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2.
Nature ; 632(8023): 157-165, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-39020175

RESUMO

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.


Assuntos
Envelhecimento , Interleucina-11 , Longevidade , Transdução de Sinais , Animais , Feminino , Masculino , Camundongos , Envelhecimento/efeitos dos fármacos , Envelhecimento/genética , Envelhecimento/metabolismo , Envelhecimento/patologia , Proteínas Quinases Ativadas por AMP/metabolismo , Fragilidade/genética , Fragilidade/metabolismo , Fragilidade/prevenção & controle , Inflamação/metabolismo , Inflamação/tratamento farmacológico , Interleucina-11/antagonistas & inibidores , Interleucina-11/deficiência , Interleucina-11/genética , Interleucina-11/metabolismo , Subunidade alfa de Receptor de Interleucina-11/metabolismo , Subunidade alfa de Receptor de Interleucina-11/deficiência , Longevidade/efeitos dos fármacos , Longevidade/genética , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/antagonistas & inibidores , Camundongos Endogâmicos C57BL , Transdução de Sinais/efeitos dos fármacos , Humanos , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/fisiologia
4.
Nat Commun ; 13(1): 7497, 2022 12 05.
Artigo em Inglês | MEDLINE | ID: mdl-36470928

RESUMO

The kidney has large regenerative capacity, but this is compromised when kidney damage is excessive and renal tubular epithelial cells (TECs) undergo SNAI1-driven growth arrest. Here we investigate the role of IL11 in TECs, kidney injury and renal repair. IL11 stimulation of TECs induces ERK- and p90RSK-mediated GSK3ß inactivation, SNAI1 upregulation and pro-inflammatory gene expression. Mice with acute kidney injury upregulate IL11 in TECs leading to SNAI1 expression and kidney dysfunction, which is not seen in Il11 deleted mice or in mice administered a neutralizing IL11 antibody in either preemptive or treatment modes. In acute kidney injury, anti-TGFß reduces renal fibrosis but exacerbates inflammation and tubule damage whereas anti-IL11 reduces all pathologies. Mice with TEC-specific deletion of Il11ra1 have reduced pathogenic signaling and are protected from renal injury-induced inflammation, fibrosis, and failure. In a model of chronic kidney disease, anti-IL11 therapy promotes TEC proliferation and parenchymal regeneration, reverses fibroinflammation and restores renal mass and function. These data highlight IL11-induced mesenchymal transition of injured TECs as an important renal pathology and suggest IL11 as a therapeutic target for restoring stalled endogenous regeneration in the diseased kidney.


Assuntos
Injúria Renal Aguda , Anticorpos Neutralizantes , Interleucina-11 , Túbulos Renais , Nefrite , Regeneração , Insuficiência Renal Crônica , Animais , Camundongos , Injúria Renal Aguda/terapia , Fibrose , Subunidade alfa de Receptor de Interleucina-11/genética , Túbulos Renais/fisiologia , Nefrite/terapia , Interleucina-11/antagonistas & inibidores , Interleucina-11/fisiologia , Deleção de Genes , Anticorpos Neutralizantes/uso terapêutico , Insuficiência Renal Crônica/terapia , Modelos Animais de Doenças
5.
Elife ; 102021 08 26.
Artigo em Inglês | MEDLINE | ID: mdl-34435951

RESUMO

It is generally accepted that IL6-mediated STAT3 signaling in hepatocytes, mediated via glycoprotein 130 (gp130; IL6ST), is beneficial and that the synthetic IL6:IL6ST fusion protein (HyperIL6) promotes liver regeneration. Recently, autocrine IL11 activity that also acts via IL6ST but uses ERK rather than STAT3 to signal, was found to be hepatotoxic. Here we examined whether the beneficial effects of HyperIL6 could reflect unappreciated competitive inhibition of IL11-dependent IL6ST signaling. In human and mouse hepatocytes, HyperIL6 reduced N-acetyl-p-aminophenol (APAP)-induced cell death independent of STAT3 activation and instead, dose-dependently, inhibited IL11-related signaling and toxicities. In mice, expression of HyperIl6 reduced ERK activation and promoted STAT3-independent hepatic regeneration (PCNA, Cyclin D1, Ki67) following administration of either IL11 or APAP. Inhibition of putative intrinsic IL6 trans-signaling had no effect on liver regeneration in mice. Following APAP, mice deleted for Il11 exhibited spontaneous liver repair but HyperIl6, despite robustly activating STAT3, had no effect on liver regeneration in this strain. These data show that synthetic IL6ST binding proteins such as HyperIL6 can have unexpected, on-target effects and suggest IL11, not IL6, as important for liver regeneration.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Hepatócitos/metabolismo , Interleucina-11/metabolismo , Interleucina-6/metabolismo , Regeneração Hepática/fisiologia , Animais , Células Cultivadas , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Glicoproteínas/metabolismo , Hepatócitos/citologia , Humanos , Interleucina-11/antagonistas & inibidores , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ligação Proteica/fisiologia , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/fisiologia
6.
FASEB J ; 35(6): e21676, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34042220

