RESUMO
Signal transducer and activator of transcription 1 (STAT1) acts as a tumor suppressor molecule in colitis-associated colorectal cancer (CAC), particularly during the very early stages, modulating immune responses and controlling mechanisms such as apoptosis and cell proliferation. Previously, using an experimental model of CAC, we reported increased intestinal cell proliferation and faster tumor development, which were consistent with more signs of disease and damage, and reduced survival in STAT1-/- mice, compared with WT counterparts. However, the mechanisms through which STAT1 might prevent colorectal cancer progression preceded by chronic inflammation are still unclear. Here, we demonstrate that increased tumorigenicity related to STAT1 deficiency could be suppressed by IL-17 neutralization. The blockade of IL-17 in STAT1-/- mice reduced the accumulation of CD11b+Ly6ClowLy6G+ cells resembling granulocytic myeloid-derived suppressor cells (MDSCs) in both spleen and circulation. Additionally, IL-17 blockade reduced the recruitment of neutrophils into intestinal tissue, the expression and production of inflammatory cytokines, and the expression of intestinal STAT3. In addition, the anti-IL-17 treatment also reduced the expression of Arginase-1 and inducible nitric oxide synthase (iNOS) in the colon, both associated with the main suppressive activity of MDSCs. Thus, a lack of STAT1 signaling induces a significant change in the colonic microenvironment that supports inflammation and tumor formation. Anti-IL-17 treatment throughout the initial stages of CAC related to STAT1 deficiency abrogates the tumor formation possibly caused by myeloid cells.
Assuntos
Neoplasias Associadas a Colite/etiologia , Granulócitos/patologia , Interleucina-17/fisiologia , Fator de Transcrição STAT1/fisiologia , Animais , Anticorpos Neutralizantes/administração & dosagem , Neoplasias Associadas a Colite/patologia , Neoplasias Associadas a Colite/fisiopatologia , Progressão da Doença , Feminino , Granulócitos/imunologia , Interleucina-17/antagonistas & inibidores , Interleucina-17/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Células Supressoras Mieloides/imunologia , Células Supressoras Mieloides/patologia , Neoplasias Experimentais/etiologia , Neoplasias Experimentais/patologia , Neoplasias Experimentais/fisiopatologia , Fator de Transcrição STAT1/deficiência , Fator de Transcrição STAT1/genética , Microambiente Tumoral/imunologiaRESUMO
The study investigated the role of cytokines IL-4 and IL-17 in the modulation of the functional activity of mononuclear phagocytes in diabetic pregnant women with hyperglycemia. Sixty pregnant women were assigned to the following groups: nondiabetic (ND), mild gestational hyperglycemia (MGH), gestational diabetes mellitus (GDM), or type 2 diabetes mellitus (DM2). The functional activity of phagocytes from maternal blood, cord blood, and colostrum was assessed by determining their superoxide release, phagocytosis, microbicidal activity, and intracellular Ca2+ release. Irrespective of glycemic status, colostrum and blood cells treated with IL-4 and IL-17 increased superoxide release in the presence of enteropathogenic Escherichia coli (EPEC). The highest phagocytosis rate was observed in cells from the DM2 group treated with IL-4. In all the groups, phagocytes from colostrum, maternal blood, and cord blood exhibited higher microbicidal activity against EPEC when treated with cytokines. IL-17 increased intracellular Ca2+ release by colostrum phagocytes in diabetic groups. The results indicate that the IL-4 and IL-17 modulate the functional activity of phagocytes in the maternal blood, cord blood, and colostrum of diabetic mother. The natural immunity resulting from the interaction between the cells and cytokines tested may be an alternative procedure to improve the prognosis of maternal and newborn infections.
Assuntos
Diabetes Gestacional/imunologia , Interleucina-17/fisiologia , Interleucina-4/fisiologia , Fagócitos/imunologia , Adolescente , Adulto , Feminino , Humanos , Pessoa de Meia-Idade , Fagocitose , Gravidez , Adulto JovemRESUMO
During mycobacterial infection, macroautophagy/autophagy, a process modulated by cytokines, is essential for mounting successful host responses. Autophagy collaborates with human immune responses against Mycobacterium tuberculosis (Mt) in association with specific IFNG secreted against the pathogen. However, IFNG alone is not sufficient to the complete bacterial eradication, and other cytokines might be required. Actually, induction of Th1 and Th17 immune responses are required for protection against Mt. Accordingly, we showed that IL17A and IFNG expression in lymphocytes from tuberculosis patients correlates with disease severity. Here we investigate the role of IFNG and IL17A during autophagy in monocytes infected with Mt H37Rv or the mutant MtΔRD1. Patients with active disease were classified as high responder (HR) or low responder (LR) according to their T cell responses against Mt. IL17A augmented autophagy in infected monocytes from HR patients through a mechanism that activated MAPK1/ERK2-MAPK3/ERK1 but, during infection of monocytes from LR patients, IL17A had no effect on the autophagic response. In contrast, addition of IFNG to infected monocytes, increased autophagy by activating MAPK14/p38 α both in HR and LR patients. Interestingly, proteins codified in the RD1 region did not interfere with IFNG and IL17A autophagy induction. Therefore, in severe tuberculosis patients' monocytes, IL17A was unable to augment autophagy because of a defect in the MAPK1/3 signaling pathway. In contrast, both IFNG and IL17A increased autophagy levels in patients with strong immunity to Mt, promoting mycobacterial killing. Our findings might contribute to recognize new targets for the development of novel therapeutic tools to fight the pathogen.
