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2.
Aging (Albany NY) ; 13(16): 20383-20394, 2021 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-34413269

RESUMO

Mechanical, metabolic, inflammatory, and immune factors contribute to the development of osteoarthritis (OA), a joint disease characterized by cartilage destruction. The circular RNA (circRNA) hsa_circ_0134111 is upregulated in the cartilage of OA patients; however, its potential role in OA pathogenesis and progression remains unexplored. In this study, the effects of hsa_circ_0134111 knockdown were evaluated in primary human chondrocytes treated with IL-1ß to simulate OA, as well as in a rat model of OA. Hsa_circ_0134111 expression was upregulated in IL-1ß-stimulated chondrocytes. CCK-8 and flow cytometry assays showed that hsa_circ_0134111 knockdown reversed IL-1ß-induced cell decline by inhibiting apoptosis. Following prediction analysis of circRNA and miRNA targets, dual-luciferase reporter and silencing/overexpression assays suggested that a regulatory network composed of hsa_circ_0134111, miR-224-5p, and CCL1 modulates IL-1ß-mediated OA-like effects in chondrocytes. Accordingly, CCL1 overexpression abrogated the prosurvival effects of hsa_circ_0134111 knockdown in vitro. Moreover, hsa_circ_0134111 silencing in vivo alleviated cartilage destruction in an OA rat model, decreased IL-6 and TNF-α levels in synovial fluid, and downregulated CCL1 expression in the affected joints. These results suggest that hsa_circ_0134111 contributes to OA development by binding to miR-224-5p, thereby releasing the inhibition that miR-224-5p exerts over CCL1.


Assuntos
Quimiocina CCL1/genética , MicroRNAs/genética , Osteoartrite/genética , RNA Circular/genética , Animais , Apoptose , Quimiocina CCL1/metabolismo , Condrócitos/metabolismo , Progressão da Doença , Humanos , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , MicroRNAs/metabolismo , Osteoartrite/metabolismo , Osteoartrite/patologia , Osteoartrite/fisiopatologia , RNA Circular/metabolismo , Ratos , Ratos Wistar
3.
Immunity ; 54(9): 2042-2056.e8, 2021 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-34407391

RESUMO

Recruitment of immune cells to the site of inflammation by the chemokine CCL1 is important in the pathology of inflammatory diseases. Here, we examined the role of CCL1 in pulmonary fibrosis (PF). Bronchoalveolar lavage fluid from PF mouse models contained high amounts of CCL1, as did lung biopsies from PF patients. Immunofluorescence analyses revealed that alveolar macrophages and CD4+ T cells were major producers of CCL1 and targeted deletion of Ccl1 in these cells blunted pathology. Deletion of the CCL1 receptor Ccr8 in fibroblasts limited migration, but not activation, in response to CCL1. Mass spectrometry analyses of CCL1 complexes identified AMFR as a CCL1 receptor, and deletion of Amfr impaired fibroblast activation. Mechanistically, CCL1 binding triggered ubiquitination of the ERK inhibitor Spry1 by AMFR, thus activating Ras-mediated profibrotic protein synthesis. Antibody blockade of CCL1 ameliorated PF pathology, supporting the therapeutic potential of targeting this pathway for treating fibroproliferative lung diseases.


Assuntos
Quimiocina CCL1/metabolismo , Fibroblastos/metabolismo , Proteínas de Membrana/metabolismo , Miofibroblastos/metabolismo , Fosfoproteínas/metabolismo , Fibrose Pulmonar/metabolismo , Receptores do Fator Autócrino de Motilidade/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Diferenciação Celular/fisiologia , Fibroblastos/patologia , Humanos , Camundongos , Miofibroblastos/patologia , Fibrose Pulmonar/patologia , Transdução de Sinais/fisiologia
4.
Biochem Pharmacol ; 188: 114565, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33872569

RESUMO

The human CC chemokine receptor 8 (CCR8) is a promising drug target for cancer immunotherapy and autoimmune disease. Besides human and viral chemokines, previous studies revealed diverse classes of CCR8-targeting small molecules. We characterized a selection of these CCR8 ligands (hCCL1, vCCL1, ZK756326, AZ6; CCR8 agonists and a naphthalene-sulfonamide-based CCR8 antagonist), in in vitro cell-based assays (hCCL1AF647 binding, calcium mobilization, cellular impedance, cell migration, ß-arrestin 1/2 recruitment), and used pharmacological tools to determine G protein-dependent and -independent signaling pathways elicited by these ligands. Our data reveal differences in CCR8-mediated signaling induced by chemokines versus small molecules, which was most pronounced in cell migration studies. Human CCL1 most efficiently induced cell migration whereby Gßγ signaling was indispensable. In contrast, Gßγ signaling did not contribute to cell migration induced by other CCR8 ligands (vCCL1, ZK756326, AZ6). Although all tested CCR8 agonists were full agonists for calcium mobilization, a significant contribution for Gßγ signaling herein was only apparent for human and viral CCL1. Despite both Gαi- and Gαq-signaling regulate intracellular Ca2+-release, cellular impedance experiments showed that CCR8 agonists predominantly induce Gαi-dependent signaling. Finally, small molecule agonists displayed higher efficacy in ß-arrestin 1 recruitment, which occurred independently of Gαi signaling. Also in this latter assay, only hCCL1-induced activity was dependent on Gßγ-signaling. Our study provides insight into CCR8 signaling and function and demonstrates differential CCR8 activation by different classes of ligands. This reflects the ability of CCR8 small molecules to evoke different subsets of the receptor's signaling repertoire, which categorizes them as biased agonists.