RESUMO

Ligamentum flavum hypertrophy (LFH) leads to lumbar spinal stenosis (LSS) caused by LF tissue inflammation and fibrosis. Emerging evidence has indicated that dysregulated microRNAs (miRNAs) have an important role in inflammation and fibrosis. Mechanical stress (MS) has been explored as an initiating step in LFH pathology progression; the inflammation-related miRNAs induced after mechanical stress have been implicated in fibrosis pathology. However, the pathophysiological mechanism of MS-miRNAs-LFH remains to be elucidated. Using miRNAs sequencing analysis and subsequent confirmation with qRT-PCR assays, we identified the decreased expression of miR-10396b-3p and increased expression of IL-11 (interleukin-11) as responses to the development of LSS in hypertrophied LF tissues. We also found that IL-11 is positively correlated with fibrosis indicators of collagen I and collagen III. The up-regulation of miR-10396b-3p significantly decreased the level of IL-11 expression, whereas miR-10396b-3p down-regulation increased IL-11 expression in vitro. Luciferase reporter assay indicates that IL-11 is a direct target of miR-10396b-3p. Furthermore, cyclic mechanical stress inhibits miR-10396b-3p and induces IL-11, collagen I, and collagen III in vitro. Our results showed that overexpression of miR-10396b-3p suppresses MS-induced LFH by inhibiting collagen I and III via the inhibition of IL-11. These data suggest that the MS-miR-10396b-3p-IL-11 axis plays a key role in the pathological progression of LFH.


Assuntos
Hipertrofia/prevenção & controle , Interleucina-11/antagonistas & inibidores , Ligamento Amarelo/crescimento & desenvolvimento , MicroRNAs/genética , Estenose Espinal/prevenção & controle , Estresse Mecânico , Feminino , Humanos , Hipertrofia/etiologia , Hipertrofia/patologia , Interleucina-11/genética , Interleucina-11/metabolismo , Ligamento Amarelo/metabolismo , Ligamento Amarelo/patologia , Masculino , Pessoa de Meia-Idade , Estenose Espinal/etiologia , Estenose Espinal/patologia
7.
J Cardiovasc Transl Res ; 14(2): 222-228, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-32592090

RESUMO

There are currently no specific treatments for cardiac fibrosis. We tested the efficacy of a neutralising anti-IL11 antibody (X203) to reduce cardiac fibrosis in two preclinical models: transverse aortic constriction (TAC) and chronic angiotensin II infusion (AngII). In the first model, male C57BL/6J mice were subjected to TAC for 2 weeks. In the second model, mice received continuous angiotensin II for 4 weeks via subcutaneous pump. In both models, mice received either 20 mg/kg of X203 or isotype-control antibody twice-weekly, starting 24 h after surgery. Cardiac fibrosis and extracellular matrix gene expression were assessed by RT-qPCR, Western blot, histology and collagen (hydroxyproline) assays. In both models, X203 significantly reduced pro-fibrotic gene expression and myocardial fibrosis (TAC: 51% reduction in total collagen, P < 0.001, 39% in perivascular fibrosis, P < 0.001; AngII: 17% reduction in total collagen, P = 0.04, 83% in perivascular fibrosis, P < 0.001). Pharmacological targeting of IL11 reduces cardiac fibrosis in preclinical models. Figa Graphical Abstract.


Assuntos
Anticorpos Neutralizantes/farmacologia , Aorta/cirurgia , Cardiomiopatias/prevenção & controle , Interleucina-11/antagonistas & inibidores , Miocárdio/metabolismo , Angiotensina II , Animais , Aorta/fisiopatologia , Pressão Arterial , Cardiomiopatias/etiologia , Cardiomiopatias/metabolismo , Cardiomiopatias/patologia , Colágeno/genética , Colágeno/metabolismo , Constrição , Modelos Animais de Doenças , Fibronectinas/genética , Fibronectinas/metabolismo , Fibrose , Hidroxiprolina/metabolismo , Interleucina-11/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Miocárdio/patologia , Transdução de Sinais
8.
PLoS One ; 14(8): e0221029, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31415618