Assuntos
Autofagia , Interleucina-17/fisiologia , Monócitos/imunologia , Tuberculose/imunologia , Células Cultivadas , Humanos , Interferon gama/fisiologia , Monócitos/microbiologia , Mycobacterium tuberculosis/fisiologia , Transdução de Sinais , Tuberculose/diagnóstico , Tuberculose/microbiologiaRESUMO
The aggressiveness of invasive ductal carcinoma (IDC) of the breast is associated with increased IL17 levels. Studying the role of IL17 in invasive breast tumor pathogenesis, we found that metastatic primary tumor-infiltrating T lymphocytes produced elevated levels of IL17, whereas IL17 neutralization inhibited tumor growth and prevented the migration of neutrophils and tumor cells to secondary disease sites. Tumorigenic neutrophils promote disease progression, producing CXCL1, MMP9, VEGF, and TNFα, and their depletion suppressed tumor growth. IL17A also induced IL6 and CCL20 production in metastatic tumor cells, favoring the recruitment and differentiation of Th17. In addition, IL17A changed the gene-expression profile and the behavior of nonmetastatic tumor cells, causing tumor growth in vivo, confirming the protumor role of IL17. Furthermore, high IL17 expression was associated with lower disease-free survival and worse prognosis in IDC patients. Thus, IL17 blockade represents an attractive approach for the control of invasive breast tumors.
Assuntos
Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/secundário , Quimiotaxia de Leucócito/fisiologia , Interleucina-17/fisiologia , Linfócitos do Interstício Tumoral/imunologia , Proteínas de Neoplasias/fisiologia , Neutrófilos/imunologia , Animais , Neoplasias da Mama/química , Neoplasias da Mama/imunologia , Neoplasias da Mama/mortalidade , Carcinoma Ductal de Mama/química , Carcinoma Ductal de Mama/imunologia , Carcinoma Ductal de Mama/mortalidade , Citocinas/biossíntese , Citocinas/genética , Citocinas/metabolismo , Progressão da Doença , Intervalo Livre de Doença , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Interleucina-17/análise , Interleucina-17/antagonistas & inibidores , Interleucina-17/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Neoplasias Mamárias Experimentais/imunologia , Neoplasias Mamárias Experimentais/patologia , Camundongos , Camundongos Endogâmicos BALB C , Proteínas de Neoplasias/análise , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/imunologia , Neutrófilos/metabolismo , Prognóstico , Células Th17/imunologiaRESUMO
Adaptive immune response has been implicated in inflammation and fibrosis as a result of exposure to mineralocorticoids and a high-salt diet. We hypothesized that in mineralocorticoid-salt-induced hypertension, activation of the mineralocorticoid receptor alters the T-helper 17 lymphocyte (Th17)/regulatory T-lymphocyte/interleukin-17 (IL-17) pathway, contributing to cardiac and renal damage. We studied the inflammatory response and tissue damage in rats treated with deoxycorticosterone acetate and high-salt diet (DOCA-salt), with or without mineralocorticoid receptor inhibition by spironolactone. To determine whether Th17 differentiation in DOCA-salt rats is caused by hypertension per se, DOCA-salt rats received antihypertensive therapy. In addition, to evaluate the pathogenic role of IL-17 in hypertension and tissue damage, we studied the effect of IL-17 blockade with a specific antibody (anti-IL-17). We found activation of Th17 cells and downregulation of forkhead box P3 mRNA in peripheral tissues, heart, and kidneys of DOCA-salt-treated rats. Spironolactone treatment prevented Th17 cell activation and increased numbers of forkhead box P3-positive cells relative to DOCA-salt rats. Antihypertensive therapy did not ameliorate Th17 activation in rats. Treatment of DOCA-salt rats with anti-IL-17 significantly reduced arterial hypertension as well as expression of profibrotic and proinflammatory mediators and collagen deposits in the heart and kidney. We conclude that mineralocorticoid receptor activation alters the Th17/regulatory T-lymphocyte/IL-17 pathway in mineralocorticoid-dependent hypertension as part of an inflammatory mechanism contributing to fibrosis.
