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1.
Am J Respir Crit Care Med ; 201(8): 934-945, 2020 04 15.
Artículo en Inglés | MEDLINE | ID: mdl-31834999

RESUMEN

Rationale: The role of FSTL-1 (follistatin-like 1) in lung homeostasis is unknown.Objectives: We aimed to define the impact of FSTL-1 attenuation on lung structure and function and to identify FSTL-1-regulated transcriptional pathways in the lung. Further, we aimed to analyze the association of FSTL-1 SNPs with lung disease.Methods: FSTL-1 hypomorphic (FSTL-1 Hypo) mice underwent lung morphometry, pulmonary function testing, and micro-computed tomography. Fstl1 expression was determined in wild-type lung cell populations from three independent research groups. RNA sequencing of wild-type and FSTL-1 Hypo mice identified FSTL-1-regulated gene expression, followed by validation and mechanistic in vitro examination. FSTL1 SNP analysis was performed in the COPDGene (Genetic Epidemiology of Chronic Obstructive Pulmonary Disease) cohort.Measurements and Main Results: FSTL-1 Hypo mice developed spontaneous emphysema, independent of smoke exposure. Fstl1 is highly expressed in the lung by mesenchymal and endothelial cells but not immune cells. RNA sequencing of whole lung identified 33 FSTL-1-regulated genes, including Nr4a1, an orphan nuclear hormone receptor that negatively regulates NF-κB (nuclear factor-κB) signaling. In vitro, recombinant FSTL-1 treatment of macrophages attenuated NF-κB p65 phosphorylation in an Nr4a1-dependent manner. Within the COPDGene cohort, several SNPs in the FSTL1 region corresponded to chronic obstructive pulmonary disease and lung function.Conclusions: This work identifies a novel role for FSTL-1 protecting against emphysema development independent of smoke exposure. This FSTL-1-deficient emphysema implicates regulation of immune tolerance in lung macrophages through Nr4a1. Further study of the mechanisms involving FSTL-1 in lung homeostasis, immune regulation, and NF-κB signaling may provide additional insight into the pathophysiology of emphysema and inflammatory lung diseases.


Asunto(s)
Proteínas Relacionadas con la Folistatina/genética , Pulmón/diagnóstico por imagen , Enfisema Pulmonar/genética , Humo/efectos adversos , Animales , Células Endoteliales/metabolismo , Proteínas Relacionadas con la Folistatina/farmacología , Regulación de la Expresión Génica , Técnicas de Silenciamiento del Gen , Humanos , Técnicas In Vitro , Pulmón/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Ratones , Mutación , Miembro 1 del Grupo A de la Subfamilia 4 de Receptores Nucleares/efectos de los fármacos , Miembro 1 del Grupo A de la Subfamilia 4 de Receptores Nucleares/metabolismo , Fosforilación/efectos de los fármacos , Polimorfismo de Nucleótido Simple , Tomografía Computarizada por Tomografía de Emisión de Positrones , Enfermedad Pulmonar Obstructiva Crónica/genética , Enfisema Pulmonar/diagnóstico por imagen , Enfisema Pulmonar/metabolismo , Tomografía Computarizada por Tomografía Computarizada de Emisión de Fotón Único , Nicotiana , Factor de Transcripción ReIA/efectos de los fármacos , Factor de Transcripción ReIA/metabolismo , Microtomografía por Rayos X
2.
Infect Immun ; 89(1)2020 12 15.
Artículo en Inglés | MEDLINE | ID: mdl-33077624

RESUMEN

Klebsiella pneumoniae is a common cause of antibiotic-resistant pneumonia. Follistatin-like protein 1 (FSTL-1) is highly expressed in the lung and is critical for lung homeostasis. The role of FSTL-1 in immunity to bacterial pneumonia is unknown. Wild-type (WT) and FSTL-1 hypomorphic (Hypo) mice were infected with Klebsiella pneumoniae to determine infectious burden, immune cell abundance, and cytokine production. FSTL-1 Hypo/TCRδ-/- and FSTL-1 Hypo/IL17ra-/- were also generated to assess the role of γδT17 cells in this model. FSTL-1 Hypo mice had reduced K. pneumoniae lung burden compared with that of WT controls. FSTL-1 Hypo mice had increased Il17a/interleukin-17A (IL-17A) and IL-17-dependent cytokine expression. FSTL-1 Hypo lungs also had increased IL-17A+ and TCRγδ+ cells. FSTL-1 Hypo/TCRδ-/- displayed a lung burden similar to that of FSTL-1 Hypo and reduced lung burden compared with the TCRδ-/- controls. However, FSTL-1 Hypo/TCRδ-/- mice had greater bacterial dissemination than FSTL-1 Hypo mice, suggesting that gamma delta T (γδT) cells are dispensable for FSTL-1 Hypo control of pulmonary infection but are required for dissemination control. Confusing these observations, FSTL-1 Hypo/TCRδ-/- lungs had an increased percentage of IL-17A-producing cells compared with that of TCRδ-/- mice. Removal of IL-17A signaling in the FSTL-1 Hypo mouse resulted in an increased lung burden. These findings identify a novel role for FSTL-1 in innate lung immunity to bacterial infection, suggesting that FSTL-1 influences type-17 pulmonary bacterial immunity.