RESUMO

Interleukin-11 (IL-11) is an interleukin-6 (IL-6) family cytokine shown to play a protective role in acute inflammatory settings including systemic infection. In this study we addressed the role of IL-11 in acute bacterial pneumonia using a mouse model of E. coli pneumonia. Compared with other related cytokines, IL-11 protein was maintained at high levels in the lung at baseline, with only mild alterations in whole lung and BALF levels during acute infection. The primary source of IL-11 in the lung was the epithelium, but steady state production was not dependent on the inflammatory transcription factor nuclear factor kappa B in cells of either myeloid or epithelial lineage. Blockade of IL-11 with neutralizing antibodies resulted in a mild but significant decrease in neutrophil recruitment and increase in pulmonary edema during pneumonia, without detectable alterations in bacterial clearance. Exogenous IL-11 administration, however, had no effect at baseline or during infection. Overall, we conclude that maintenance of lung IL-11 concentrations may influence acute pulmonary inflammation during infection, albeit modestly.


Assuntos
Interleucina-11/imunologia , Infiltração de Neutrófilos/imunologia , Neutrófilos/imunologia , Pneumonia Bacteriana/imunologia , Edema Pulmonar/imunologia , Doença Aguda , Animais , Anticorpos Neutralizantes/farmacologia , Interleucina-11/antagonistas & inibidores , Interleucina-11/genética , Camundongos , Camundongos Knockout , Infiltração de Neutrófilos/efeitos dos fármacos , Neutrófilos/patologia , Pneumonia Bacteriana/tratamento farmacológico , Pneumonia Bacteriana/genética , Pneumonia Bacteriana/patologia , Edema Pulmonar/tratamento farmacológico , Edema Pulmonar/genética , Edema Pulmonar/patologia
9.
Gastroenterology ; 157(3): 777-792.e14, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31078624

RESUMO

BACKGROUND & AIMS: We studied the role of interleukin 11 (IL11) signaling in the pathogenesis of nonalcoholic steatohepatitis (NASH) using hepatic stellate cells (HSCs), hepatocytes, and mouse models of NASH. METHODS: We stimulated mouse and human fibroblasts, HSCs, or hepatocytes with IL11 and other cytokines and analyzed them by imaging, immunoblot, and functional assays and enzyme-linked immunosorbent assays. Mice were given injections of IL11. Mice with disruption of the interleukin 11 receptor subunit alpha1 gene (Il11ra1-/-) mice and Il11ra1+/+ mice were fed a high-fat methionine- and choline-deficient diet (HFMCD) or a Western diet with liquid fructose (WDF) to induce steatohepatitis; control mice were fed normal chow. db/db mice were fed with methionine- and choline-deficient diet for 12 weeks and C57BL/6 NTac were fed with HFMCD for 10 weeks or WDF for 16 weeks. Some mice were given intraperitoneal injections of anti-IL11 (X203), anti-IL11RA (X209), or a control antibody at different timepoints on the diets. Livers and blood were collected; blood samples were analyzed by biochemistry and liver tissues were analyzed by histology, RNA sequencing, immunoblots, immunohistochemistry, hydroxyproline, and mass cytometry time of flight assays. RESULTS: HSCs incubated with cytokines produced IL11, resulting in activation (phosphorylation) of ERK and expression of markers of fibrosis. Livers of mice given injections of IL11 became damaged, with increased markers of fibrosis, hepatocyte cell death and inflammation. Following the HFMCD or WDF, livers from Il11ra1-/- mice had reduced steatosis, fibrosis, expression of markers of inflammation and steatohepatitis, compared to and Il11ra1+/+ mice on the same diets. Depending on the time of administration of anti-IL11 or anti-IL11RA antibodies to wild-type mice on the HFMCD or WDF, or to db/db mice on the methionine and choline-deficient diet, the antibodies prevented, stopped, or reversed development of fibrosis and steatosis. Blood samples from Il11ra1+/+ mice fed the WDF and given injections of anti-IL11 or anti-IL11RA, as well as from Il11ra1-/- mice fed WDF, had lower serum levels of lipids and glucose than mice not injected with antibody or with disruption of Il11ra1. CONCLUSIONS: Neutralizing antibodies that block IL11 signaling reduce fibrosis, steatosis, hepatocyte death, inflammation and hyperglycemia in mice with diet-induced steatohepatitis. These antibodies also improve the cardiometabolic profile of mice and might be developed for the treatment of NASH.