Assuntos
Sistemas de Liberação de Medicamentos/métodos , Receptores CCR8/agonistas , Receptores CCR8/antagonistas & inibidores , Transdução de Sinais/fisiologia , Quimiocina CCL1/administração & dosagem , Quimiocina CCL1/metabolismo , Quimiocina CCL8/administração & dosagem , Quimiocina CCL8/metabolismo , Quimiocinas CC/administração & dosagem , Quimiocinas CC/metabolismo , Relação Dose-Resposta a Droga , Humanos , Células Jurkat , Ligantes , Receptores CCR8/metabolismo , Transdução de Sinais/efeitos dos fármacos
5.
Cytokine ; 138: 155378, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33248911

RESUMO

In this study we investigated the effects of snake venom Group IA secreted phospholipase A2 (svGIA) on the release of inflammatory and angiogenic mediators from human lung macrophages (HLMs). HLMs were incubated with lipopolysaccharide (LPS) or svGIA with or without macrophage-polarizing stimuli (IL-4, IL-10, IFN-γ or the adenosine analogue NECA). M2-polarizing cytokines (IL-4 and IL-10) inhibited TNF-α, IL-6, IL-12, IL-1ß, CXCL8 and CCL1 release induced by both LPS and svGIA. IL-4 inhibited also the release of IL-10. IFN-γ reduced IL-10 and IL-12 and increased CCL1 release by both the LPS and svGIA-stimulated HLMs, conversely IFN-γ reduced IL-1ß only by svGIA-stimulated HLMs. In addition, IFNγ promoted TNF-α and IL-6 release from svGIA-stimulated HLMs to a greater extent than LPS. NECA inhibited TNF-α and IL-12 but promoted IL-10 release from LPS-stimulated HLMs according to the well-known effect of adenosine in down-regulating M1 activation. By contrast NECA reduced TNF-α, IL-10, CCL1 and IL-1ß release from svGIA-activated HLM. IL-10 and NECA increased both LPS- and svGIA-induced vascular endothelial growth factor A (VEGF-A) release. By contrast, IL-10 reduced angiopoietin-1 (ANGPT1) production from activated HLMs. IFN-γ and IL-4 reduced VEGF-A and ANGPT1 release from both LPS- and svGIA-activated HLMs. Moreover, IL-10 inhibited LPS-induced ANGPT2 production. In conclusion, we demonstrated a fine-tuning modulation of svGIA-activated HLMs differentially exerted by the classical macrophage-polarizing cytokines.


Assuntos
Fosfolipases A2 do Grupo IB/metabolismo , Pulmão/metabolismo , Macrófagos/metabolismo , Angiopoietina-1/metabolismo , Animais , Diferenciação Celular , Quimiocina CCL1/metabolismo , Citocinas/metabolismo , Humanos , Inflamação , Interleucina-10/metabolismo , Interleucina-4/metabolismo , Interleucina-8/metabolismo , Lipopolissacarídeos/farmacologia , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos Alveolares/metabolismo , Monócitos/citologia , Neovascularização Patológica , Serpentes , Fator de Necrose Tumoral alfa/metabolismo
6.
Cytokine ; 133: 155123, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32447247

RESUMO

We previously reported higher levels of C-C chemokine ligand (CCL) 1 in the bronchoalveolar lavage (BAL) fluid (BALF) of patients with sarcoidosis than in BALF of patients with immunoglobulin G4 (IgG4)-related disease (IgG4-RD), indicating that CCL1 might act as a marker of disease activity in sarcoidosis. Notably, less invasive sampling sources are desirable, as BAL cannot always be performed due to its inherent risk. In this study, we sought to decipher the correlation between serum levels of CCL1 and clinical characteristics of sarcoidosis. Serum samples were obtained from 44 patients with clinically confirmed sarcoidosis, 14 patients with IgG4-RD, and 14 healthy controls. The clinical and radiological findings were retrospectively evaluated. Serum levels of CCL1 were measured using a sandwich enzyme-linked immunosorbent assay. Serum levels of other 17 cytokines and chemokines were measured using a MILLIPLEX® MAP KIT and Luminex® magnetic beads. Serum levels of CCL1 were significantly higher in patients with sarcoidosis than in patients with IgG4-RD and healthy controls. Serum CCL1 was positively correlated with the degree of hilar lymph node swelling on chest computed tomography and serum levels of soluble interleukin 2 receptor. Positive correlations were also observed between serum CCL1 and total cell counts, lymphocyte counts in BALF, and serum T helper 1 mediators such as IP-10 and TNF-α in patients with sarcoidosis. Serum CCL1 levels were significantly elevated in sarcoidosis and correlated with clinical parameters of the disease. In addition, serum and BALF levels of CCL1 were positively correlated in a statistically significant manner. Although further research in this field is necessary, CCL1 might have the potential to be a reliable serological marker of disease activity in sarcoidosis.