Asunto(s)
Proteínas Relacionadas con la Folistatina/genética , Interacciones Huésped-Patógeno/genética , Interacciones Huésped-Patógeno/inmunología , Inmunomodulación , Neumonía Bacteriana/etiología , Animales , Carga Bacteriana , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades , Proteínas Relacionadas con la Folistatina/metabolismo , Inmunofenotipificación , Interleucina-17/metabolismo , Infecciones por Klebsiella/genética , Infecciones por Klebsiella/inmunología , Infecciones por Klebsiella/microbiología , Klebsiella pneumoniae/inmunología , Recuento de Linfocitos , Ratones , Ratones Noqueados , Neumonía Bacteriana/metabolismo , Receptores de Antígenos de Linfocitos T gamma-delta/metabolismo , Transducción de Señal , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo
3.
Clin Immunol ; 212: 108360, 2020 03.
Artículo en Inglés | MEDLINE | ID: mdl-32035179

RESUMEN

Rheumatoid arthritis (RA) is characterized by the production of anti-citrullinated protein antibodies (ACPAs). To gain insights into the relationship between ACPA-expressing B cells in peripheral blood (PB) and synovial tissue (ST), we sequenced the B cell repertoire in paired PB and ST samples from five individuals with established, ACPA+ RA. Bioinformatics analysis of paired heavy- and light-chain sequences revealed clonally-related family members shared between PB and ST. ST-derived antibody repertoires exhibited reduced diversity and increased normalized clonal family size compared to PB-derived repertoires. Functional characterization showed that seven recombinant antibodies (rAbs) expressed from subject-derived sequences from both compartments bound citrullinated antigens and immune complexes (ICs) formed using one ST-derived rAb stimulated macrophage TNF-α production. Our findings demonstrate B cell trafficking between PB and ST in subjects with RA and ST repertoires include B cells that encode ACPA capable of forming ICs that stimulate cellular responses implicated in RA pathogenesis.


Asunto(s)
Anticuerpos Antiproteína Citrulinada/inmunología , Complejo Antígeno-Anticuerpo/inmunología , Artritis Reumatoide/inmunología , Linfocitos B/inmunología , Macrófagos/inmunología , Membrana Sinovial/inmunología , Factor de Necrosis Tumoral alfa/inmunología , Diversidad de Anticuerpos/inmunología , Biología Computacional , Humanos , Activación de Macrófagos/inmunología , Membrana Sinovial/citología
4.
Immunol Cell Biol ; 95(8): 656-665, 2017 09.
Artículo en Inglés | MEDLINE | ID: mdl-28377613

RESUMEN

Follistatin-like protein 1 (FSTL-1) possesses several newly identified roles in mammalian biology, including interleukin (IL)-17-driven inflammation, though the mechanism underlying FSTL-1 influence on IL-17-mediated cytokine production is unknown. Using parallel in vitro bone marrow stromal cell models of FSTL-1 suppression, we employed unbiased microarray analysis to identify FSTL-1-regulated genes and pathways that could influence IL-17-dependent production of IL-6 and granulocyte colony-stimulating factor. We discovered that FSTL-1 modulates Il17rc gene expression. Specifically, FSTL-1 was necessary for Il17rc gene transcription, IL-17RC surface protein expression and IL-17-dependent cytokine production. This work identifies a mechanism by which FSTL-1 influences IL-17-driven inflammatory signaling in vitro and reveals a novel function for FSTL-1, as a modulator of gene expression. Thus enhanced understanding of the interplay between FSTL-1 and IL-17-mediated inflammation may provide insight into potential therapeutic targets of IL-17-mediated diseases and warrants ongoing study of in vivo models and clinical scenarios of FSTL-1-influenced diseases.