Assuntos
Anticorpos Neutralizantes/farmacologia , Hepatite/prevenção & controle , Subunidade alfa de Receptor de Interleucina-11/metabolismo , Interleucina-11/antagonistas & inibidores , Cirrose Hepática Experimental/prevenção & controle , Fígado/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Animais , Morte Celular/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibroblastos/patologia , Células Estreladas do Fígado/efeitos dos fármacos , Células Estreladas do Fígado/metabolismo , Células Estreladas do Fígado/patologia , Hepatite/genética , Hepatite/metabolismo , Hepatite/patologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Hepatócitos/patologia , Humanos , Mediadores da Inflamação/metabolismo , Interleucina-11/metabolismo , Subunidade alfa de Receptor de Interleucina-11/deficiência , Subunidade alfa de Receptor de Interleucina-11/genética , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática Experimental/genética , Cirrose Hepática Experimental/metabolismo , Cirrose Hepática Experimental/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Transdução de Sinais/efeitos dos fármacos , Células THP-1
10.
Biochem Biophys Res Commun ; 505(2): 453-459, 2018 10 28.
Artigo em Inglês | MEDLINE | ID: mdl-30268501

RESUMO

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.


Assuntos
Anticorpos/farmacologia , Interleucina-11/imunologia , Animais , Azoximetano , Carcinógenos , Proliferação de Células/efeitos dos fármacos , Neoplasias do Colo , Sulfato de Dextrana , Interleucina-11/antagonistas & inibidores , Interleucina-11/deficiência , Interleucina-6 , Camundongos , Camundongos Knockout , Fosforilação/efeitos dos fármacos , Fator de Transcrição STAT3/metabolismo , Células Estromais
11.
Clin Immunol ; 197: 45-53, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30149119

RESUMO

IL-11 induced differentiation and expansion of Th17 cells in patients with early relapsing-remitting multiple sclerosis (RRMS). In mice with relapsing-remitting experimental autoimmune encephalomyelitis (RREAE), IL-11 exacerbated disease, induced demyelination in the central nervous system (CNS), increased the percentage of IL-17A+CD4+ Th17 cells in the CNS in the early acute phase, and up-regulated serum IL-17A levels and the percentage of IL-17A+CD4+ Th17 cells in lymph nodes, and IFN-γ+CD4+ T cells in spinal cord in the RR phase. IL-11 antagonist suppressed RREAE disease activities, inhibited IL-17A+CD4+ cell infiltration and demyelination in the CNS, and decreased the percentage of IL-17A+CD4+ T cells in peripheral blood mononuclear cells and ICAM1+CD4+ T cells in brain and SC. Diffusion Tensor Imaging indicated that IL-11 antagonist inhibited demyelination in several brain regions. We conclude that by suppressing Th17 cell-mediated neuroinflammation and demyelination, IL-11 antagonist can be further studied as a potential selective and early therapy for RRMS.


Assuntos
Encéfalo/diagnóstico por imagem , Encefalomielite Autoimune Experimental/imunologia , Interleucina-11/antagonistas & inibidores , Medula Espinal/diagnóstico por imagem , Células Th17/imunologia , Animais , Encéfalo/imunologia , Imagem de Tensor de Difusão , Inflamação , Interleucina-11/imunologia , Subunidade alfa de Receptor de Interleucina-11 , Leucócitos Mononucleares , Camundongos , Esclerose Múltipla Recidivante-Remitente , Proteínas Recombinantes de Fusão , Medula Espinal/imunologia
12.
Reprod Biomed Online ; 36(3): 250-258, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29361454

RESUMO

Interleukin (IL)11 is a crucial regulator during the initiation of pregnancy in humans and mice. Elevated levels are detected in serum, placenta and decidua of women with pre-eclampsia. Elevated IL11 during placentation recapitulates pre-eclampsia in mice, although withdrawal rescues pre-eclampsia features, suggesting that IL11 could provide a novel therapeutic target. The aim of this study was to determine the safety profile of an IL11 antagonist ligated to polyethylene glycol (PEGIL11A) during pregnancy in mice. Blocking IL11 signalling during mid to late gestation pregnancy in mice did not affect pregnancy viability, or alter placental or fetal weight, or morphology. Importantly, decidual area remained unchanged. PEGIL11A did not affect maternal blood pressure, urinary protein or term pup weight. PEGIL11A administration to non-pregnant mice did not affect subsequent fertility; there was no difference in number of implantation sites, or placental or fetal weight between PEGIL11A and PEG-treated mice. These data show that blocking IL11Rα during placentation does not alter the placenta, decidua, fetus, maternal blood pressure or kidneys. These findings highlight the potential of IL11 signalling inhibition as a safe therapy to alleviate pre-eclampsia symptoms and demonstrate the potential for IL11 inhibition as a novel fertility-preserving therapy for women with cancer.


