252226 and TLR2 rs4696480 polymorphisms interacted with regard to SCORAD. Higher SCORAD was observed in patients being the TLR2 rs4696480 major homozygotes and carrying at the same time the FCER1A rs2252226 minor allele, compared to those characterized by (any other of) the remaining combined rs2252226 and rs4696480 genotypes. The observation of the epistatic effect of TLR2 and FCER1A genetic variants on SCORAD is in line with the involvement of the interaction TLRs-FcεRI in the pathophysiology of AD.
Asunto(s)
Dermatitis Atópica/genética , Polimorfismo de Nucleótido Simple , Receptores de IgE/genética , Índice de Severidad de la Enfermedad , Receptor Toll-Like 2/genética , Adulto , Alelos , Estudios de Casos y Controles , Dermatitis Atópica/sangre , Dermatitis Atópica/epidemiología , Dermatitis Atópica/fisiopatología , Femenino , Predisposición Genética a la Enfermedad/genética , Genotipo , Humanos , Inmunoglobulina E/sangre , Masculino , Polonia/epidemiología , Regiones Promotoras GenéticasRESUMEN
We evaluated the effect of gut bacterial metabolites of polyunsaturated fatty acids on inflammation and found that 10-oxo-cis-6,trans-11-octadecadienoic acid (γKetoC) strikingly suppressed LPS-induced IL-6 release from bone marrow-derived macrophages (BMMs), which was accompanied by reduced mRNA expression of Il6, TNF, and Il1b. γKetoC decreased the cAMP concentration in BMMs, suggesting that γKetoC stimulated G protein-coupled receptors. A Gq agonist significantly suppressed LPS-induced IL-6 expression in BMMs, whereas a Gi inhibitor partially abrogated γKetoC-mediated IL-6 suppression. Cytosolic Ca2+ was markedly increased by γKetoC, which was partly but not fully abrogated by an ion channel inhibitor. Taken together, these data suggest that γKetoC suppresses inflammatory cytokine expression in macrophages primarily through Gq and partially through Gi. γKetoC suppressed osteoclast development and IL-6 expression in synovial fibroblasts from rheumatoid arthritis (RA) patients, suggesting the beneficial effect of γKetoC on the prevention or treatment of RA.
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Ácidos Grasos Insaturados/metabolismo , Microbioma Gastrointestinal , Lactobacillales/metabolismo , Monocitos/metabolismo , Animales , Artritis Reumatoide/etiología , Artritis Reumatoide/metabolismo , Línea Celular , Células Cultivadas , Citocinas/metabolismo , Femenino , Humanos , Inflamación/etiología , Inflamación/metabolismo , Macrófagos/metabolismo , Ratones , Ratones Endogámicos C57BL , Factores Protectores , Células RAW 264.7RESUMEN
PD-L2, which has been identified as a PD-1 ligand, is specifically expressed in dendritic cells (DCs) and macrophages. The transcription factors that determine the cell type-specific expression of PD-L2 are largely unknown, although PD-1 and its ligands, which have been shown to play important roles in T cell suppression, have been vigorously analyzed in the field of cancer immunology. To reveal the mechanism by which Pdcd1lg2 gene expression is regulated, we focused on DCs, which play key roles in innate and acquired immunity. The knockdown of the hematopoietic cell-specific transcription factors PU.1 and IRF4 decreased PD-L2 expression in GM-CSF-induced mouse bone marrow-derived DCs. Chromatin immunoprecipitation assays, luciferase assays, and electrophoretic mobility shift assays demonstrated that PU.1 and IRF4 bound directly to the Pdcd1lg2 gene via an Ets-IRF composite element sequence and coordinately transactivated the Pdcd1lg2 gene. Furthermore, PU.1 knockdown reduced the histone acetylation of the Pdcd1lg2 gene. The knockdown of the typical histone acetyltransferase p300, which has been reported to interact with PU.1, decreased the expression and H3K27 acetylation of the Pdcd1lg2 gene. GM-CSF stimulation upregulated the Pdcd1lg2 gene expression, which was accompanied by an increase in PU.1 binding and histone acetylation in Flt3L-generated mouse bone marrow-derived DCs. The involvement of PU.1, IRF4, and p300 were also observed in mouse splenic DCs. Overall, these results indicate that PU.1 positively regulates Pdcd1lg2 gene expression as a transactivator and an epigenetic regulator in DCs.
Asunto(s)
Células Dendríticas/inmunología , Epigénesis Genética/inmunología , Factores Reguladores del Interferón/inmunología , Proteína 2 Ligando de Muerte Celular Programada 1/inmunología , Proteínas Proto-Oncogénicas/inmunología , Transactivadores/inmunología , Activación Transcripcional/inmunología , Animales , Células Dendríticas/citología , Células HEK293 , Humanos , Ratones , Ratones Endogámicos BALB CRESUMEN
Plants respond to herbivory by perceiving herbivore danger signal(s) (HDS(s)), including "elicitors", that are present in herbivores' oral secretions (OS) and act to induce defense responses. However, little is known about HDS-specific molecules and intracellular signaling. Here we explored soybean receptor-like kinases (RLKs) as candidates that might mediate HDS-associated RLKs' (HAKs') actions in leaves in response to OS extracted from larvae of a generalist herbivore, Spodoptera litura. Fractionation of OS yielded Frα, which consisted of polysaccharides. The GmHAKs composed of their respective homomultimers scarcely interacted with Frα. Moreover, Arabidopsis HAK1 homomultimers interacted with cytoplasmic signaling molecule PBL27, resulting in herbivory resistance, in an ethylene-dependent manner. Altogether, our findings suggest that HAKs are herbivore-specific RLKs mediating HDS-transmitting, intracellular signaling through interaction with PBL27 and the subsequent ethylene signaling for plant defense responses in host plants.