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1.
Sci Immunol ; 3(30)2018 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-30578351

RESUMO

Hundreds of patients with autosomal recessive, complete IL-12p40 or IL-12Rß1 deficiency have been diagnosed over the last 20 years. They typically suffer from invasive mycobacteriosis and, occasionally, from mucocutaneous candidiasis. Susceptibility to these infections is thought to be due to impairments of IL-12-dependent IFN-γ immunity and IL-23-dependent IL-17A/IL-17F immunity, respectively. We report here patients with autosomal recessive, complete IL-12Rß2 or IL-23R deficiency, lacking responses to IL-12 or IL-23 only, all of whom, unexpectedly, display mycobacteriosis without candidiasis. We show that αß T, γδ T, B, NK, ILC1, and ILC2 cells from healthy donors preferentially produce IFN-γ in response to IL-12, whereas NKT cells and MAIT cells preferentially produce IFN-γ in response to IL-23. We also show that the development of IFN-γ-producing CD4+ T cells, including, in particular, mycobacterium-specific TH1* cells (CD45RA-CCR6+), is dependent on both IL-12 and IL-23. Last, we show that IL12RB1, IL12RB2, and IL23R have similar frequencies of deleterious variants in the general population. The comparative rarity of symptomatic patients with IL-12Rß2 or IL-23R deficiency, relative to IL-12Rß1 deficiency, is, therefore, due to lower clinical penetrance. There are fewer symptomatic IL-23R- and IL-12Rß2-deficient than IL-12Rß1-deficient patients, not because these genetic disorders are rarer, but because the isolated absence of IL-12 or IL-23 is, in part, compensated by the other cytokine for the production of IFN-γ, thereby providing some protection against mycobacteria. These experiments of nature show that human IL-12 and IL-23 are both required for optimal IFN-γ-dependent immunity to mycobacteria, both individually and much more so cooperatively.


Assuntos
Imunidade Inata/imunologia , Interferon gama/imunologia , Interleucina-12/imunologia , Interleucina-23/imunologia , Infecções por Micobactéria não Tuberculosa/imunologia , Mycobacterium/imunologia , Humanos , Interleucina-12/deficiência , Interleucina-12/genética , Interleucina-23/deficiência , Interleucina-23/genética , Linhagem
2.
Sci Immunol ; 3(30)2018 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-30578352

RESUMO

Inherited IL-12Rß1 and TYK2 deficiencies impair both IL-12- and IL-23-dependent IFN-γ immunity and are rare monogenic causes of tuberculosis, each found in less than 1/600,000 individuals. We show that homozygosity for the common TYK2 P1104A allele, which is found in about 1/600 Europeans and between 1/1000 and 1/10,000 individuals in regions other than East Asia, is more frequent in a cohort of patients with tuberculosis from endemic areas than in ethnicity-adjusted controls (P = 8.37 × 10-8; odds ratio, 89.31; 95% CI, 14.7 to 1725). Moreover, the frequency of P1104A in Europeans has decreased, from about 9% to 4.2%, over the past 4000 years, consistent with purging of this variant by endemic tuberculosis. Surprisingly, we also show that TYK2 P1104A impairs cellular responses to IL-23, but not to IFN-α, IL-10, or even IL-12, which, like IL-23, induces IFN-γ via activation of TYK2 and JAK2. Moreover, TYK2 P1104A is properly docked on cytokine receptors and can be phosphorylated by the proximal JAK, but lacks catalytic activity. Last, we show that the catalytic activity of TYK2 is essential for IL-23, but not IL-12, responses in cells expressing wild-type JAK2. In contrast, the catalytic activity of JAK2 is redundant for both IL-12 and IL-23 responses, because the catalytically inactive P1057A JAK2, which is also docked and phosphorylated, rescues signaling in cells expressing wild-type TYK2. In conclusion, homozygosity for the catalytically inactive P1104A missense variant of TYK2 selectively disrupts the induction of IFN-γ by IL-23 and is a common monogenic etiology of tuberculosis.


Assuntos
Interferon gama/imunologia , Interleucina-23/imunologia , Mutação de Sentido Incorreto/genética , TYK2 Quinase/genética , Tuberculose/imunologia , Células Cultivadas , Homozigoto , Humanos , Interleucina-23/deficiência , TYK2 Quinase/imunologia
3.
Immunity ; 49(5): 943-957.e9, 2018 11 20.
Artigo em Inglês | MEDLINE | ID: mdl-30389414

RESUMO

Although commensal flora is involved in the regulation of immunity, the interplay between cytokine signaling and microbiota in atherosclerosis remains unknown. We found that interleukin (IL)-23 and its downstream target IL-22 restricted atherosclerosis by repressing pro-atherogenic microbiota. Inactivation of IL-23-IL-22 signaling led to deterioration of the intestinal barrier, dysbiosis, and expansion of pathogenic bacteria with distinct biosynthetic and metabolic properties, causing systemic increase in pro-atherogenic metabolites such as lipopolysaccharide (LPS) and trimethylamine N-oxide (TMAO). Augmented disease in the absence of the IL-23-IL-22 pathway was mediated in part by pro-atherogenic osteopontin, controlled by microbial metabolites. Microbiota transfer from IL-23-deficient mice accelerated atherosclerosis, whereas microbial depletion or IL-22 supplementation reduced inflammation and ameliorated disease. Our work uncovers the IL-23-IL-22 signaling as a regulator of atherosclerosis that restrains expansion of pro-atherogenic microbiota and argues for informed use of cytokine blockers to avoid cardiovascular side effects driven by microbiota and inflammation.