Asunto(s)
Proteínas Relacionadas con la Folistatina/genética , Interleucina-17/metabolismo , Células Madre Mesenquimatosas/fisiología , ARN Mensajero/genética , Receptores de Interleucina/metabolismo , Animales , Células Cultivadas , Técnicas de Cultivo de Embriones , Proteínas Relacionadas con la Folistatina/metabolismo , Regulación de la Expresión Génica , Técnicas de Inactivación de Genes , Inflamación/genética , Ratones , Ratones Endogámicos C57BL , Análisis de Secuencia por Matrices de Oligonucleótidos , Estabilidad del ARN , ARN Interferente Pequeño/genética , Receptores de Interleucina/genética , Transducción de Señal
5.
Pflugers Arch ; 465(9): 1249-60, 2013 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-23515871

RESUMEN

The Ca(2+) sensor stromal interacting molecule 1 (STIM1) and the Ca(2+) channel Orai1 mediate the ubiquitous store-operated Ca(2+) entry (SOCE) pathway activated by depletion of internal Ca(2+) stores and mediated through the highly Ca(2+)-selective, Ca(2+) release-activated Ca(2+) (CRAC) current. Furthermore, STIM1 and Orai1, along with Orai3, encode store-independent Ca(2+) currents regulated by either arachidonate or its metabolite, leukotriene C4. Orai channels are emerging as important contributors to numerous cell functions, including proliferation, migration, differentiation, and apoptosis. Recent studies suggest critical involvement of STIM/Orai proteins in controlling the development of several cancers, including malignancies of the breast, prostate, and cervix. Here, we quantitatively compared the magnitude of SOCE and the expression levels of STIM1 and Orai1 in non-malignant human primary astrocytes (HPA) and in primary human cell lines established from surgical samples of the brain tumor glioblastoma multiforme (GBM). Using Ca(2+) imaging, patch-clamp electrophysiology, pharmacological reagents, and gene silencing, we established that in GBM cells, SOCE and CRAC are mediated by STIM1 and Orai1. We further found that GBM cells show upregulation of SOCE and increased Orai1 levels compared to HPA. The functional significance of SOCE was evaluated by studying the effects of STIM1 and Orai1 knockdown on cell proliferation and invasion. Utilizing Matrigel assays, we demonstrated that in GBM, but not in HPA, downregulation of STIM1 and Orai1 caused a dramatic decrease in cell invasion. In contrast, the effects of STIM1 and Orai1 knockdown on GBM cell proliferation were marginal. Overall, these results demonstrate that STIM1 and Orai1 encode SOCE and CRAC currents and control invasion of GBM cells. Our work further supports the potential use of channels contributed by Orai isoforms as therapeutic targets in cancer.


Asunto(s)
Neoplasias Encefálicas/metabolismo , Canales de Calcio/metabolismo , Señalización del Calcio , Glioblastoma/metabolismo , Proteínas de la Membrana/metabolismo , Proteínas de Neoplasias/metabolismo , Potenciales de Acción , Astrocitos/metabolismo , Neoplasias Encefálicas/patología , Calcio/metabolismo , Canales de Calcio/genética , Línea Celular Tumoral , Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Glioblastoma/patología , Humanos , Proteínas de la Membrana/genética , Invasividad Neoplásica , Proteínas de Neoplasias/genética , Proteína ORAI1 , Molécula de Interacción Estromal 1 , Transcripción Genética , Regulación hacia Arriba
6.
Microcirculation ; 20(4): 330-6, 2013 May.
Artículo en Inglés | MEDLINE | ID: mdl-23312019

RESUMEN

Store-operated Ca²âº entry (SOCE) is a receptor-regulated Ca²âº entry pathway that is both ubiquitous and evolutionarily conserved. SOCE is activated by depletion of intracellular Ca²âº stores through receptor-mediated production of inositol 1,4,5-trisphosphate (IP3). The depletion of endoplasmic reticulum (ER) Ca²âº is sensed by stromal interaction molecule 1 (STIM1). On store depletion, STIM1 aggregates and moves to areas where the ER comes close to the plasma membrane (PM; within 25 nm) to interact with Orai1 channels and activate Ca²âº entry. Ca²âº entry through store-operated Ca²âº (SOC) channels, originally thought to mediate the replenishment of Ca²âº stores, participate in active downstream signaling by coupling to the activation of enzymes and transcription factors that control a wide variety of long-term cell functions such as proliferation, growth, and migration. SOCE has also been proposed to contribute to short-term cellular responses such as muscle contractility. While there are significant STIM1/Orai1 protein levels and SOCE activity in adult skeletal muscle, the precise role of SOCE in skeletal muscle contractility is not clear. The dependence on SOCE during cardiac and smooth muscle contractility is even less certain. Here, we will hypothesize on the contribution of SOCE in muscle and its potential role in contractility and signaling.


