RESUMEN
For healthspan and lifespan, ERK, AMPK and mTORC1 represent critical pathways and inflammation is a centrally important hallmark1-7. Here we examined whether IL-11, a pro-inflammatory cytokine of the IL-6 family, has a negative effect on age-associated disease and lifespan. As mice age, IL-11 is upregulated across cell types and tissues to regulate an ERK-AMPK-mTORC1 axis to modulate cellular, tissue- and organismal-level ageing pathologies. Deletion of Il11 or Il11ra1 protects against metabolic decline, multi-morbidity and frailty in old age. Administration of anti-IL-11 to 75-week-old mice for 25 weeks improves metabolism and muscle function, and reduces ageing biomarkers and frailty across sexes. In lifespan studies, genetic deletion of Il11 extended the lives of mice of both sexes, by 24.9% on average. Treatment with anti-IL-11 from 75 weeks of age until death extends the median lifespan of male mice by 22.5% and of female mice by 25%. Together, these results demonstrate a role for the pro-inflammatory factor IL-11 in mammalian healthspan and lifespan. We suggest that anti-IL-11 therapy, which is currently in early-stage clinical trials for fibrotic lung disease, may provide a translational opportunity to determine the effects of IL-11 inhibition on ageing pathologies in older people.
Asunto(s)
Envejecimiento , Interleucina-11 , Longevidad , Transducción de Señal , Animales , Femenino , Masculino , Ratones , Envejecimiento/efectos de los fármacos , Envejecimiento/genética , Envejecimiento/metabolismo , Envejecimiento/patología , Proteínas Quinasas Activadas por AMP/metabolismo , Fragilidad/genética , Fragilidad/metabolismo , Fragilidad/prevención & control , Inflamación/metabolismo , Inflamación/tratamiento farmacológico , Interleucina-11/antagonistas & inhibidores , Interleucina-11/deficiencia , Interleucina-11/genética , Interleucina-11/metabolismo , Subunidad alfa del Receptor de Interleucina-11/metabolismo , Subunidad alfa del Receptor de Interleucina-11/deficiencia , Longevidad/efectos de los fármacos , Longevidad/genética , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Diana Mecanicista del Complejo 1 de la Rapamicina/antagonistas & inhibidores , Ratones Endogámicos C57BL , Transducción de Señal/efectos de los fármacos , Humanos , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/fisiologíaRESUMEN
Interleukin (IL)-11 belongs to the members of the IL-6 family of cytokines and is involved in a variety of biological responses, including hematopoiesis, bone development, and carcinogenesis. However, the cellular sources of IL-11 and regulation of IL-11 expression under physiological and pathological conditions are not fully understood. One of the causes to prevent characterization of IL-11 in vivo is due to the lack of reliable antibodies that detect IL-11 by immunohistochemistry. Moreover, although mice lacking Il11ra have been generated and extensively characterized, Il11-deficient mice have not been characterized yet. Here we generated two anti-IL-11 antibodies that blocked biological activities of IL-11 and detected IL-11 by immunohistochemistry, respectively. One clone of anti-IL-11 antibodies blocked IL-11-, but not IL-6-induced cell proliferation and IL-11-induced phosphorylation of STAT3 of an IL-11-dependent cell line. Moreover, we used recently established Il11-deficient mice to test the specificity of anti-IL-11 antibodies for immunohistochemistry. Another clone of anti-IL-11 antibodies stained stromal cells surrounding tumors of the colon of wild-type, but not Il11-deficient mice following treatment with Azoxymethane plus dextran sulfate sodium. Together, these newly developed anti-IL-11 antibodies provide a better understanding of the functions of IL-11 in vivo under various physiological and pathological conditions.
Asunto(s)
Anticuerpos/farmacología , Interleucina-11/inmunología , Animales , Azoximetano , Carcinógenos , Proliferación Celular/efectos de los fármacos , Neoplasias del Colon , Sulfato de Dextran , Interleucina-11/antagonistas & inhibidores , Interleucina-11/deficiencia , Interleucina-6 , Ratones , Ratones Noqueados , Fosforilación/efectos de los fármacos , Factor de Transcripción STAT3/metabolismo , Células del EstromaRESUMEN
Multiple cytokines, including interleukin 6 (IL-6), IL-11, IL-27, oncostatin M (OSM), and leukemia inhibitory factor (LIF), signal via the common GP130 cytokine receptor subunit. In this study, we describe a patient with a homozygous mutation of IL6ST (encoding GP130 p.N404Y) who presented with recurrent infections, eczema, bronchiectasis, high IgE, eosinophilia, defective B cell memory, and an impaired acute-phase response, as well as skeletal abnormalities including craniosynostosis. The p.N404Y missense substitution is associated with loss of IL-6, IL-11, IL-27, and OSM signaling but a largely intact LIF response. This study identifies a novel immunodeficiency with phenotypic similarities to STAT3 hyper-IgE syndrome caused by loss of function of GP130.