Assuntos
Aterosclerose/etiologia , Aterosclerose/metabolismo , Dieta , Microbioma Gastrointestinal , Homeostase , Interleucina-23/metabolismo , Interleucinas/metabolismo , Animais , Aterosclerose/patologia , Biomarcadores , Modelos Animais de Doenças , Progressão da Doença , Expressão Gênica , Imunofenotipagem , Interleucina-23/deficiência , Metabolismo dos Lipídeos , Camundongos , Camundongos Knockout , Osteopontina/genética , Osteopontina/metabolismo , Transdução de Sinais
4.
Am J Respir Cell Mol Biol ; 55(5): 697-707, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27351934

RESUMO

We recently reported that IL-17A plays a critical role in the development of porcine pancreatic elastase (PPE)-induced emphysema. The proliferation of T-helper type 17 (Th17) cells was induced by IL-23. To determine the contribution of IL-23 to the development of pulmonary emphysema, a mouse model of PPE-induced emphysema was used in which responses of IL-23p19-deficient (IL-23-/-) and wild-type (WT) mice were compared. Intratracheal instillation of PPE induced emphysematous changes in the lungs and was associated with increased levels of IL-23 in lung homogenates. Compared with WT mice, IL-23-/- mice developed significantly lower static compliance values and markedly reduced emphysematous changes on histological analyses after PPE instillation. These changes were associated with lower levels of IL-17A and fewer Th17 cells in the lung. The neutrophilia seen in bronchoalveolar lavage fluid of WT mice was attenuated in IL-23-/- mice, and the reduction was associated with decreased levels of keratinocyte-derived cytokine and macrophage inflammatory protein-2 in bronchoalveolar lavage fluid. Treatment with anti-IL-23p40 monoclonal antibody significantly attenuated PPE-induced emphysematous changes in the lungs of WT mice. These data identify the important contributions of IL-23 to the development of elastase-induced pulmonary inflammation and emphysema, mediated through an IL-23/IL-17 pathway. Targeting IL-23 in emphysema is a potential therapeutic strategy for delaying disease progression.


Assuntos
Interleucina-23/metabolismo , Pneumonia/induzido quimicamente , Pneumonia/metabolismo , Enfisema Pulmonar/induzido quimicamente , Enfisema Pulmonar/metabolismo , Animais , Anticorpos Monoclonais/farmacologia , Líquido da Lavagem Broncoalveolar/citologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/metabolismo , Quimiocinas/metabolismo , Progressão da Doença , Interferon gama/metabolismo , Interleucina-17/metabolismo , Interleucina-23/deficiência , Cinética , Pulmão/patologia , Contagem de Linfócitos , Camundongos Endogâmicos C57BL , Elastase Pancreática , Pneumonia/complicações , Pneumonia/patologia , Enfisema Pulmonar/complicações , Enfisema Pulmonar/patologia , Sus scrofa
5.
Eur J Immunol ; 46(3): 582-92, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26660726

RESUMO

Using a mouse model of experimental autoimmune myocarditis (EAM), we showed for the first time that IL-23 stimulation of CD4(+) T cells is required only briefly at the initiation of GM-CFS-dependent cardiac autoimmunity. IL-23 signal, acting as a switch, turns on pathogenicity of CD4(+) T cells, and becomes dispensable once autoreactivity is established. Il23a(-/-) mice failed to mount an efficient Th17 response to immunization, and were protected from myocarditis. However, remarkably, transient IL-23 stimulation ex vivo fully restored pathogenicity in otherwise nonpathogenic CD4(+) T cells raised from Il23a(-/-) donors. Thus, IL-23 may no longer be necessary to uphold inflammation in established autoimmune diseases. In addition, we demonstrated that IL-23-induced GM-CSF mediates the pathogenicity of CD4(+) T cells in EAM. The neutralization of GM-CSF abrogated cardiac inflammation. However, sustained IL-23 signaling is required to maintain IL-17A production in CD4(+) T cells. Despite inducing inflammation in Il23a(-/-) recipients comparable to wild-type (WT), autoreactive CD4(+) T cells downregulated IL-17A production without persistent IL-23 signaling. This divergence on the controls of GM-CSF-dependent pathogenicity on one side and IL-17A production on the other side may contribute to the discrepant efficacies of anti-IL-23 therapy in different autoimmune diseases.


