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1.
Blood Adv ; 3(4): 541-551, 2019 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-30782613

RESUMO

Multiple myeloma (MM) is a hematological malignancy that grows in multiple sites of the axial skeleton and causes debilitating osteolytic disease. Interleukin-34 (IL-34) is a newly discovered cytokine that acts as a ligand of colony-stimulating factor-1 (CSF-1) receptor and can replace CSF-1 for osteoclast differentiation. In this study, we identify IL-34 as an osteoclastogenic cytokine that accelerates osteolytic disease in MM. IL-34 was found to be expressed in the murine MM cell line MOPC315.BM, and the expression of IL-34 was enhanced by stimulation with proinflammatory cytokines or by bone marrow (BM) stromal cells. MM-cell-derived IL-34 promoted osteoclast formation from mouse BM cells in vitro. Targeting Il34 by specific small interfering RNA impaired osteoclast formation in vitro and attenuated osteolytic disease in vivo. In BM aspirates from MM patients, the expression levels of IL-34 in CD138+ populations vary among patients from high to weak to absent. MM cell-derived IL-34 promoted osteoclast formation from human CD14+ monocytes, which was reduced by a neutralizing antibody against IL-34. Taken together, this study describes for the first time the expression of IL-34 in MM cells, indicating that it may enhance osteolysis and suggesting IL-34 as a potential therapeutic target to control pathological osteoclastogenesis in MM patients.


Assuntos
Interleucinas/imunologia , Mieloma Múltiplo/complicações , Osteólise/etiologia , Animais , Linhagem Celular , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Interleucinas/análise , Interleucinas/genética , Camundongos , Camundongos Endogâmicos BALB C , Mieloma Múltiplo/genética , Mieloma Múltiplo/imunologia , Osteólise/genética , Osteólise/imunologia , Interferência de RNA , RNA Interferente Pequeno/genética , Células Tumorais Cultivadas
2.
Sci Rep ; 8(1): 418, 2018 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-29323162

RESUMO

Despite recent advances in diagnosis and treatment of lung cancers, the 5-year survival rate remains unsatisfactory, which necessitates the identification of novel factors that associates with disease progression and malignant degree for improving diagnostic and therapeutic strategies. Recent progress in cancer immunology research has unveiled critical roles for colony stimulating factor 1 receptor (CSF1R) in multiple aspects of the tumor microenvironment. CSF1R is expressed on tumor-associated macrophages (TAMs), and mediates important pro-tumorigenic functions. CSF1R also provides critical autocrine signals that promote cancer cell survival and proliferation. Activation of CSF1R can be achieved by two independent ligands; macrophage colony-stimulating factor (M-CSF) and interleukin 34 (IL-34). Accordingly, the expression of these ligands in cancer is expected to result in poor prognosis. In this study, we show that IL-34 and M-CSF expression correlates with poor survival in a cohort of lung cancer patients. Importantly, high co-expression of IL-34 and M-CSF associates with the poorest survival compared to cancers that show weak or absent expression of the two ligands. Furthermore, high expression of IL-34 and M-CSF associates with advanced stages of lung cancers. Together, these results indicate a correlation between IL-34/M-CSF expression with poor survival and disease progression in lung cancer patients.


Assuntos
Interleucinas/metabolismo , Neoplasias Pulmonares/patologia , Fator Estimulador de Colônias de Macrófagos/metabolismo , Análise Serial de Tecidos/métodos , Regulação para Cima , Adulto , Idoso , Idoso de 80 Anos ou mais , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/metabolismo , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Análise de Sobrevida , Microambiente Tumoral
3.
Biochem Biophys Res Commun ; 467(2): 383-8, 2015 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-26431873