Assuntos
Quimiocina CCL1/metabolismo , Doença Relacionada a Imunoglobulina G4/metabolismo , Imunoglobulina G/metabolismo , Sarcoidose/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Líquido da Lavagem Broncoalveolar , Feminino , Humanos , Ligantes , Masculino , Pessoa de Meia-Idade , Receptores de Interleucina-2/metabolismo , Estudos Retrospectivos , Adulto Jovem
7.
Mol Cell ; 78(6): 1192-1206.e10, 2020 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-32470318

RESUMO

Tumor-derived extracellular vesicles are important mediators of cell-to-cell communication during tumorigenesis. Here, we demonstrated that hepatocellular carcinoma (HCC)-derived ectosomes remodel the tumor microenvironment to facilitate HCC progression in an ectosomal PKM2-dependent manner. HCC-derived ectosomal PKM2 induced not only metabolic reprogramming in monocytes but also STAT3 phosphorylation in the nucleus to upregulate differentiation-associated transcription factors, leading to monocyte-to-macrophage differentiation and tumor microenvironment remodeling. In HCC cells, sumoylation of PKM2 induced its plasma membrane targeting and subsequent ectosomal excretion via interactions with ARRDC1. The PKM2-ARRDC1 association in HCC was reinforced by macrophage-secreted cytokines/chemokines in a CCL1-CCR8 axis-dependent manner, further facilitating PKM2 excretion from HCC cells to form a feedforward regulatory loop for tumorigenesis. In the clinic, ectosomal PKM2 was clearly detected in the plasma of HCC patients. This study highlights a mechanism by which ectosomal PKM2 remodels the tumor microenvironment and reveals ectosomal PKM2 as a potential diagnostic marker for HCC.


Assuntos
Proteínas de Transporte/metabolismo , Micropartículas Derivadas de Células/metabolismo , Proteínas de Membrana/metabolismo , Hormônios Tireóideos/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Proteínas de Transporte/genética , Diferenciação Celular/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Micropartículas Derivadas de Células/genética , Micropartículas Derivadas de Células/patologia , Quimiocina CCL1/metabolismo , Progressão da Doença , Células Hep G2 , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Macrófagos/metabolismo , Masculino , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Monócitos/metabolismo , Prognóstico , Fator de Transcrição STAT3/metabolismo , Hormônios Tireóideos/genética , Microambiente Tumoral
8.
J Pharm Pharmacol ; 72(5): 709-718, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32037551

RESUMO

OBJECTIVES: Gadolinium (Gd) affects microglial polarization during remyelination. We previously reported that the suppression of proinflammatory microglia was neuroprotective in intracerebral haemorrhage (ICH). The objective of the present study was to investigate the effects of Gd on microglial polarization and neuronal injury after ICH. METHODS: Gadolinium was intraperitoneally administered to ICH mice prepared by an intrastriatal microinjection of collagenase type VII. The polarization of M1, 2a, b and c microglia was evaluated by real-time PCR using the respective markers. Changes in representative mRNAs were also confirmed by immunological methods. Neuroprotective effects were evaluated by counting NeuN-positive cells and a behavioural analysis. KEY FINDINGS: One day after ICH, the mRNA levels of proinflammatory M1 microglial markers, such as inducible nitric oxide synthase (iNOS), and anti-inflammatory M2 microglial markers, such as arginase1 (M2a, c), Ym1 (M2a), and transforming growth factor-ß (M2c), increased, while those of chemokine CCL1 (M2b) only increased after 3 days. Gd decreased the levels of all M1 and M2 markers. Arginase1 and iNOS protein levels also increased, and Gd reduced them due to apoptotic cell death. Gadolinium attenuated oedema, neuron loss, neurological deficits and the mortality rate without affecting haematoma sizes. CONCLUSIONS: Gadolinium induced M1 and M2 microglial apoptosis and exerted acute neuroprotective effects after ICH.