Assuntos
Doenças Autoimunes/imunologia , Linfócitos T CD4-Positivos/imunologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Interleucina-23/metabolismo , Miocardite/imunologia , Transdução de Sinais , Animais , Modelos Animais de Doenças , Feminino , Interleucina-17/biossíntese , Interleucina-17/genética , Interleucina-23/deficiência , Interleucina-23/genética , Interleucina-23/farmacologia , Camundongos , Miocardite/fisiopatologia , Baço/citologia , Baço/efeitos dos fármacos , Baço/metabolismo , Células Th17/imunologia
6.
J Invest Dermatol ; 135(8): 1946-1953, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25972190

RESUMO

Biologics that neutralize specific cytokines have improved outcomes for several immune-mediated disorders but may also increase risks for particular side effects. This article postulates potential immunologic consequences of inhibiting components of the IL-23/T-helper cell 17 pathway-the target of next-generation biologics for treating psoriasis-based on clinical phenotypes of inherent or acquired deficiencies in this pathway. Generally, downstream deficiencies (e.g., IL-17A, IL-17F) are associated with fewer disorders compared with upstream deficiencies, suggesting that selectively blocking downstream targets may result in a narrower range of side effects. However, safety of these specific inhibitions must be established in long-term studies.


Assuntos
Produtos Biológicos/uso terapêutico , Doenças do Sistema Imunitário/tratamento farmacológico , Interleucina-17/deficiência , Interleucina-23/deficiência , Fenótipo , Transdução de Sinais/fisiologia , Produtos Biológicos/farmacologia , Humanos , Doenças do Sistema Imunitário/fisiopatologia , Interleucina-17/antagonistas & inibidores , Interleucina-17/genética , Interleucina-23/efeitos dos fármacos , Interleucina-23/genética , Mutação/genética , Infecções por Micobactéria não Tuberculosa/tratamento farmacológico , Infecções por Micobactéria não Tuberculosa/fisiopatologia , Psoríase/tratamento farmacológico , Psoríase/fisiopatologia , Infecções por Salmonella/tratamento farmacológico , Infecções por Salmonella/fisiopatologia , Transdução de Sinais/efeitos dos fármacos , Resultado do Tratamento , Tuberculose/tratamento farmacológico , Tuberculose/fisiopatologia
7.
J Exp Med ; 211(10): 2075-84, 2014 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-25200028

RESUMO

Oropharyngeal candidiasis (OPC) is an opportunistic fungal infection caused by Candida albicans. OPC is frequent in HIV/AIDS, implicating adaptive immunity. Mice are naive to Candida, yet IL-17 is induced within 24 h of infection, and susceptibility is strongly dependent on IL-17R signaling. We sought to identify the source of IL-17 during the early innate response to candidiasis. We show that innate responses to Candida require an intact TCR, as SCID, IL-7Rα(-/-), and Rag1(-/-) mice were susceptible to OPC, and blockade of TCR signaling by cyclosporine induced susceptibility. Using fate-tracking IL-17 reporter mice, we found that IL-17 is produced within 1-2 d by tongue-resident populations of γδ T cells and CD3(+)CD4(+)CD44(hi)TCRß(+)CCR6(+) natural Th17 (nTh17) cells, but not by TCR-deficient innate lymphoid cells (ILCs) or NK cells. These cells function redundantly, as TCR-ß(-/-) and TCR-δ(-/-) mice were both resistant to OPC. Whereas γδ T cells were previously shown to produce IL-17 during dermal candidiasis and are known to mediate host defense at mucosal surfaces, nTh17 cells are poorly understood. The oral nTh17 population expanded rapidly after OPC, exhibited high TCR-ß clonal diversity, and was absent in Rag1(-/-), IL-7Rα(-/-), and germ-free mice. These findings indicate that nTh17 and γδ T cells, but not ILCs, are key mucosal sentinels that control oral pathogens.


Assuntos
Candida albicans/imunologia , Candidíase/prevenção & controle , Imunidade Inata/imunologia , Boca/imunologia , Células Th17/imunologia , Animais , Candidíase/imunologia , Citometria de Fluxo , Interleucina-23/deficiência , Camundongos , Camundongos Knockout , Microscopia Confocal , Boca/citologia , Boca/microbiologia , Reação em Cadeia da Polimerase em Tempo Real , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Receptores de Interleucina-17/deficiência , Receptores de Interleucina-17/metabolismo
8.
Circ Heart Fail ; 7(1): 161-71, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24300243

RESUMO

BACKGROUND: CD4+ cells are implicated in the healing process after myocardial infarction (MI). We sought to investigate the role of interleukin-23 (IL-23) deficiency, a cytokine important in differentiation of CD4+ cells, in scar formation of the ischemic heart. METHODS AND RESULTS: MI was performed in wild-type and IL23p19-/- mice. Thirty-day mortality, hemodynamic function 4 days after MI and myocardial inflammation, and remodeling 4 and 30 days after MI were examined. Differentiation of fibroblasts from infarcted and noninfarcted hearts into myofibroblasts was examined under basal conditions and after stimulation with interferon-γ, IL-17α and IL-23. Interleukin-23p19-/- mice showed higher expression of proinflammatory cytokines and immune cell infiltration in the scar early after MI compared with wild-type mice. A stronger interferon-γ/Th1 reaction seemed to be responsible for the increased inflammation under IL-23 deficiency. Expression of α-smooth muscle actin (α-SMA), collagen I and III was significantly higher in the heart tissue and isolated cardiac fibroblasts 4 days after MI in the wild-type mice. Interleukin-23p19-/- mice showed impaired healing compared with wild-type mice, as seen by significantly higher mortality because of ventricular rupture (40% higher after 30 days) and stronger left ventricular dilation early after MI. Stimulation of cardiac fibroblasts with interferon-γ, the main Th1 cytokine, but not with IL-23 or IL-17α, led to a significant downregulation of α-smooth muscle actin, collagen I and III and decreased migration and differentiation to myofibroblasts. CONCLUSIONS: IL-23 deficiency leads to increased myocardial inflammation and decreased cardiac fibroblast activation, associated with impaired scar formation and adverse remodeling after MI.