Assuntos
Pressão Sanguínea/efeitos dos fármacos , Fertilidade/efeitos dos fármacos , Interleucina-11/antagonistas & inibidores , Placentação/efeitos dos fármacos , Polietilenoglicóis/química , Animais , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Gravidez , Resultado da Gravidez , Transdução de Sinais
13.
Nature ; 552(7683): 110-115, 2017 12 07.
Artigo em Inglês | MEDLINE | ID: mdl-29160304

RESUMO

Fibrosis is a common pathology in cardiovascular disease. In the heart, fibrosis causes mechanical and electrical dysfunction and in the kidney, it predicts the onset of renal failure. Transforming growth factor ß1 (TGFß1) is the principal pro-fibrotic factor, but its inhibition is associated with side effects due to its pleiotropic roles. We hypothesized that downstream effectors of TGFß1 in fibroblasts could be attractive therapeutic targets and lack upstream toxicity. Here we show, using integrated imaging-genomics analyses of primary human fibroblasts, that upregulation of interleukin-11 (IL-11) is the dominant transcriptional response to TGFß1 exposure and required for its pro-fibrotic effect. IL-11 and its receptor (IL11RA) are expressed specifically in fibroblasts, in which they drive non-canonical, ERK-dependent autocrine signalling that is required for fibrogenic protein synthesis. In mice, fibroblast-specific Il11 transgene expression or Il-11 injection causes heart and kidney fibrosis and organ failure, whereas genetic deletion of Il11ra1 protects against disease. Therefore, inhibition of IL-11 prevents fibroblast activation across organs and species in response to a range of important pro-fibrotic stimuli. These results reveal a central role of IL-11 in fibrosis and we propose that inhibition of IL-11 is a potential therapeutic strategy to treat fibrotic diseases.


Assuntos
Sistema Cardiovascular/metabolismo , Sistema Cardiovascular/patologia , Fibrose/metabolismo , Fibrose/patologia , Interleucina-11/metabolismo , Animais , Comunicação Autócrina , Células Cultivadas , Feminino , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibroblastos/patologia , Fibrose/induzido quimicamente , Coração , Humanos , Interleucina-11/antagonistas & inibidores , Interleucina-11/genética , Subunidade alfa de Receptor de Interleucina-11/deficiência , Subunidade alfa de Receptor de Interleucina-11/genética , Rim/patologia , Masculino , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Miocárdio/metabolismo , Miocárdio/patologia , Escores de Disfunção Orgânica , Biossíntese de Proteínas , Fator de Crescimento Transformador beta1/metabolismo , Fator de Crescimento Transformador beta1/farmacologia , Transgenes/genética
14.
Cytokine Growth Factor Rev ; 32: 41-61, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27312790

RESUMO

Human Interleukin (IL)-11 is a multifunctional cytokine, recognized for its thrombopoietic effects for more than two decades; clinically, IL-11 is used in the treatment of thrombocytopenia. IL-11 shares structural and functional similarities with IL-6, a related family member. In recent years, there has been a renewed interest in IL-11, because its distinct biological activities associated with cancers of epithelial origin and inflammatory disorders have been revealed. Although the crystal structure of IL-11 was resolved more than two years, a better understanding of the mechanisms of IL-11 action is required to further extend the clinical use of IL-11. This review will discuss the available structural, functional, and bioinformatics knowledge concerning IL-11 and will summarize its relationship with several diseases.


Assuntos
Interleucina-11 , Animais , Simulação por Computador , Humanos , Interleucina-11/antagonistas & inibidores , Interleucina-11/química , Interleucina-11/imunologia , Interleucina-11/metabolismo , Estrutura Molecular , Transdução de Sinais
15.
J Infect Dis ; 214(3): 496-501, 2016 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-27190186

RESUMO

Earlier we demonstrated that blocking of interleukin 11 (IL-11) by systemic administration of anti-IL-11 antibodies attenuates severity of Mycobacterium tuberculosis infection in mice. The substitution W147A in the IL-11 molecule creates the form of cytokine capable to disrupt gp130/IL11R signaling complex formation, thus serving as a high-affinity specific antagonist of IL-11-mediated signaling. We hypothesized that this mutant form of IL-11 may serve as an effective tool for inhibition of native IL-11 activity in vivo. We established the recombinant W147A mutant form of IL-11 in an optimized Escherichia coli expression system and administered it as the aerosol in the lungs of M. tuberculosis-susceptible I/St mice infected with M. tuberculosis Our results show that this therapeutic approach markedly inhibits tuberculous inflammation in lungs, increases the survival time of infected animals, and decreases expression of key inflammatory factors at the RNA and protein levels. These findings are a step toward clinical evaluation of the anti-IL-11 therapy for tuberculosis.