Asunto(s)
Craneosinostosis/genética , Receptor gp130 de Citocinas/genética , Síndromes de Inmunodeficiencia/genética , Mutación Missense/genética , Preescolar , Receptor gp130 de Citocinas/fisiología , Exoma/genética , Femenino , Humanos , Interleucina-11/deficiencia , Interleucina-6/deficiencia , Interleucinas/deficienciaRESUMEN
Current therapies for multiple sclerosis target inflammation but do not directly address oligodendrocyte protection or myelin repair. The gp130 family cytokines ciliary neurotrophic factor, leukemia inhibitory factor, and IL-11 have been identified as oligodendrocyte growth factors, and IL-11 is also strongly immunoregulatory, but their underlying mechanisms of action are incompletely characterized. In this study, we demonstrate that these effects of IL-11 are mediated via differential regulation of apoptosis in oligodendrocytes versus Ag-presenting dendritic cells (DCs), and are dependent on lineage-specific activity of the transcription factors Stat1 versus Stat3. Focal demyelinating lesions induced in cerebral cortices of IL-11Rα(-/-) mice using stereotactic microinjection of lysolecithin were larger than in controls, and remyelination was delayed. In IL-11Rα(-/-) mice, lesions displayed extensive oligodendrocyte loss and axonal transection, and increased infiltration by inflammatory cells including CD11c(+) DCs, CD3(+) lymphocytes, and CD11b(+) phagocytes. In oligodendrocyte progenitor cell (OPC) cultures, IL-11 restricted caspase 9 activation and apoptosis, and it increased myelination in OPC-neuron cocultures. Importantly, siRNA inhibition of Stat1 enhanced the antiapoptotic effects of IL-11 on OPCs, but IL-11 induced apoptosis in the presence of Stat3 silencing. In contrast, IL-11 augmented caspase activation and apoptosis in cultures of CD11c(+) DCs, but not in CD11b(+) or CD3(+) cells. Inhibition of Stat3 exacerbated the proapoptotic effects of IL-11 on DCs, whereas they were ablated in Stat1(-/-) cultures. Collectively, these findings reveal novel mechanisms underlying the actions of a neuroprotective and immunoregulatory member of the gp130 cytokine family, suggesting avenues to enhance oligodendrocyte viability and restrict CNS inflammation in multiple sclerosis.
Asunto(s)
Proteínas Reguladoras de la Apoptosis/fisiología , Interleucina-11/uso terapéutico , Fármacos Neuroprotectores/uso terapéutico , Factor de Transcripción STAT1/fisiología , Factor de Transcripción STAT3/fisiología , Animales , Linaje de la Célula/genética , Linaje de la Célula/inmunología , Supervivencia Celular/genética , Supervivencia Celular/inmunología , Células Cultivadas , Técnicas de Cocultivo , Enfermedades Desmielinizantes/inmunología , Enfermedades Desmielinizantes/patología , Enfermedades Desmielinizantes/terapia , Células Dendríticas/inmunología , Células Dendríticas/patología , Modelos Animales de Enfermedad , Marcación de Gen/métodos , Interleucina-11/deficiencia , Interleucina-11/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/patología , Esclerosis Múltiple/terapia , Oligodendroglía/inmunología , Oligodendroglía/metabolismo , Oligodendroglía/patología , Ratas , Ratas Sprague-Dawley , Células Madre/inmunología , Células Madre/metabolismo , Células Madre/patologíaRESUMEN
Members of the interleukin-6 family of cytokines include leukaemia inhibitory factor (LIF), interleukin-6, interleukin-11, cardiotrophin, ciliary neurotropic growth factor, oncostatin M and the recently discovered cardiotropin-like cytokine (NNT-1). These ligands signal via heterodimeric receptors composed of ligand-specific alpha chains and the common signal-transducing subunit gp130. Gene targeting in mice provided the first indication of a role for interleukin 6 family cytokines in implantation with the generation of mice with a null mutation of the gene encoding LIF. LIF null female mice were infertile because of failure of blastocyst implantation. More recently, interleukin-11 signalling has been shown to be required for the uterine decidualization response. This review describes the insights into the role of interleukin-6 family cytokines in female fertility that have come from gene targeting experiments in mice.
Asunto(s)
Implantación del Embrión/inmunología , Inhibidores de Crecimiento/fisiología , Interleucina-11/fisiología , Linfocinas/fisiología , Animales , Endometrio/inmunología , Femenino , Inhibidores de Crecimiento/deficiencia , Inhibidores de Crecimiento/genética , Humanos , Interleucina-11/deficiencia , Interleucina-11/genética , Interleucina-6/deficiencia , Interleucina-6/genética , Interleucina-6/fisiología , Factor Inhibidor de Leucemia , Linfocinas/deficiencia , Linfocinas/genética , Ratones , Ratones Noqueados , Fenotipo , Embarazo , Útero/inmunologíaRESUMEN
Mice lacking thrombopoietin (TPO) or its receptor c-Mpl are severely thrombocytopenic, consistent with a dominant physiological role for this cytokine in megakaryocytopoiesis. However, these mice remain healthy and show no signs of spontaneous hemorrhage, implying that TPO-independent mechanisms for platelet production exist and are sufficient for hemostasis. To investigate the roles of cytokines that act through the gp130 signaling chain in the residual platelet production of mpl (-/-) mice, mpl (-/-)IL-6(-/-), mpl(-/-)LIF(-/-), and mpl(-/-)IL-11Ralpha(-/-) double-mutant mice were generated. In each of these compound mutants, the number of circulating platelets was no lower than that observed in mice lacking only the c-mpl gene. Moreover, the deficits in the numbers of megakaryocytes and megakaryocyte progenitor cells in the bone marrow and spleen were no further exacerbated in mpl(-/-)IL-6(-/-), mpl(-/-)LIF(-/-), or mpl(-/-)IL-11Ralpha(-/-) double-mutant mice compared with those in Mpl-deficient animals. In single IL-6(-/-), LIF(-/-), and IL-11Ralpha(-/-) mutant mice, platelet production was normal. These data establish that, as single regulators, IL-6, IL-11, and LIF have no essential role in normal steady-state megakaryocytopoiesis, and are not required for the residual megakaryocyte and platelet production seen in the c-mpl(-/-) mouse. (Blood. 2000;95:528-534)