Assuntos
Interleucina-23/deficiência , Interleucina-23/fisiologia , Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio/fisiopatologia , Cicatrização/fisiologia , Animais , Diferenciação Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Células Cultivadas , Cicatriz/patologia , Cicatriz/fisiopatologia , Citocinas/metabolismo , Modelos Animais de Doenças , Fibroblastos/efeitos dos fármacos , Fibroblastos/patologia , Interferon gama/farmacologia , Interleucina-17/farmacologia , Interleucina-23/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Infarto do Miocárdio/mortalidade , Prognóstico
9.
Am J Reprod Immunol ; 70(6): 472-84, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24238108

RESUMO

OBJECTIVE: Chlamydia trachomatis infections are a significant cause of reproductive tract pathology. Protective and pathological immune mediators must be differentiated to design a safe and effective vaccine. METHODS: Wild-type mice and mice deficient in IL-22 and IL-23 were infected intravaginally with Chlamydia muridarum, and their course of infection and oviduct pathology were compared. Local genital tract and draining lymph node immune responses were also examined in IL-23-deficient mice. RESULTS: IL-22- and IL-23-deficient mice exhibited normal susceptibility to infection and oviduct pathology. IL-23 was required for the development of a Chlamydia-specific Th17 response in the lymph nodes and for production of IL-22 and IL-17 in the genital tract. However, influx of Th1 and innate immune cells was not compromised in the absence of IL-23. CONCLUSION: IL-22 and IL-23 play either redundant or minimal roles in the pathogenesis of Chlamydia infection in the mouse model. Induction of Th17-associated cytokines by a Chlamydia vaccine should be avoided as these responses are not central to resolution of infection and have pathologic potential.


Assuntos
Infecções por Chlamydia/imunologia , Chlamydia muridarum/imunologia , Interleucina-17/biossíntese , Interleucina-23/imunologia , Interleucinas/biossíntese , Infecções do Sistema Genital/imunologia , Animais , Células Cultivadas , Infecções por Chlamydia/microbiologia , Infecções por Chlamydia/patologia , Feminino , Interleucina-17/imunologia , Interleucina-23/deficiência , Interleucinas/deficiência , Interleucinas/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Oviductos/imunologia , Oviductos/patologia , Infecções do Sistema Genital/microbiologia , Infecções do Sistema Genital/patologia
10.
Nature ; 491(7423): 254-8, 2012 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-23034650

RESUMO

Approximately 2% of colorectal cancer is linked to pre-existing inflammation known as colitis-associated cancer, but most develops in patients without underlying inflammatory bowel disease. Colorectal cancer often follows a genetic pathway whereby loss of the adenomatous polyposis coli (APC) tumour suppressor and activation of ß-catenin are followed by mutations in K-Ras, PIK3CA and TP53, as the tumour emerges and progresses. Curiously, however, 'inflammatory signature' genes characteristic of colitis-associated cancer are also upregulated in colorectal cancer. Further, like most solid tumours, colorectal cancer exhibits immune/inflammatory infiltrates, referred to as 'tumour-elicited inflammation'. Although infiltrating CD4(+) T(H)1 cells and CD8(+) cytotoxic T cells constitute a positive prognostic sign in colorectal cancer, myeloid cells and T-helper interleukin (IL)-17-producing (T(H)17) cells promote tumorigenesis, and a 'T(H)17 expression signature' in stage I/II colorectal cancer is associated with a drastic decrease in disease-free survival. Despite its pathogenic importance, the mechanisms responsible for the appearance of tumour-elicited inflammation are poorly understood. Many epithelial cancers develop proximally to microbial communities, which are physically separated from immune cells by an epithelial barrier. We investigated mechanisms responsible for tumour-elicited inflammation in a mouse model of colorectal tumorigenesis, which, like human colorectal cancer, exhibits upregulation of IL-23 and IL-17. Here we show that IL-23 signalling promotes tumour growth and progression, and development of a tumoural IL-17 response. IL-23 is mainly produced by tumour-associated myeloid cells that are likely to be activated by microbial products, which penetrate the tumours but not adjacent tissue. Both early and late colorectal neoplasms exhibit defective expression of several barrier proteins. We propose that barrier deterioration induced by colorectal-cancer-initiating genetic lesions results in adenoma invasion by microbial products that trigger tumour-elicited inflammation, which in turn drives tumour growth.