Assuntos
Fatores Imunológicos/administração & dosagem , Interleucina-11/antagonistas & inibidores , Proteínas Mutantes/administração & dosagem , Proteínas Recombinantes/administração & dosagem , Tuberculose Pulmonar/tratamento farmacológico , Administração por Inalação , Aerossóis , Substituição de Aminoácidos , Animais , Modelos Animais de Doenças , Feminino , Inflamação/patologia , Pulmão/patologia , Camundongos , Análise de Sobrevida , Usos Terapêuticos
16.
Oncotarget ; 6(2): 679-95, 2015 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-25528766

RESUMO

IL-1 is key driver of gastric tumorigenesis and is a downstream target of IL-11 signaling. Recently, IL-1 cytokines, particularly IL-1ß, have been flagged as therapeutic targets for gastric cancer treatment. Here, we assess the requirement for IL-1 signaling in gastric tumorigenesis. gp130757FF xIL-1RT1-/- mice were generated to determine the pathological consequence of ablated IL-1 signaling in the IL-11 dependent gp130757FF mouse model of gastric tumorigenesis. Gastric lesions in gp130757FF xIL-1RT1-/- mice were increased in incidence and size compared to gp130757FF mice. Proximal gastric lesions originated from the cardiac region and were associated with elevated STAT3 activation, loss of specialized gastric cells and a modulated immune response including increased expression of TNF-α and MDSC associated genes. Administration of IL-11 to IL-1RT1-/- mice showed similar changes to gp130757FF xIL-1RT1-/- mice. Spleens from IL-11 treated wildtype mice showed an enrichment of MDSC and gp130757FF xIL-1RT1-/- mice had increased MDSCs in the stomach compared to gp130757FF mice. Furthermore, crossing TNF-α-/- to gp130757FF mice resulted in reduced lesion size. We conclude that IL-1 signaling antagonizes IL-11/STAT3 mediated pathology and the genetic deletion of IL-1RT1 results in increased tumor burden. We provide evidence that a likely mechanism is due to IL-11/STAT3 dependent enrichment of MDSCs.


Assuntos
Neoplasias Cardíacas/metabolismo , Interleucina-11/antagonistas & inibidores , Células Progenitoras Mieloides/metabolismo , Receptores Tipo I de Interleucina-1/metabolismo , Fator de Transcrição STAT3/metabolismo , Neoplasias Gástricas/metabolismo , Animais , Linhagem Celular Tumoral , Proliferação de Células , Neoplasias Cardíacas/patologia , Humanos , Interleucina-11/metabolismo , Camundongos , Células Progenitoras Mieloides/patologia , Transdução de Sinais , Neoplasias Gástricas/patologia
17.
IUBMB Life ; 66(12): 854-9, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25545915

RESUMO

Both pro-inflammatory cytokines and anti-inflammatory cytokines generated by chondrocytes play essential roles in the process of Rheumatoid arthritis and osteoarthritis (OA). Bornyl acetate is the main volatile constituent in numerous conifer oils and some Chinese traditional herbs, which has displayed an anti-inflammatory effect before. In this study, we found that bornyl acetate elevates the expression of IL-11 at both the mRNA and protein levels. Interestingly, our results indicated that IL-1ß-mediated up-regulation of IL-6, IL-8, MMP-1, and MMP-13 was significantly compromised by IL-11 co-treatment on mRNA levels and protein levels. The antagonistic effects of bornyl acetate on IL-1ß induced targets MMP-1 and MMP-13 were diminished by IL-11 knockdown. Mechanistically, our results indicated that bornyl acetate significantly elevates the expression of AP-1 component c-fos, which may influence gross AP-1 activity and initial the transcription of IL-11. Indeed, expression of IL-11 was reversed upon c-fos knockdown. Our results suggest the therapeutic potentials of bornyl acetate in patients with OA.


Assuntos
Anti-Inflamatórios/farmacologia , Canfanos/farmacologia , Condrócitos/efeitos dos fármacos , Mediadores da Inflamação/metabolismo , Inflamação/tratamento farmacológico , Interleucina-11/metabolismo , Western Blotting , Células Cultivadas , Condrócitos/imunologia , Condrócitos/metabolismo , Citocinas/genética , Citocinas/metabolismo , Ensaio de Imunoadsorção Enzimática , Humanos , Inflamação/metabolismo , Inflamação/patologia , Interleucina-11/antagonistas & inibidores , Interleucina-11/genética , Interleucina-1beta/farmacologia , Metaloproteinase 13 da Matriz/genética , Metaloproteinase 13 da Matriz/metabolismo , NF-kappa B , RNA Mensageiro/genética , RNA Interferente Pequeno/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/efeitos dos fármacos , Fator de Transcrição AP-1/genética , Fator de Transcrição AP-1/metabolismo
18.
J Dermatol Sci ; 71(1): 58-66, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23639700