Assuntos
Acetato de Desoxicorticosterona/efeitos adversos , Cardiopatias/prevenção & controle , Hipertensão/induzido quimicamente , Nefropatias/prevenção & controle , Espironolactona/farmacologia , Linfócitos T Reguladores/efeitos dos fármacos , Células Th17/efeitos dos fármacos , Animais , Anticorpos/imunologia , Anticorpos/farmacologia , Acetato de Desoxicorticosterona/farmacologia , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/fisiologia , Fatores de Transcrição Forkhead/efeitos dos fármacos , Fatores de Transcrição Forkhead/fisiologia , Cardiopatias/etiologia , Cardiopatias/fisiopatologia , Hipertensão/complicações , Hipertensão/fisiopatologia , Interleucina-17/antagonistas & inibidores , Interleucina-17/imunologia , Interleucina-17/fisiologia , Nefropatias/etiologia , Nefropatias/fisiopatologia , Masculino , Antagonistas de Receptores de Mineralocorticoides/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de Mineralocorticoides/efeitos dos fármacos , Receptores de Mineralocorticoides/fisiologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Linfócitos T Reguladores/patologia , Células Th17/patologiaRESUMO
Intracellular pattern recognition receptors such as the nucleotide-binding oligomerization domain (NOD)-like receptors family members are key for innate immune recognition of microbial infection and may play important roles in the development of inflammatory diseases, including rheumatic diseases. In this study, we evaluated the role of NOD1 and NOD2 on development of experimental arthritis. Ag-induced arthritis was generated in wild-type, NOD1(-/-), NOD2(-/-), or receptor-interacting serine-threonine kinase 2(-/-) (RIPK2(-/-)) immunized mice challenged intra-articularly with methylated BSA. Nociception was determined by electronic Von Frey test. Neutrophil recruitment and histopathological analysis of proteoglycan lost was evaluated in inflamed joints. Joint levels of inflammatory cytokine/chemokine were measured by ELISA. Cytokine (IL-6 and IL-23) and NOD2 expressions were determined in mice synovial tissue by RT-PCR. The NOD2(-/-) and RIPK2(-/-), but not NOD1(-/-), mice are protected from Ag-induced arthritis, which was characterized by a reduction in neutrophil recruitment, nociception, and cartilage degradation. NOD2/RIPK2 signaling impairment was associated with a reduction in proinflammatory cytokines and chemokines (TNF, IL-1ß, and CXCL1/KC). IL-17 and IL-17 triggering cytokines (IL-6 and IL-23) were also reduced in the joint, but there is no difference in the percentage of CD4(+) IL-17(+) cells in the lymph node between arthritic wild-type and NOD2(-/-) mice. Altogether, these findings point to a pivotal role of the NOD2/RIPK2 signaling in the onset of experimental arthritis by triggering an IL-17-dependent joint immune response. Therefore, we could propose that NOD2 signaling is a target for the development of new therapies for the control of rheumatoid arthritis.
Assuntos
Artrite Experimental/imunologia , Interleucina-17/metabolismo , Articulação do Joelho/imunologia , Proteína Adaptadora de Sinalização NOD2/fisiologia , Proteína Serina-Treonina Quinases de Interação com Receptores/fisiologia , Transdução de Sinais/imunologia , Animais , Artrite Experimental/metabolismo , Artrite Experimental/patologia , Bovinos , Células Cultivadas , Interleucina-17/fisiologia , Articulação do Joelho/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína Adaptadora de Sinalização NOD1/deficiência , Proteína Adaptadora de Sinalização NOD2/deficiência , Proteína Serina-Treonina Quinase 2 de Interação com Receptor , Proteína Serina-Treonina Quinases de Interação com Receptores/deficiência , Soroalbumina Bovina/imunologia , Soroalbumina Bovina/toxicidade , Transdução de Sinais/genéticaRESUMO
We studied the features of parallel immunoneuroendocrine responses in patients with different degrees of chronic Chagas myocarditis (indeterminate, mild/moderate or severe). A systemic inflammatory scenario was evident in patients with severe myocarditis compared to healthy subjects. This was paralleled by a disrupted activation of the hypothalamus-pituitary-adrenal axis, characterized by decreased concentrations of dehydroepiandrosterone-sulfate (DHEA-s) and an unbalanced cortisol/DHEA-s ratio, reinforcing the view that severe Chagas disease is devoid of an adequate anti-inflammatory milieu, likely involved in pathology. Our study constitutes the first demonstration of neuroendocrine disturbances, in parallel to a systemic inflammatory profile, during progressive human Chagas disease.