Assuntos
Adenoma/microbiologia , Adenoma/patologia , Transformação Celular Neoplásica/patologia , Neoplasias Colorretais/microbiologia , Neoplasias Colorretais/patologia , Interleucina-17/imunologia , Interleucina-23/imunologia , Adenoma/genética , Adenoma/imunologia , Animais , Bactérias/metabolismo , Bactérias/patogenicidade , Divisão Celular , Colite/complicações , Neoplasias Colorretais/genética , Neoplasias Colorretais/imunologia , Modelos Animais de Doenças , Intervalo Livre de Doença , Genes APC , Humanos , Inflamação/genética , Inflamação/imunologia , Inflamação/microbiologia , Inflamação/patologia , Interleucina-17/genética , Interleucina-23/deficiência , Interleucina-23/genética , Camundongos , Camundongos Endogâmicos C57BL , Células Mieloides/imunologia , Células Mieloides/metabolismo , Fator 88 de Diferenciação Mieloide/imunologia , Fator 88 de Diferenciação Mieloide/metabolismo , Transdução de Sinais , Receptores Toll-Like/imunologia , Receptores Toll-Like/metabolismo , Microambiente Tumoral , beta Catenina/metabolismo
11.
Nat Immunol ; 13(10): 947-53, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22922363

RESUMO

Microbiota are essential for weight gain in mouse models of diet-induced obesity (DIO), but the pathways that cause the microbiota to induce weight gain are unknown. We report that mice deficient in lymphotoxin, a key molecule in gut immunity, were resistant to DIO. Ltbr(-/-) mice had different microbial community composition compared to their heterozygous littermates, including an overgrowth of segmented filamentous bacteria (SFB). Furthermore, cecal transplantation conferred leanness to germ-free recipients. Housing Ltbr(-/-) mice with their obese siblings rescued weight gain in Ltbr(-/-) mice, demonstrating the communicability of the obese phenotype. Ltbr(-/-) mice lacked interleukin 23 (IL-23) and IL-22, which can regulate SFB. Mice deficient in these pathways also resisted DIO, demonstrating that intact mucosal immunity guides diet-induced changes to the microbiota to enable obesity.


Assuntos
Imunidade nas Mucosas , Receptor beta de Linfotoxina/fisiologia , Linfotoxina-alfa/fisiologia , Obesidade , Animais , Bactérias/crescimento & desenvolvimento , Bactérias/imunologia , Ceco/microbiologia , Ceco/transplante , Dieta , Metabolismo Energético , Vida Livre de Germes , Interleucina-23/deficiência , Interleucina-23/fisiologia , Interleucinas/deficiência , Interleucinas/fisiologia , Receptor beta de Linfotoxina/genética , Linfotoxina-alfa/deficiência , Linfotoxina-alfa/genética , Metagenoma , Camundongos , Camundongos Knockout , Obesidade/etiologia , Obesidade/imunologia , Obesidade/metabolismo , Ganho de Peso/imunologia
12.
Gastroenterology ; 143(3): 765-776.e3, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22687286

RESUMO

BACKGROUND & AIMS: Interleukin (IL)-17 signaling has been implicated in lung and skin fibrosis. We examined the role of IL-17 signaling in the pathogenesis of liver fibrosis in mice. METHODS: Using cholestatic and hepatotoxic models of liver injury, we compared the development of liver fibrosis in wild-type mice with that of IL-17RA(-/-) mice and of bone marrow chimeric mice devoid of IL-17 signaling in immune and Kupffer cells (IL-17RA(-/-) to wild-type and IL-17A(-/-) to wild-type mice) or liver resident cells (wild-type to IL-17RA(-/-) mice). RESULTS: In response to liver injury, levels of Il-17A and its receptor increased. IL-17A increased appeared to promote fibrosis by activating inflammatory and liver resident cells. IL-17 signaling facilitated production of IL-6, IL-1, and tumor necrosis factor-α by inflammatory cells and increased the expression of transforming growth factor-1, a fibrogenic cytokine. IL-17 directly induced production of collagen type I in hepatic stellate cells by activating the signal transducer and activator of transcription 3 (Stat3) signaling pathway. Mice devoid of Stat3 signaling in hepatic stellate cells (GFAPStat3(-/-) mice) were less susceptible to fibrosis. Furthermore, deletion of IL-23 from immune cells attenuated liver fibrosis, whereas deletion of IL-22 exacerbated fibrosis. Administration of IL-22 and IL-17E (IL-25, a negative regulator of IL-23) protected mice from bile duct ligation-induced liver fibrosis. CONCLUSIONS: IL-17 induces liver fibrosis through multiple mechanisms in mice. Reagents that block these pathways might be developed as therapeutics for patients with cirrhosis.