RESUMO

BACKGROUND: The loss of subcutaneous (sc) fat is associated with aging. Inflammatory cytokines, such as interleukin-1 α (IL-1α), interleukin-11 (IL-11) and tumor necrosis factor-α (TNF-α), are known to inhibit the differentiation of preadipocytes. OBJECTIVE: This study investigated the potential role of inflammatory cytokines in solar-radiation-induced facial fat loss. METHODS: Cultured fibroblasts, keratinocytes, and skin equivalents were exposed to various doses of radiation from a solar simulator. Inflammatory cytokines' mRNA production and protein secretion were examined by qRT-PCR and ELISA, respectively. In some experiments, epidermal-dermal equivalents were pretreated topically with a broad-spectrum sunscreen prior to solar simulated radiation (SSR). Human facial preadipocytes treated with recombinant IL-11 or with conditioned media from solar-irradiated equivalents were evaluated for the level of adipocyte differentiation by image analyses, Oil red O staining, and the expression of adipocyte differentiation markers. RESULTS: IL-11, IL-1α, IL-6, and TNF-α protein secretion were induced from epidermal-dermal equivalents by exposure to SSR. A sunscreen prevented SSR-induced inflammatory cytokines production from such equivalents. Exposure of facial preadipocytes to conditioned medium from solar-irradiated epidermal-dermal equivalents inhibited their differentiation into mature adipocytes. Consequently, conditioned medium from sunscreen-pretreated, solar-irradiated equivalents did not inhibit differentiation of preadipocytes. A cocktail of neutralizing antibodies to IL-11, IL-1α, IL-6 and TNF-α significantly reduced the SSR-induced inhibition of preadipocyte differentiation. CONCLUSION: These results support the hypothesis that SSR-induced inflammatory cytokine may be involved in the photoaging-induced loss of facial subcutaneous fat. Inhibition of this process, e.g. by sunscreens, might slow or prevent photoaging-induced changes in facial contouring.


Assuntos
Mediadores da Inflamação/metabolismo , Interleucina-11/metabolismo , Interleucina-1alfa/metabolismo , Interleucina-6/metabolismo , Envelhecimento da Pele/efeitos da radiação , Pele/efeitos da radiação , Gordura Subcutânea/efeitos da radiação , Fator de Necrose Tumoral alfa/metabolismo , Raios Ultravioleta , Adipócitos/imunologia , Adipócitos/efeitos da radiação , Adipogenia/efeitos da radiação , Anticorpos Neutralizantes/farmacologia , Células Cultivadas , Meios de Cultivo Condicionados/metabolismo , Fibroblastos/imunologia , Fibroblastos/efeitos da radiação , Humanos , Mediadores da Inflamação/antagonistas & inibidores , Interleucina-11/antagonistas & inibidores , Interleucina-11/genética , Interleucina-1alfa/antagonistas & inibidores , Interleucina-1alfa/genética , Interleucina-6/antagonistas & inibidores , Interleucina-6/genética , Queratinócitos/imunologia , Queratinócitos/efeitos da radiação , RNA Mensageiro/metabolismo , Pele/efeitos dos fármacos , Pele/imunologia , Pele/patologia , Envelhecimento da Pele/efeitos dos fármacos , Gordura Subcutânea/efeitos dos fármacos , Gordura Subcutânea/imunologia , Gordura Subcutânea/patologia , Protetores Solares/farmacologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/genética , Regulação para Cima
19.
BMC Cancer ; 13: 16, 2013 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-23311882