Assuntos
Apoptose/efeitos dos fármacos , Hemorragia Cerebral/tratamento farmacológico , Gadolínio/uso terapêutico , Microglia/efeitos dos fármacos , Microglia/metabolismo , Fármacos Neuroprotetores/uso terapêutico , Animais , Arginase/metabolismo , Comportamento Animal/efeitos dos fármacos , Biomarcadores/metabolismo , Edema Encefálico/tratamento farmacológico , Hemorragia Cerebral/metabolismo , Hemorragia Cerebral/patologia , Quimiocina CCL1/metabolismo , Masculino , Camundongos , Fármacos Neuroprotetores/farmacologia , Óxido Nítrico Sintase Tipo II/metabolismo , RNA Mensageiro/metabolismo , Fator de Crescimento Transformador beta/metabolismo
9.
Innate Immun ; 26(4): 285-293, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31744342

RESUMO

A greater demand for food animal production without antibiotics has created the common practice of feeding food animals dietary immunomodulatory feed additives (IFA) throughout their life cycle. However, little is known about the impact of IFA on cytokine and chemokine signaling in non-stressed, non-pathogen-challenged food animals during the early feeding period. We evaluated the expression of 82 genes related to cytokine and chemokine signaling in the whole blood of growing Angus heifers to determine the effect of IFA supplementation on cytokine and chemokine signaling during the first 28 d of feeding. One gene (CCL1) was significantly up-regulated and 14 genes (17%) were significantly down-regulated by IFA feeding during the entire early feeding period including 5 of 21 (24%) evaluated chemokine and IL receptors (CCR1, CCR2, IL1R1, IL10RA, IL10RB). These data when taken together suggest providing an IFA in the diet of growing beef cattle during the early feeding period may suppress the inflammatory response through cytokine-cytokine receptor signaling.


Assuntos
Ração Animal , Dieta/veterinária , Inflamação/metabolismo , Compostos Fitoquímicos/metabolismo , Animais , Bovinos , Quimiocina CCL1/genética , Quimiocina CCL1/metabolismo , Feminino , Regulação da Expressão Gênica , Imunomodulação , Inflamação/genética , Inflamação/veterinária , Receptores de Quimiocinas/genética , Receptores de Quimiocinas/metabolismo , Transdução de Sinais/genética
10.
Neurosci Res ; 154: 20-26, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31121204

RESUMO

Chronic postoperative pain might be a pivotal component hindering recovery and regains the function after bone fracture and orthopedic surgery. However, the underlying mechanisms remain largely unclear. AMPA receptor of excitatory synapses is considered due to its critical role in pathologic pain. Chemokine CCL1 related neuroinflammation plays a role in excitatory synaptic transmission and nociceptive transduction. This study examined whether spinal CCL1 is associated with fracture-associated postoperative pain via AMPA receptor. We herein discovered that the tibial fracture with orthopedic surgery initiated and maintained chronic postoperative pain along with spinal up-regulation of CCL1/CCR8 expression and phosphorylation of GluA1-containing AMPA receptor. Central CCL1/CCR8 inhibition impaired mechanical and cold allodynia, and phosphorylated GluA1-containing AMPA receptor in the spinal dorsal horn. Intrathecal injection of GluA1-containing AMPA receptor antagonist NASPM alleviated fracture-related postoperative pain. Also, exogenous CCL1 delivery facilitated acute pain behaviors and spinal phosphorylation of GluA1-containing AMPA receptor in naïve mice, reversing by co-application of NASPM. Our current results indicated that spinal CCL1/CCR8-mediated GluA1-containing AMPA receptor activation is vital in the pathogenesis of fracture associated postoperative pain in mice.


Assuntos
Quimiocina CCL1/metabolismo , Receptores de AMPA/metabolismo , Receptores CCR8/imunologia , Fraturas da Tíbia/metabolismo , Animais , Hiperalgesia/metabolismo , Masculino , Camundongos , Procedimentos Ortopédicos , Dor Pós-Operatória/etiologia , Dor Pós-Operatória/metabolismo , Dor Pós-Operatória/patologia , Fosforilação , Receptores CCR8/metabolismo , Corno Dorsal da Medula Espinal/metabolismo , Fraturas da Tíbia/patologia
11.
Nat Cell Biol ; 21(11): 1403-1412, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31685984

RESUMO

The development of effective therapies against brain metastasis is currently hindered by limitations in our understanding of the molecular mechanisms driving it. Here we define the contributions of tumour-secreted exosomes to brain metastatic colonization and demonstrate that pre-conditioning the brain microenvironment with exosomes from brain metastatic cells enhances cancer cell outgrowth. Proteomic analysis identified cell migration-inducing and hyaluronan-binding protein (CEMIP) as elevated in exosomes from brain metastatic but not lung or bone metastatic cells. CEMIP depletion in tumour cells impaired brain metastasis, disrupting invasion and tumour cell association with the brain vasculature, phenotypes rescued by pre-conditioning the brain microenvironment with CEMIP+ exosomes. Moreover, uptake of CEMIP+ exosomes by brain endothelial and microglial cells induced endothelial cell branching and inflammation in the perivascular niche by upregulating the pro-inflammatory cytokines encoded by Ptgs2, Tnf and Ccl/Cxcl, known to promote brain vascular remodelling and metastasis. CEMIP was elevated in tumour tissues and exosomes from patients with brain metastasis and predicted brain metastasis progression and patient survival. Collectively, our findings suggest that targeting exosomal CEMIP could constitute a future avenue for the prevention and treatment of brain metastasis.