Assuntos
Células Estreladas do Fígado/imunologia , Mediadores da Inflamação/metabolismo , Interleucina-17/metabolismo , Macrófagos do Fígado/imunologia , Cirrose Hepática Experimental/imunologia , Fígado/imunologia , Transdução de Sinais , Animais , Ductos Biliares/cirurgia , Transplante de Medula Óssea , Tetracloreto de Carbono , Linhagem Celular , Colágeno Tipo I/metabolismo , Progressão da Doença , Regulação da Expressão Gênica , Genótipo , Células Estreladas do Fígado/metabolismo , Células Estreladas do Fígado/patologia , Humanos , Mediadores da Inflamação/administração & dosagem , Interleucina-1/metabolismo , Interleucina-17/administração & dosagem , Interleucina-17/deficiência , Interleucina-17/genética , Interleucina-23/deficiência , Interleucina-23/genética , Interleucina-6/metabolismo , Interleucinas/administração & dosagem , Interleucinas/deficiência , Interleucinas/genética , Macrófagos do Fígado/metabolismo , Macrófagos do Fígado/patologia , Ligadura , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática Alcoólica/imunologia , Cirrose Hepática Alcoólica/patologia , Cirrose Hepática Experimental/etiologia , Cirrose Hepática Experimental/genética , Cirrose Hepática Experimental/metabolismo , Cirrose Hepática Experimental/patologia , Cirrose Hepática Experimental/prevenção & controle , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fenótipo , Receptores de Interleucina-17/deficiência , Receptores de Interleucina-17/genética , Fator de Transcrição STAT3/deficiência , Fator de Transcrição STAT3/genética , Fatores de Tempo , Fator de Crescimento Transformador beta1/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
13.
Immunity ; 36(2): 276-87, 2012 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-22306017

RESUMO

Microbial penetration of the intestinal epithelial barrier triggers inflammatory responses that include induction of the bactericidal C-type lectin RegIIIγ. Systemic administration of flagellin, a bacterial protein that stimulates Toll-like receptor 5 (TLR5), induces epithelial expression of RegIIIγ and protects mice from intestinal colonization with antibiotic-resistant bacteria. Flagellin-induced RegIIIγ expression is IL-22 dependent, but how TLR signaling leads to IL-22 expression is incompletely defined. By using conditional depletion of lamina propria dendritic cell (LPDC) subsets, we demonstrated that CD103(+)CD11b(+) LPDCs, but not monocyte-derived CD103(-)CD11b(+) LPDCs, expressed high amounts of IL-23 after bacterial flagellin administration and drove IL-22-dependent RegIIIγ production. Maximal expression of IL-23 subunits IL-23p19 and IL-12p40 occurred within 60 min of exposure to flagellin. IL-23 subsequently induced a burst of IL-22 followed by sustained RegIIIγ expression. Thus, CD103(+)CD11b(+) LPDCs, in addition to promoting long-term tolerance to ingested antigens, also rapidly produce IL-23 in response to detection of flagellin in the lamina propria.


Assuntos
Células Dendríticas/imunologia , Flagelina/imunologia , Interleucina-23/biossíntese , Mucosa Intestinal/imunologia , Mucosa Intestinal/microbiologia , Animais , Antígenos CD/metabolismo , Antígeno CD11b/metabolismo , Células Dendríticas/classificação , Flagelina/administração & dosagem , Imunidade Inata , Imunidade nas Mucosas , Cadeias alfa de Integrinas/metabolismo , Interleucina-23/deficiência , Interleucina-23/genética , Interleucinas/biossíntese , Interleucinas/deficiência , Interleucinas/genética , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Associadas a Pancreatite , Proteínas/genética , Transdução de Sinais/imunologia , Receptor 5 Toll-Like/deficiência , Receptor 5 Toll-Like/genética , Receptor 5 Toll-Like/metabolismo , Regulação para Cima
14.
Am J Pathol ; 180(4): 1547-59, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22342846

RESUMO

The cytokines IL-23 and IL-17 have been implicated in resistance to cryptococcal disease, but it is not clear whether IL-23-mediated production of IL-17 promotes fungal containment following pulmonary challenge with Cryptococcus neoformans. We used mice lacking IL-23 (IL-23p19(-/-)) or IL-17RA (IL-17RA(-/-)), and wild type (WT) C57BL/6 mice to examine the IL-23/IL-17 axis after intranasal infection with the C. neoformans strain 52D. The absence of IL-23 or IL-17RA had no effect on pulmonary or brain fungal burden at 1 or 6 weeks after infection. However, survival of IL-23p19(-/-) mice was reduced compared to IL-17RA(-/-) mice. IL-I7 production by CD4 T cells and natural killer T (NKT) cells was impaired in IL-23p19(-/-) lungs, but was not completely abolished. Both IL-23p19(-/-) and IL-17RA(-/-) mice exhibited impaired neutrophil recruitment, increased serum levels of IgE and IgG2b, and increased deposition of YM1/YM2 crystals in the lung, but only IL-23p19(-/-) mice developed persistent lung eosinophilia. Although survival of IL-17RA(-/-) and WT mice was similar after 17 weeks of infection, only surviving IL-17RA(-/-) mice exhibited cryptococcal dissemination to the blood. These data demonstrate that IL-23 dampens the allergic response to cryptococcal infection through IL-17-independent suppression of eosinophil recruitment and IL-17-dependent regulation of antibody production and crystal deposition. Furthermore, IL-23, and to a lesser extent IL-17, contribute to disease resistance.