RESUMO

Dendritic cell inhibitory receptor 1 (DCIR1, also known as DCIR and Clec4a2) and dendritic cell activating receptor 2 (DCAR2, also known as DCAR and Clec4b1) are mouse lectin receptors expressed on antigen presenting cells. They have structurally similar C-type lectin domains, of which amino acid sequences show 90.5% identity, and commercially available antibodies against them cross-react each other. Here we have established novel antibodies against DCIR1 and DCAR2 that can unambiguously discriminate DCIR1 and DCAR2 and examined their distribution among various immune cells. While DCIR1 was ubiquitously expressed on myeloid cells, including conventional DCs (cDCs), macrophages, neutrophils and eosinophils, in various immune organs, significant expression of DCAR2 was detected only on subpopulations of cDCs from bone marrow and skin-draining lymph nodes. Interestingly, in FITC-painted mice, DCAR2 was expressed on all of the FITC(+) cDCs, which had migrated from the skin after FITC painting, suggesting that DCAR2 can be a marker of migratory cDCs in skin-draining lymph nodes. Our findings provide a basis to investigate in vivo function of DCIR1 and DCAR2.


Assuntos
Anticorpos Monoclonais/química , Células Dendríticas/metabolismo , Lectinas Tipo C/genética , Células Mieloides/metabolismo , Receptores de Superfície Celular/genética , Animais , Anticorpos Monoclonais/biossíntese , Anticorpos Monoclonais/isolamento & purificação , Células da Medula Óssea/citologia , Células da Medula Óssea/metabolismo , Células Dendríticas/citologia , Feminino , Citometria de Fluxo , Expressão Gênica , Imunofenotipagem , Lectinas Tipo C/metabolismo , Linfonodos/citologia , Linfonodos/metabolismo , Mesentério/citologia , Mesentério/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Células Mieloides/classificação , Células Mieloides/citologia , Ratos , Ratos Endogâmicos Lew , Receptores de Superfície Celular/metabolismo , Pele/citologia , Pele/metabolismo , Baço/citologia , Baço/metabolismo
4.
J Biol Chem ; 284(40): 27327-35, 2009 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-19654330

RESUMO

The killer cell lectin-like receptor G1, KLRG1, is a cell surface receptor expressed on subsets of natural killer (NK) cells and T cells. KLRG1 was recently found to recognize E-cadherin and thus inhibit immune responses by regulating the effector function and the developmental processes of NK and T cells. E-cadherin is expressed on epithelial cells and exhibits Ca(2+)-dependent homophilic interactions that contribute to cell-cell junctions. However, the mechanism underlying the molecular recognition of KLRG1 by E-cadherin remains unclear. Here, we report structural, binding, and functional analyses of this interaction using multiple methods. Surface plasmon resonance demonstrated that KLRG1 binds the E-cadherin N-terminal domains 1 and 2 with low affinity (K(d) approximately 7-12 microm), typical of cell-cell recognition receptors. NMR binding studies showed that only a limited N-terminal region of E-cadherin, comprising the homodimer interface, exhibited spectrum perturbation upon KLRG1 complex formation. It was confirmed by binding studies using a series of E-cadherin mutants. Furthermore, killing assays using KLRG1(+)NK cells and reporter cell assays demonstrated the functional significance of the N-terminal region of E-cadherin. These results suggest that KLRG1 recognizes the N-terminal homodimeric interface of domain 1 of E-cadherin and binds only the monomeric form of E-cadherin to inhibit the immune response. This raises the possibility that KLRG1 detects monomeric E-cadherin at exposed cell surfaces to control the activation threshold of NK and T cells.


Assuntos
Caderinas/metabolismo , Receptores Imunológicos/metabolismo , Sequência de Aminoácidos , Animais , Sítios de Ligação , Caderinas/química , Caderinas/genética , Bovinos , Linhagem Celular Tumoral , Regulação da Expressão Gênica , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Lectinas Tipo C , Espectroscopia de Ressonância Magnética , Camundongos , Modelos Moleculares , Dados de Sequência Molecular , Mutagênese , Ligação Proteica , Multimerização Proteica , Estrutura Quaternária de Proteína , Estrutura Terciária de Proteína , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Coloração e Rotulagem , Ressonância de Plasmônio de Superfície
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