Assuntos
Neoplasias Encefálicas/genética , Exossomos/metabolismo , Regulação Neoplásica da Expressão Gênica , Hialuronoglucosaminidase/genética , Neovascularização Patológica/genética , Microambiente Tumoral/genética , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Quimiocina CCL1/genética , Quimiocina CCL1/metabolismo , Quimiocina CXCL1/genética , Quimiocina CXCL1/metabolismo , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Exossomos/patologia , Humanos , Hialuronoglucosaminidase/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Nus , Metástase Neoplásica , Neovascularização Patológica/metabolismo , Neovascularização Patológica/mortalidade , Neovascularização Patológica/patologia , Transdução de Sinais , Análise de Sobrevida , Carga Tumoral , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
12.
J Exp Med ; 216(12): 2763-2777, 2019 12 02.
Artigo em Inglês | MEDLINE | ID: mdl-31537642

RESUMO

Group 2 innate lymphoid cells (ILC2s) possess indispensable roles during type 2-mediated inflammatory diseases. Although their physiological and detrimental immune functions seem to depend on the anatomical compartment they reside, their tissue tropism and the molecular and immunological processes regulating the self-renewal of the local pool of ILC2s in the context of inflammation or infection are incompletely understood. Here, we analyzed the role of the CC-chemokine receptor CCR8 for the biological functions of ILC2s. In vitro and in vivo experiments indicated that CCR8 is in comparison to the related molecule CCR4 less important for migration of these cells. However, we found that activated mouse and human ILC2s produce the CCR8 ligand CCL1 and are a major source of CCL1 in vivo. CCL1 signaling to ILC2s regulates their proliferation and supports their capacity to protect against helminthic infections. In summary, we identify a novel chemokine receptor-dependent mechanism by which ILC2s are regulated during type 2 responses.


Assuntos
Quimiocina CCL1/metabolismo , Imunidade Inata , Inflamação/etiologia , Inflamação/metabolismo , Subpopulações de Linfócitos/imunologia , Subpopulações de Linfócitos/metabolismo , Receptores CCR8/metabolismo , Animais , Comunicação Autócrina , Biomarcadores , Movimento Celular/genética , Movimento Celular/imunologia , Citocinas/metabolismo , Expressão Gênica , Helmintos/imunologia , Interações Hospedeiro-Parasita/genética , Interações Hospedeiro-Parasita/imunologia , Humanos , Imunofenotipagem , Mediadores da Inflamação/metabolismo , Camundongos , Camundongos Knockout , Receptores CCR8/genética
13.
Pathology ; 51(6): 586-592, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31445808

RESUMO

Development, course of disease and prognosis of hepatocellular carcinomas (HCC) are strongly influenced by the immune system. Immunosuppressive regulatory T cells (Treg) have been shown to negatively impact disease progression and survival. To further understand the mechanisms of Treg attraction to HCC lesions, this study provides an analysis of Treg attracting chemokines in human HCC tissues. We analysed the expression of the Treg attracting chemokines CCL1 and CCL22 as well as the infiltration of FoxP3+ Treg and CD8+ T cells in paraffin-embedded tissue sections of 62 HCC patients. Expression of both chemokines was detected in 47 of 62 tissue slides. Chemokine expression was generally higher in tumour stroma and peritumoural liver tissue than in the tumour tissue itself. CD8+ T cells and FoxP3+ Treg were found at high levels in many tumour tissues. Intratumoural infiltration of Treg positively correlated with CCL22 levels in peritumoural liver tissue. In contrast, no correlation of Treg numbers and expression of CCL1 was detected. In summary, we describe here that the chemokines CCL1 and CCL22 are expressed in HCC tissues and, to a higher extent, in the stroma and peritumoural liver tissue. CCL22 may contribute to Treg recruitment and immunosuppression, whereas the role of CCL1 remains to be defined. It will be interesting to investigate the potential of these chemokines as drug targets for cancer therapy.


Assuntos
Carcinoma Hepatocelular/metabolismo , Quimiocina CCL1/metabolismo , Quimiocina CCL22/metabolismo , Neoplasias Hepáticas/metabolismo , Linfócitos do Interstício Tumoral/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Linfócitos T CD8-Positivos/metabolismo , Carcinoma Hepatocelular/patologia , Feminino , Fatores de Transcrição Forkhead/metabolismo , Humanos , Neoplasias Hepáticas/patologia , Linfócitos do Interstício Tumoral/patologia , Masculino , Pessoa de Meia-Idade , Linfócitos T Reguladores/metabolismo , Adulto Jovem
14.
J Cell Biochem ; 120(10): 16614-16623, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31161659