Assuntos
Criptococose/imunologia , Cryptococcus neoformans/imunologia , Interleucina-17/imunologia , Interleucina-23/imunologia , Pneumopatias Fúngicas/imunologia , Animais , Anticorpos Antifúngicos/biossíntese , Encéfalo/patologia , Linfócitos T CD4-Positivos/imunologia , Criptococose/patologia , Cryptococcus neoformans/isolamento & purificação , Cristalização , Modelos Animais de Doenças , Imunoglobulina E/biossíntese , Interleucina-17/biossíntese , Interleucina-23/deficiência , Células Matadoras Naturais/imunologia , Leucócitos/imunologia , Pulmão/imunologia , Pneumopatias Fúngicas/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Eosinofilia Pulmonar/imunologia , Eosinofilia Pulmonar/microbiologia , Eosinofilia Pulmonar/patologia , Receptores de Interleucina-17/deficiência , Receptores de Interleucina-17/imunologia
15.
J Immunol ; 187(10): 5402-7, 2011 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-22003199

RESUMO

IL-23 is required for the IL-17 response to infection with Mycobacterium tuberculosis, but is not required for the early control of bacterial growth. However, mice deficient for the p19 component of IL-23 (Il23a(-/-)) exhibit increased bacterial growth late in infection that is temporally associated with smaller B cell follicles in the lungs. Cxcl13 is required for B cell follicle formation and immunity during tuberculosis. The absence of IL-23 results in decreased expression of Cxcl13 within M. tuberculosis-induced lymphocyte follicles in the lungs, and this deficiency was associated with increased cuffing of T cells around the vessels in the lungs of these mice. Il23a(-/-) mice also poorly expressed IL-17A and IL-22 mRNA. These cytokines were able to induce Cxcl13 in mouse primary lung fibroblasts, suggesting that these cytokines are likely involved in B cell follicle formation. Indeed, IL-17RA-deficient mice generated smaller B cell follicles early in the response, whereas IL-22-deficient mice had smaller B cell follicles at an intermediate time postinfection; however, only Il23a(-/-) mice had a sustained deficiency in B cell follicle formation and reduced immunity. We propose that in the absence of IL-23, expression of long-term immunity to tuberculosis is compromised due to reduced expression of Cxcl13 in B cell follicles and reduced ability of T cells to migrate from the vessels and into the lesion. Further, although IL-17 and IL-22 can both contribute to Cxcl13 production and B cell follicle formation, it is IL-23 that is critical in this regard.


Assuntos
Centro Germinativo/imunologia , Centro Germinativo/patologia , Interleucina-23/fisiologia , Mycobacterium tuberculosis/imunologia , Tuberculose Pulmonar/imunologia , Tuberculose Pulmonar/patologia , Animais , Células Cultivadas , Quimiocina CXCL13/biossíntese , Centro Germinativo/microbiologia , Interleucina-23/deficiência , Interleucina-23/genética , Pulmão/imunologia , Pulmão/microbiologia , Pulmão/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mycobacterium tuberculosis/crescimento & desenvolvimento , Fatores de Tempo , Tuberculose Pulmonar/microbiologia
16.
Infect Immun ; 79(10): 3966-77, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21807912

RESUMO

We have previously reported that compromised interleukin 17A (IL-17A) production in the lungs increased susceptibility to infection with the invasive fungal pathogen Aspergillus fumigatus. Here we have shown that culturing lung cells from A. fumigatus-challenged mice ex vivo demonstrated Dectin-1-dependent IL-17A production. In this system, neutralization of IL-23 but not IL-6, IL-1ß, or IL-18 resulted in attenuated IL-17A production. Il23 mRNA expression was found to be lower in lung cells from A. fumigatus-challenged Dectin-1-deficient mice, whereas bone marrow-derived dendritic cells from Dectin-1-deficient mice failed to produce IL-23 in response to A. fumigatus in vitro. Addition of recombinant IL-23 augmented IL-17A production by wild-type (WT) and Dectin-1-deficient lung cells, although the addition of IL-6 or IL-1ß did not augment the effect of IL-23. Intracellular cytokine staining of lung cells revealed lower levels of CD11b(+) IL-17A(+) and Ly-6G(+) IL-17A(+) cells in A. fumigatus-challenged Dectin-1-deficient mice. Ly-6G(+) neutrophils purified from the lungs of A. fumigatus-challenged Dectin-1-deficient mice displayed lower Il17a mRNA expression but surprisingly had intact Rorc and Rora mRNA expression. We further demonstrated that Ly-6G(+) neutrophils required the presence of myeloid cells for IL-17A production. Finally, upon in vitro stimulation with A. fumigatus, thioglycolate-elicited peritoneal neutrophils were positive for intracellular IL-17A expression and produced IL-17A in a Dectin-1- and IL-23-dependent manner. In summary, Dectin-1-dependent IL-17A production in the lungs during invasive fungal infection is mediated in part by CD11b(+) Ly-6G(+) neutrophils in an IL-23-dependent manner.