Asunto(s)
Canales de Calcio/metabolismo , Señalización del Calcio/fisiología , Calcio/metabolismo , Proteínas de la Membrana/metabolismo , Músculo Esquelético/metabolismo , Músculo Liso/metabolismo , Proteínas de Neoplasias/metabolismo , Animales , Membrana Celular/metabolismo , Humanos , Proteína ORAI1 , Molécula de Interacción Estromal 1
7.
Cytokine ; 64(1): 404-12, 2013 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-23800789

RESUMEN

Prostaglandin E2 (PGE2), IL-23 and IL-1ß are implicated in inflammatory bowel disease susceptibility, likely in part by modulating IL-17 producing CD4(+) T helper (Th17) cells. To better understand how these three mediators affect Th17 cell memory responses, we characterized the gene expression profiles of activated human peripheral CD4(+) effector memory T cells and sorted Th17 memory cells from healthy donors concurrent with IL17A mRNA induction mediated by PGE2 and/or IL-23 plus IL-1ß. We discovered that PGE2 and IL-23 plus IL-1ß differentially regulate Th17 cytokine expression and synergize to induce IL-17A, but not IL-17F. IL-23 plus IL-1ß preferentially induce IL-17F expression. The addition of PGE2 to IL-23 plus IL-1ß only enhances IL-17A expression as mediated by the PGE2 EP4 receptor, and promotes a switch from an IL-17F to an IL-17A predominant immune response. The human Th17 HuT-102 cell line was also found to constitutively express IL-17A, but not IL-17F. We went on to show that the IL17A and IL17F loci have divergent epigenetic architectures in unstimulated HuT-102 and primary Th17 cells and are poised for preferential expression of IL17A. We conclude that the chromatin for IL17A and IL17F are distinctly regulated, which may play an important role in mucosal health and disease.


Asunto(s)
Histonas/metabolismo , Interleucina-17/genética , Subtipo EP4 de Receptores de Prostaglandina E/metabolismo , Células Th17/metabolismo , Línea Celular , Cromatina/genética , Cromatina/metabolismo , AMP Cíclico/metabolismo , Histonas/genética , Humanos , Memoria Inmunológica/inmunología , Interleucina-17/metabolismo , Interleucina-1beta/metabolismo , Interleucina-23/metabolismo , Prostaglandinas E/metabolismo , ARN Mensajero/biosíntesis , Transducción de Señal/inmunología , Células Th17/inmunología
8.
J Bacteriol ; 192(22): 5972-81, 2010 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-20833803

RESUMEN

PilO is an oligosaccharyl transferase (OTase) that catalyzes the O-glycosylation of Pseudomonas aeruginosa 1244 pilin by adding a single O-antigen repeating unit to the ß carbon of the C-terminal residue (a serine). While PilO has an absolute requirement for Ser/Thr at this position, it is unclear if this enzyme must recognize other pilin features. To test this, pilin constructs containing peptide extensions terminating with serine were tested for the ability to support glycosylation. It was found that a 15-residue peptide, which had been modeled on the C-proximal region of strain 1244 pilin, served as a PilO substrate when it was expressed on either group II or group III pilins. In addition, adding a 3-residue extension culminating in serine to the C terminus of a group III pilin supported PilO activity. A protein fusion composed of strain 1244 pilin linked at its C terminus with Escherichia coli alkaline phosphatase (which, in turn, contained the above-mentioned 15 amino acids at its C terminus) was glycosylated by PilO. E. coli alkaline phosphatase lacking the pilin membrane anchor and containing the 15-residue peptide was also glycosylated by PilO. Addition of the 3-residue extension did not allow glycosylation of either of these constructs. Site-directed mutagenesis of strain 1244 pilin residues of the C-proximal region common to the group I proteins showed that this structure was not required for glycosylation. These experiments indicate that pilin common sequence is not required for glycosylation and show that nonpilin protein can be engineered to be a PilO substrate.