RESUMO

MicroRNAs (miRNA) play important roles in neuroinflammation and neuropathic pain development; however, the underlying mechanism requires further investigation. The expression of miR-21-5p was remarkably upregulated in chronic constrictive injury (CCI) rat model. A significant alleviated neuropathic pain development and reduced the expression of cytokines was observed in CCI rat after exogenous injection of miR-21-5p mimic. The dual-luciferase analysis revealed that tissue inhibitor of metalloproteinase-3 (TIMP3) and chemokines C-C motif ligand 1 (CCL1) was direct downstream target of miR-21-5p. Moreover, silencing of TIMP3 and CCL1 could rescue mechanical allodynia, thermal hyperalgesia and cytokine release in CCI rat, suggesting that TIMP3 and CCL1 exert their function by mediating neuroinflammation in neuropathic pain development. Therefore, we have identified a novel miR-21-5p-CCL1/TIMP3-cytokine axis in regulation of neuropathic pain development in CCI rat model, which is valuable for enhancing our understanding of neuropathic pain and developing miRNAs as potential therapeutic options in the future.


Assuntos
Quimiocina CCL1/metabolismo , MicroRNAs/metabolismo , Neuralgia/metabolismo , Transdução de Sinais , Inibidor Tecidual de Metaloproteinase-3/metabolismo , Animais , Quimiocina CCL1/genética , Modelos Animais de Doenças , MicroRNAs/genética , Neuralgia/genética , Neuralgia/patologia , Ratos , Inibidor Tecidual de Metaloproteinase-3/genética
15.
Cytokine ; 120: 125-129, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31063909

RESUMO

BACKGROUND: We previously reported that the cytokine profiles in the bronchoalveolar lavage fluid (BALF) of IgG4-related respiratory disease (IgG4-RRD) more closely resemble the T-helper (Th) 2 response than sarcoidosis. The present study aimed to assess the chemokines in the BALF of IgG4-RRD and sarcoidosis in order to evaluate any possible associations between these chemokines and other markers. METHODS: We examined 12 chemokines using a MILLIPLEX® MAP Kit (Millipore, Darmstadt, Germany) in the same BALF samples of the same 44 patients (IgG4-RRD, n = 11; sarcoidosis, n = 33) in which we had previously evaluated the cytokines. RESULTS: The levels of CC-chemokine ligand (CCL)26 in the BALF of IgG4-RRD patients (median 24.5, range 3.1-401.1 pg/mL) were significantly higher than those in the BALF of sarcoidosis patients (median 3.1, range 3.1-155.6 pg/mL, p < 0.05). Interestingly, the BALF levels of CCL1 in the sarcoidosis patients (median 13.1, range 0.1-106.9 pg/mL) were significantly higher than those of the IgG4-RRD patients (median 9.8, range 0.1-14.7 pg/mL, p < 0.05). Furthermore, the CCL1 levels in the BALF were correlated with the total cell count (ρ = 0.539, p < 0.001), lymphocyte fraction (R = 0.406, P < 0.05), lymphocyte count (R = 0.686, P < 0.001), TNF-α level, (R = 0.748, P < 0.001), and IL-2 level (R = 0.757, P < 0.001) in the BALF of sarcoidosis patients. CONCLUSIONS: CCL1 might reflect disease activity and its involvement in the pathogenesis of sarcoidosis might be more closely related to Th1 than to Th2.


Assuntos
Líquido da Lavagem Broncoalveolar/química , Quimiocina CCL1/metabolismo , Quimiocinas/metabolismo , Imunoglobulina G/imunologia , Doenças Respiratórias/imunologia , Sarcoidose/imunologia , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
16.
Int J Mol Sci ; 19(7)2018 06 26.
Artigo em Inglês | MEDLINE | ID: mdl-29949879

RESUMO

PPARγ belongs to the group of nuclear receptors which is expressed in the trophoblast and together with other factors is responsible for the maintenance of pregnancy. Apart from that PPARγ is also a main factor for macrophage polarization. The aim of this study was to investigate the combined expression pattern and frequency of PPARγ under physiological circumstances and in spontaneous and recurrent miscarriages in the trophoblast and in maternal macrophages of the decidua. Human placental tissues of the first trimester (15 physiologic pregnancies, 15 spontaneous abortion and 16 recurrent miscarriage placentas) were analyzed for expression of the nuclear receptor PPARγ. Expression changes were evaluated by immunohistochemistry and real time PCR (RT-PCR) in trophoblast and in maternal macrophages of the decidua. Maternal macrophages were identified by double immunofluorescence using cluster of differentiation 68 (CD68) as marker for macrophages and further characterized regarding their M1/M2 polarization status. The intermediate villous trophoblast revealed a significantly lower PPARγ expression in spontaneous and recurrent abortion. Maternal macrophages express PPARγ. Their number is significantly enhanced in the decidua of spontaneous miscarriages whereas in recurrent miscarriages maternal macrophages seem to express PPARγ only in very few cases. PPARγ is associated with an M2 polarization state that is common for decidual macrophages. The lack of PPARγ in recurrent miscarriage decidual macrophages seems to be associated with a specific inflammatory response against the fetus.