Assuntos
Aspergillus fumigatus/patogenicidade , Interleucina-17/biossíntese , Interleucina-23/metabolismo , Proteínas de Membrana/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Neutrófilos/metabolismo , Aspergilose Pulmonar/imunologia , Animais , Aspergillus fumigatus/imunologia , Células Cultivadas , Interleucina-23/deficiência , Interleucina-23/genética , Lectinas Tipo C , Pulmão/citologia , Pulmão/imunologia , Pulmão/metabolismo , Proteínas de Membrana/deficiência , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Proteínas do Tecido Nervoso/deficiência , Proteínas do Tecido Nervoso/genética , Neutrófilos/imunologia , Aspergilose Pulmonar/microbiologia
17.
Cell Microbiol ; 13(11): 1639-47, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21740501

RESUMO

Non-typhoidal Salmonella (NTS) serotypes cause a localized gastroenteritis in immunocompetent individuals. In contrast, primary immunodeficiencies that impair interleukin-23 (IL-23)-dependent pathways are associated in humans with disseminated NTS bloodstream infections (bacteraemia). The recent use of animal models has helped to define the role the IL-23 axis plays during NTS gastroenteritis, but additional work is needed to elucidate how this host defence pathway prevents NTS bacteraemia.


Assuntos
Interleucina-23/imunologia , Infecções por Salmonella/imunologia , Infecções por Salmonella/patologia , Salmonella/imunologia , Salmonella/patogenicidade , Animais , Modelos Animais de Doenças , Gastroenterite/imunologia , Gastroenterite/microbiologia , Gastroenterite/patologia , Humanos , Interleucina-23/deficiência , Sepse/imunologia , Sepse/microbiologia , Sepse/patologia
18.
Am J Pathol ; 179(3): 1188-98, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21741931

RESUMO

T helper (Th)17 cells might contribute to immune-mediated renal injury. Thus, we sought to define the time course of IL-17A-induced kidney damage and examined the relation between Th17 and Th1 cells in a model of crescentic anti-glomerular basement membrane glomerulonephritis. Renal injury and immune responses were assessed in wild-type and in IL-17A-deficient mice on days 6, 14, and 21 of disease development. On day 6, when mild glomerulonephritis developed, IL-17A-deficient mice were protected from renal injury. On day 14, when more severe disease developed, protection from renal injury due to IL-17A deficiency was less evident. On day 21, when crescentic glomerulonephritis was fully established, disease was enhanced in IL-17A(-/-) mice, with increased glomerular T-cell accumulation and fibrin deposition, and augmented Th1 responses. Mice lacking the Th17-promoting cytokine, IL-23 (p19), also developed more severe disease than wild-type animals on day 21. In contrast, mice deficient in the key Th1-promoting cytokine, IL-12 (p35), had decreased Th1 and increased Th17 responses and developed less severe crescentic glomerulonephritis than wild-type animals. These studies show that IL-17A contributes to early glomerular injury, but it attenuates established crescentic glomerulonephritis by suppressing Th1 responses. They provide further evidence that Th1 cells mediate crescentic injury in this model and that Th1 and Th17 cells counterregulate each other during disease development.


Assuntos
Lesão Renal Aguda/imunologia , Doença Antimembrana Basal Glomerular/imunologia , Interleucina-17/deficiência , Células Th1/fisiologia , Animais , Moléculas de Adesão Celular/metabolismo , Sobrevivência Celular , Fibrina/metabolismo , Imunidade Celular/imunologia , Imunoglobulinas , Interferon gama/metabolismo , Interleucina-12/deficiência , Interleucina-17/metabolismo , Interleucina-23/deficiência , Interleucina-23/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL
19.
Cancer Res ; 71(6): 2077-86, 2011 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-21282337

RESUMO

Immunosuppressive barricades erected by tumors during the evolution of immune escape represent a major obstacle to many potentially effective cancer therapies and vaccines. We have shown that host interleukin (IL)-23 suppresses the innate immune response during carcinogenesis and metastasis, independently of effects on the proinflammatory cytokine IL-17A. Based on these findings, we envisioned that IL-23 neutralization might offer a promising strategy to modulate immunosuppression, particularly in combination with immunostimulatory agents. Here we show that by itself a neutralizing monoclonal antibody (mAb) to IL-23 suppressed early experimental lung metastases in the B16F10 mouse model of melanoma and also modestly inhibited the subcutaneous growth of primary tumors. These antitumor effects were respectively mediated by natural killer cells or CD8(+) T cells. More notably, combinatorial treatments of anti-IL-23 mAb with IL-2 or anti-erbB2 mAb significantly inhibited subcutaneous growth of established mammary carcinomas and suppressed established experimental and spontaneous lung metastases. Overall, our results suggest the potential of anti-human IL-23 mAbs to improve the immunostimulatory effects of IL-2 and trastuzumab in the current management of some advanced human cancers.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Interleucina-23/imunologia , Neoplasias Pulmonares/prevenção & controle , Neoplasias/tratamento farmacológico , Animais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/imunologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Feminino , Humanos , Interleucina-2/administração & dosagem , Interleucina-23/deficiência , Interleucina-23/genética , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/secundário , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neoplasias/imunologia , Neoplasias/patologia , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/imunologia , Neoplasias Experimentais/patologia , Receptor ErbB-2/imunologia , Carga Tumoral/efeitos dos fármacos
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