Asunto(s)
Proteínas Bacterianas/metabolismo , Proteínas Fimbrias/metabolismo , Hexosiltransferasas/metabolismo , Proteínas de la Membrana/metabolismo , Pseudomonas aeruginosa/metabolismo , Fosfatasa Alcalina/genética , Fosfatasa Alcalina/metabolismo , Secuencia de Aminoácidos , Sustitución de Aminoácidos/genética , Proteínas Bacterianas/genética , Proteínas de Escherichia coli/genética , Proteínas de Escherichia coli/metabolismo , Proteínas Fimbrias/genética , Glicosilación , Datos de Secuencia Molecular , Mutagénesis Sitio-Dirigida , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Especificidad por Sustrato
9.
Eukaryot Cell ; 8(11): 1808-11, 2009 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-19717739

RESUMEN

Saccharomyces cerevisiae produces extracellular glycerophosphoinositol through phospholipase-mediated turnover of phosphatidylinositol and transports glycerophosphoinositol into the cell upon nutrient limitation. A screening identified the RAS GTPase-activating proteins Ira1 and Ira2 as required for utilization of glycerophosphoinositol as the sole phosphate source, but the RAS/cyclic AMP pathway does not appear to be involved in the growth phenotype. Ira1 and Ira2 affect both the production and transport of glycerophosphoinositol.


Asunto(s)
Proteínas Activadoras de GTPasa/metabolismo , Fosfatos de Inositol/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/metabolismo , Transporte Biológico , Proteínas Activadoras de GTPasa/genética , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/genética
10.
Cell Rep ; 22(10): 2642-2653, 2018 03 06.
Artículo en Inglés | MEDLINE | ID: mdl-29514093

RESUMEN

Th17 cells drive autoimmune disease but also control commensal microbes. A common link among antigens from self-proteins or commensal microbiota is relatively low activation of T cell receptor (TCR) and costimulation signaling. Indeed, strong TCR/CD28 stimulation suppressed Th17 cell differentiation from human naive T cells, but not effector/memory cells. CD28 suppressed the classical Th17 transcriptional program, while inducing known Th17 regulators, and acted through an Akt-dependent mechanism. Th17 cells differentiated without CD28 were not anergic: they showed robust proliferation and maintained Th17 cytokine production following restimulation. Interleukin (IL)-23 and IL-1ß promoted glucose uptake and increased glycolysis. Although modestly increased compared to CD28 costimulation, glycolysis was necessary to support Th17 differentiation, indicating that cytokine-mediated metabolic shifts were sufficient to obviate the classical requirement for CD28 in Th17 differentiation. Together, these data propose that, in humans, strength of TCR/CD28/Akt activation serves as a rheostat tuning the magnitude of Th17 development driven by IL-23 and IL-1ß.


Asunto(s)
Antígenos CD28/metabolismo , Diferenciación Celular , Interleucina-1beta/metabolismo , Interleucina-23/metabolismo , Células Th17/citología , Células Th17/metabolismo , Adulto , Anergia Clonal , Perfilación de la Expresión Génica , Humanos , Activación de Linfocitos/inmunología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Receptores de Antígenos de Linfocitos T/metabolismo
11.
Sci Rep ; 6: 39474, 2016 12 22.
Artículo en Inglés | MEDLINE | ID: mdl-28004828

RESUMEN

Th17 and TfH cells are thought to promote tissue inflammation and autoantibody production, respectively, in autoimmune diseases including rheumatoid arthritis (RA). TfH cells that co-express Th17 markers (CXCR5+Th17) encompass both of these pathogenic functions, and are increased in some human autoimmune settings including juvenile dermatomyositis. We investigated CXCR5+Th17 cells in RA subjects with stable or active disease and before and after TNF inhibitor therapy. CXCR5+Th17 cell frequency was increased in RA compared to healthy controls, but other helper T cell subsets were not different. CXCR5+Th17 cells correlated with disease activity in subjects with active RA prior to initiation of TNF inhibitor therapy. Baseline CXCR5+Th17 cells also correlated with numbers of swollen joints as late as one year post-therapy. CXCR5+Th17 cell frequencies were unaltered by TNF blockade and in fact remained remarkably stable within individuals. We conclude that CXCR5+Th17 cells are not a direct target of TNF blockade and therefore cannot serve as a biomarker of current disease activity. However, basal CXCR5+Th17 cell frequency may indicate underlying differences in disease phenotype between patients and predict ultimate success of TNF inhibitor therapy.