RESUMO

BACKGROUND: Interleukin (IL)-11, a cytokine produced by breast cancer, has been implicated in breast cancer-induced osteolysis (bone destruction) but the mechanism(s) of action remain controversial. Some studies show that IL-11 is able to promote osteoclast formation independent of the receptor activator of NF-κB ligand (RANKL), while others demonstrate IL-11 can induce osteoclast formation by inducing osteoblasts to secrete RANKL. This work aims to further investigate the role of IL-11 in metastasis-induced osteolysis by addressing a new hypothesis that IL-11 exerts effects on osteoclast progenitor cells. METHODS: To address the precise role of breast cancer-derived IL-11 in osteoclastogenesis, we determined the effect of breast cancer conditioned media on osteoclast progenitor cells with or without an IL-11 neutralizing antibody. We next investigated whether recombinant IL-11 exerts effects on osteoclast progenitor cells and survival of mature osteoclasts. Finally, we examined the ability of IL-11 to mediate osteoclast formation in tissue culture dishes and on bone slices in the absence of RANKL, with suboptimal levels of RANKL, or from RANKL-pretreated murine bone marrow macrophages (BMMs). RESULTS: We found that freshly isolated murine bone marrow cells cultured in the presence of breast cancer conditioned media for 6 days gave rise to a population of cells which were able to form osteoclasts upon treatment with RANKL and M-CSF. Moreover, a neutralizing anti-IL-11 antibody significantly inhibited the ability of breast cancer conditioned media to promote the development and/or survival of osteoclast progenitor cells. Similarly, recombinant IL-11 was able to sustain a population of osteoclast progenitor cells. However, IL-11 was unable to exert any effect on osteoclast survival, induce osteoclastogenesis independent of RANKL, or promote osteoclastogenesis in suboptimal RANKL conditions. CONCLUSIONS: Our data indicate that a) IL-11 plays an important role in osteoclastogenesis by stimulating the development and/or survival of osteoclast progenitor cells and b) breast cancer may promote osteolysis in part by increasing the pool of osteoclast progenitor cells via tumor cell-derived IL-11. However, given the heterogeneous nature of the bone marrow cells, the precise mechanism by which IL-11 treatment gives rise to a population of osteoclast progenitor cells warrants further investigation.


Assuntos
Neoplasias da Mama/metabolismo , Interleucina-11/metabolismo , Osteoclastos/metabolismo , Osteólise/metabolismo , Comunicação Parácrina , Células-Tronco/metabolismo , Animais , Anticorpos Neutralizantes/farmacologia , Neoplasias da Mama/imunologia , Linhagem Celular Tumoral , Sobrevivência Celular , Meios de Cultivo Condicionados/metabolismo , Feminino , Humanos , Interleucina-11/antagonistas & inibidores , Fator Estimulador de Colônias de Macrófagos/metabolismo , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Osteoclastos/efeitos dos fármacos , Osteoclastos/imunologia , Osteólise/imunologia , Comunicação Parácrina/efeitos dos fármacos , Ligante RANK/metabolismo , Proteínas Recombinantes/metabolismo , Células-Tronco/efeitos dos fármacos , Células-Tronco/imunologia , Fatores de Tempo
20.
J Cell Biochem ; 113(11): 3353-62, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22644863

RESUMO

Interleukin-11 (IL-11) was originally identified as the cytokine that could induce the proliferation of human cells. Recent studies have shown that IL-11 plays a critical role in tumor growth, angiogenesis, and metastasis. Chondrosarcoma is a type of highly malignant tumor with a potent capacity to invade locally and cause distant metastasis. However, the effects of IL-11 on human chondrosarcoma cells are largely unknown. Here, we found that IL-11 increased the migration and expression of intercellular adhesion molecule-1 (ICAM)-1 in human chondrosarcoma cells. We also found that human chondrosarcoma tissues had significant expression of the IL-11 which was higher than that in primary chondrocytes. The phosphatidylinositol 3-kinase (PI3K), Akt, and NF-κB pathways were activated by IL-11 treatment, and the IL-11-induced expression of ICAM-1 and migration activity were inhibited by the specific inhibitors and mutant forms of PI3K, Akt, and NF-κB cascades. Taken together, our results indicate that IL-11 enhanced the migration of the chondrosarcoma cells by increasing ICAM-1 expression through the IL-11Rα receptor, PI3K, Akt, and NF-κB signal transduction pathway.


Assuntos
Neoplasias Ósseas/metabolismo , Condrossarcoma/metabolismo , Molécula 1 de Adesão Intercelular/metabolismo , Interleucina-11/genética , Neoplasias Ósseas/genética , Neoplasias Ósseas/patologia , Estudos de Casos e Controles , Movimento Celular/efeitos dos fármacos , Condrócitos/citologia , Condrócitos/metabolismo , Condrossarcoma/genética , Condrossarcoma/patologia , Inibidores Enzimáticos/farmacologia , Humanos , Molécula 1 de Adesão Intercelular/genética , Interleucina-11/antagonistas & inibidores , Subunidade alfa de Receptor de Interleucina-11/genética , Subunidade alfa de Receptor de Interleucina-11/metabolismo , NF-kappa B/genética , NF-kappa B/metabolismo , Fosfatidilinositol 3-Quinase/genética , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Interferente Pequeno/genética , Transdução de Sinais/efeitos dos fármacos , Células Tumorais Cultivadas , Regulação para Cima/efeitos dos fármacos
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