Assuntos
Aborto Habitual/genética , Aborto Habitual/patologia , Macrófagos/metabolismo , PPAR gama/genética , Placenta/metabolismo , Placenta/patologia , Adolescente , Adulto , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Receptor 1 de Quimiocina CX3C/metabolismo , Quimiocina CCL1/metabolismo , Decídua/metabolismo , Decídua/patologia , Demografia , Feminino , Humanos , Óxido Nítrico Sintase Tipo II/metabolismo , PPAR gama/metabolismo , Gravidez , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptor 2 Toll-Like/metabolismo , Trofoblastos/metabolismo , Trofoblastos/patologia , Adulto Jovem
17.
Cancer Res Treat ; 50(3): 894-907, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28934847

RESUMO

Purpose: Cancer-associated fibroblasts (CAFs) activated by cancer cells has a central role in development and malignant biological behavior in colorectal cancer (CRC). Adult fibroblasts do not express Snail, but Snail-positive fibroblasts are discovered in the stroma of malignant CRC and reported to be the key role to chemoresistance. However, the reciprocal effect of CAFs expressed Snail to chemoresistance on CRC cells and the underlying molecular mechanisms are not fully characterized. Materials and Methods: Snail-overexpressed 3T3 stable cell lines were generated by lipidosome and CT26 mixed with 3T3-Snail subcutaneous transplanted CRC models were established by subcutaneous injection. Cell Counting Kit-8, flow cytometry and western blotting assays were performed, and immunohistochemistry staining was studied. The cytokines participated in chemoresistance was validated with reverse transcriptase-polymerase chain reaction and heatmap. Results: Snail-expression fibroblasts are discovered in human and mouse spontaneous CRCs. Overexpression of Snail induces 3T3 fibroblasts transdifferentiation to CAFs. CT26 co-cultured with 3T3-Snail resisted the impairment from 5-fluorouracil and paclitaxel in vitro. The subcutaneous transplanted tumor models included 3T3-Snail cells develop without restrictions even after treating with 5-fluorouracil or paclitaxel. Moreover, these chemoresistant processes may be mediated by CCL1 secreted by Snail-expression fibroblasts via transforming growth factor ß/nuclear factor-κB signaling pathways. Conclusion: Taken together, Snail-expressing 3T3 fibroblasts display CAFs properties that support 5-fluorouracil and paclitaxel chemoresistance in CRC via participation of CCL1 and suggest that inhibition of the Snail-expression fibroblasts in tumor may be a useful strategy to limit chemoresistance.


Assuntos
Fibroblastos Associados a Câncer/citologia , Quimiocina CCL1/metabolismo , Neoplasias Colorretais/metabolismo , Resistencia a Medicamentos Antineoplásicos , Fatores de Transcrição da Família Snail/metabolismo , Células 3T3 , Animais , Fibroblastos Associados a Câncer/efeitos dos fármacos , Fibroblastos Associados a Câncer/metabolismo , Linhagem Celular Tumoral , Quimiocina CCL1/genética , Técnicas de Cocultura , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Fluoruracila/farmacologia , Humanos , Camundongos , NF-kappa B/metabolismo , Transplante de Neoplasias , Paclitaxel/farmacologia , Transdução de Sinais , Fator de Crescimento Transformador beta/metabolismo
18.
J Microbiol Immunol Infect ; 51(1): 18-26, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27325144

RESUMO

BACKGROUND/PURPOSE: Asthma is a chronic airway inflammatory disease mediated by T-helper (Th)2 cells. Montelukast (trade name Singulair) is a cysteinyl leukotriene receptor antagonist used for asthma treatment. Mirroring Th1-Th2 polarization, two distinct states of macrophages have been recognized: the classically activated (M1) macrophages and the alternatively activated (M2) macrophages. M2 polarization is known to be a response to the Th2 cytokines; however, the effects of montelukast on M2 macrophages have not been well characterized. The aim of the present study was to investigate the effects of montelukast on the expression of cytokines and chemokines in M2-like macrophages, and to explore possible intracellular signaling pathways. METHODS: The human monocytic leukemia cell line THP-1 and human monocytes from healthy donors were cultured with interleukin-4 for M2 polarization, and then the cells were pretreated with or without montelukast before lipopolysaccharide (LPS) stimulation. Supernatants were collected to determine interleukin-10, I-309/CCL1, and MDC/CCL22 levels by enzyme-linked immunosorbent assay. Intracellular signaling was investigated using nuclear factor (NF)-κB inhibitors, mitogen-activated protein kinase (MAPK) inhibitors, and western blot analysis. RESULTS: LPS-induced interleukin-10 and I-309/CCL1 expression was significantly suppressed by montelukast in THP-1-derived and human monocyte-derived M2 macrophages after LPS stimulation. MDC/CCL22 expression was only significantly suppressed by montelukast in THP-1-derived M2 macrophages after 48 hours of incubation. In western blot analysis, montelukast was able to suppress LPS-induced MAPK-phospho-p38 and NF-κB-phospho-p65 expression. CONCLUSION: Montelukast suppressed LPS-induced M2-related cytokines and chemokines in alternatively activated macrophages, and the effects might be mediated through the MAPK-p38 and NF-κB-p65 pathways.