Asunto(s)
Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/metabolismo , Receptores CXCR5/metabolismo , Células Th17/citología , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Adulto , Anciano , Alelos , Biomarcadores/metabolismo , Estudios de Casos y Controles , Estudios de Cohortes , Femenino , Citometría de Flujo , Humanos , Inflamación/metabolismo , Leucocitos Mononucleares/citología , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Monocitos/citología
12.
Cell Rep ; 16(5): 1339-1351, 2016 08 02.
Artículo en Inglés | MEDLINE | ID: mdl-27452457

RESUMEN

Interleukin-23 (IL-23) is required for inflammatory Th17 cell function in experimental autoimmune encephalomyelitis (EAE), and IL-23 blockade reduces the number of effector Th17 cells in the CNS. We report that pro-inflammatory Th17 cells express high integrin ß3 that is IL-23 dependent. Integrin ß3 was not upregulated on all activated T cells; rather, integrin ß3 was upregulated along with its functional partner integrin αv on effector Th17 cells and "ex-Th17" cells, and αvß3(hi) RORγt(+) cells expanded during EAE. Integrin αvß3 inhibitors ameliorated clinical signs of EAE, and integrin ß3 deficiency on CD4(+) T cells alone was sufficient to block EAE induction. Furthermore, integrin-ß3-deficient Th17 cells, but not Th1 cells, were impaired in their ability to induce EAE. Integrin ß3(-/-) T cells induced smaller demyelinated lesions and showed reduced spread and accumulation within the CNS, corresponding with impaired extracellular-matrix-mediated migration. Hence, integrin ß3 is required for Th17 cell-mediated autoimmune CNS inflammation.


Asunto(s)
Inflamación/inmunología , Integrina alfaVbeta3/inmunología , Células Th17/inmunología , Animales , Linfocitos T CD4-Positivos/inmunología , Sistema Nervioso Central/inmunología , Encefalomielitis Autoinmune Experimental/inmunología , Interleucina-23/inmunología , Ratones , Ratones Endogámicos C57BL , Células TH1/inmunología
13.
Clin Transl Sci ; 4(4): 268-73, 2011 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-21884514

RESUMEN

Prostaglandin E2 (PGE2), interleukin (IL)-23, and IL-1beta (ß) propagate inflammatory bowel disease (IBD) by enhancing the development and function of IL-17 producing CD4(+) T helper (Th17) cells. CD4(+) T cells that express the C-type lectin-like receptor CD161 have been proposed to be the physiologic pool of circulating Th17 cells implicated in IBD. We sought to understand how PGE2, alone and in combination with IL-23 and IL-1ß, modulate human peripheral CD161(+) CD4(+) memory T cells. We found that CD161(+) cells comprise a significant proportion of human peripheral CD4(+) memory T cells. PGE2 and IL-23 plus IL-1ß synergistically induced early IL-17A secretion from CD161(+) CD4(+) memory T cells and the selective enrichment of IL-17A(+) CD161(+) CD4(+) memory T cells in culture. Conversely, IL-23 plus IL-1ß partially opposed the PGE2-mediated repression of early interferon gamma (IFN-γ) secretion from CD161(+) cells, as well as the PGE2-mediated depletion of IFN-γ(+) CD161(+) cells. Our results suggest that PGE2 and IL-23 plus IL-1ß induce the Th17 immune response preferentially in CD161(+) CD4(+) memory T cells, while divergently regulating their ability to express IFN-γ. We hypothesize that Th17-mediated chronic inflammation in IBD depends on the net response of CD161(+) CD4(+) memory T cells to both PGE2 and IL-23 plus IL-1ß.


Asunto(s)
Dinoprostona/farmacología , Memoria Inmunológica/efectos de los fármacos , Interleucina-1beta/farmacología , Interleucina-23/farmacología , Subfamilia B de Receptores Similares a Lectina de Células NK/metabolismo , Células TH1/inmunología , Células Th17/inmunología , Antígenos CD4/metabolismo , Células Cultivadas , Humanos , Integrina alfa4/metabolismo , Interferón gamma/metabolismo , Interleucina-17/metabolismo , Células TH1/efectos de los fármacos , Células TH1/metabolismo , Células Th17/efectos de los fármacos , Células Th17/metabolismo
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