Assuntos
Acetatos/farmacologia , Quimiocinas/metabolismo , Citocinas/metabolismo , Macrófagos/efeitos dos fármacos , Quinolinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Quimiocina CCL1/metabolismo , Quimiocina CCL22/metabolismo , Ciclopropanos , Humanos , Interleucina-10/metabolismo , Interleucina-4 , Lipopolissacarídeos/farmacologia , Macrófagos/metabolismo , Monócitos/efeitos dos fármacos , NF-kappa B/metabolismo , Sulfetos , Células THP-1/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
19.
Iran J Immunol ; 14(4): 281-292, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29276181

RESUMO

BACKGROUND: Hepatitis viruses are non-cytopathic viruses that lead to the infection and pathogenesis of liver diseases as a result of immunologically mediated events. OBJECTIVE: To investigate the expression of human inflammatory cytokines in chronic hepatitis B patients according to the severity of the infection. METHODS: We recruited a total of 120 patients, 40 of whom from cirrhotic, 40 non-cirrhotic, and 40 acute flare chronic hepatitis B and 40 healthy controls. For all groups total cellular RNA was extracted from whole blood samples, genomic DNA was eliminated, and cDNA was synthesized using the RT2 first strand kit, as instructed by the manufacturer. The real-time profiler PCR array was performed on a master cycler ep realplex and the data were analyzed using an online data analysis software. RESULTS: Non-cirrhotic chronic hepatitis B patients were found to significantly upregulate interleukin 10 receptors that regulate the balance between T helpers 1 and 2. On the other hand, patients with cirrhosis were found to have significant upregulated interleukin 3 gene expression. CONCLUSION: Our finding suggests that upregulation of anti-inflammatory and downregulation of pro-inflammatory cytokines may play a role in the progression of non-cirrhotic chronic hepatitis B patients to cirrhotic and acute flare. However, a multi-center study with a larger sample size is needed to confirm our findings.


Assuntos
Fibrose/imunologia , Vírus da Hepatite B/imunologia , Hepatite B Crônica/imunologia , Fígado/metabolismo , Quimiocina CCL1/genética , Quimiocina CCL1/metabolismo , Quimiocina CCL26/genética , Quimiocina CCL26/metabolismo , Complemento C5/genética , Complemento C5/metabolismo , Estudos Transversais , Progressão da Doença , Fibrose/genética , Regulação da Expressão Gênica , Hepatite B Crônica/genética , Humanos , Mediadores da Inflamação/metabolismo , Fígado/patologia
20.
Virol J ; 14(1): 234, 2017 12 04.
Artigo em Inglês | MEDLINE | ID: mdl-29202792

RESUMO

BACKGROUND: Chemokine (C-C motif) ligand 1 (CCL1) is produced by activated monocytes/ macrophages and T-lymphocytes, and acts as a potent attractant for Th2 cells and a subset of T-regulatory (Treg) cells. Previous reports have indicated that CCL1 is overexpressed in adult T-cell leukemia cells, mediating an autocrine anti-apoptotic loop. Because CCL1 is also known as a potent chemoattractant that plays a major role in inflammatory processes, we investigated the role of CCL1 in the pathogenesis of human T-cell leukemia virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP). RESULTS: The results showed that: (1) CCL1 was preferentially expressed in HAM/TSP-derived HTLV-1-infected T-cell lines, (2) CCL1 expression was induced along with Tax expression in the Tax-inducible T-cell line JPX9, (3) transient Tax expression in an HTLV-1-negative T-cell line activated the CCL1 gene promoter, (4) plasma levels of CCL1 were significantly higher in patients with HAM/TSP than in HTLV-1-seronegative patients with multiple sclerosis and HTLV-1-infected asymptomatic healthy carriers, and (5) minocycline inhibited the production of CCL1 in HTLV-1-infected T-cell lines. CONCLUSIONS: The present results suggest that elevated CCL1 levels may be associated with the pathogenesis of HAM/TSP. Although further studies are required to determine the in vivo significance, minocycline may be considered as a potential candidate for the long-term treatment of HAM/TSP via its anti-inflammatory effects, which includes the inhibition of CCL1 expression.


Assuntos
Quimiocina CCL1/genética , Regulação para Baixo/efeitos dos fármacos , Produtos do Gene tax/metabolismo , Minociclina/farmacologia , Paraparesia Espástica Tropical/fisiopatologia , Regulação para Cima/genética , Adulto , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Linhagem Celular , Quimiocina CCL1/metabolismo , Citometria de Fluxo , Humanos , Minociclina/uso terapêutico , Paraparesia Espástica Tropical/tratamento farmacológico , Regiões Promotoras Genéticas , Reação em Cadeia da Polimerase em Tempo Real , Receptores CCR8/metabolismo , Ativação Transcricional/efeitos dos fármacos
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