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1.
Front Immunol ; 11: 1418, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32774335

RESUMO

Long non-coding RNAs are essential regulators of the inflammatory response, especially for transcriptional regulation of inflammatory genes. It has been reported that the expression of transmembrane channel-like 3 (TMC3)-AS1 is increased following lipopolysaccharide stimulation. However, the potential function of TMC3-AS1 in immunity is largely unknown. Herein, we report a specific role for TMC3-AS1 in the regulation of inflammatory gene expression. TMC3-AS1 negatively regulates the expression of interleukin 10 (IL-10) in macrophage and intestinal epithelial cell lines. Mechanistically, TMC3-AS1 may interact with p65 in the nucleus, preventing p65 from binding to the κB consensus site within IL-10 promoter. These findings suggest that TMC3-AS1 may function as an important regulator in the innate immune response.


Assuntos
Regulação da Expressão Gênica/genética , Interleucina-10/biossíntese , Mucosa Intestinal/imunologia , Macrófagos/imunologia , RNA Longo não Codificante/metabolismo , Animais , Humanos , Imunidade Inata/imunologia , Inflamação/genética , Inflamação/imunologia , Mucosa Intestinal/metabolismo , Canais Iônicos , Lipopolissacarídeos/farmacologia , Macrófagos/metabolismo , Camundongos
2.
J Immunol ; 203(6): 1548-1559, 2019 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-31383742

RESUMO

Long noncoding RNAs are important regulators of gene expression in innate immune responses. Antisense IL-7 (IL-7-AS) is a newly discovered long noncoding RNA in human and mouse that has been reported to regulate the expression of IL-6. However, the potential function of IL-7-AS in innate immune system is not fully understood. In this study, we found that the expression of IL-7-AS is primarily dependent on the NF-κB and MAPK signaling pathways in macrophages and intestinal epithelial cells. Functionally, IL-7-AS promotes the expression of several inflammatory genes, including CCL2, CCL5, CCL7, and IL-6, in cells in response to LPS. Specifically, IL-7-AS physically interacts with p300 to regulate histone acetylation levels around the promoter regions of these gene loci. Moreover, IL-7-AS and p300 complex modulate the assembly of SWI/SNF complex to the promoters. IL-7-AS regulates chemotaxis activity of monocytes to intestine epithelial cells with involvement of CCL2. Therefore, our data indicate a new promoting role for NF-κB/MAPK-responsive IL-7-AS in the transcriptional regulation of inflammatory genes in the innate immune system although modulation of histone acetylation around the promoters of related genes.


Assuntos
Montagem e Desmontagem da Cromatina/genética , Histonas/genética , Inflamação/genética , Interleucina-7/genética , RNA Longo não Codificante/genética , Transcrição Genética/genética , Acetilação , Animais , Linhagem Celular , Linhagem Celular Tumoral , Feminino , Células HEK293 , Humanos , Imunidade Inata/genética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Regiões Promotoras Genéticas/genética , Células RAW 264.7 , Transdução de Sinais/genética , Células U937
3.
J Immunol ; 199(10): 3571-3582, 2017 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-28993514

RESUMO

Long noncoding RNAs, a newly identified class of noncoding RNAs, are important regulators of gene expression in innate immunity. We report in this study that the transcription of FIRRE, a conserved long noncoding RNA between humans and mice, is controlled by NF-κB signaling in macrophages and intestinal epithelial cells. Functionally, FIRRE appears to positively regulate the expression of several inflammatory genes in macrophages or intestinal epithelial cells in response to LPS stimulation via posttranscriptional mechanisms. Specifically, FIRRE physically interacts with heterogeneous nuclear ribonucleoproteins U, regulating the stability of mRNAs of selected inflammatory genes through targeting the AU-rich elements of their mRNAs in cells following LPS stimulation. Therefore, our data indicate a new regulatory role for NF-κB-responsive FIRRE in the posttranscriptional regulation of inflammatory genes in the innate immune system.


Assuntos
Sequência Conservada/genética , Inflamação/genética , Mucosa Intestinal/imunologia , Macrófagos/imunologia , NF-kappa B/metabolismo , RNA Longo não Codificante/genética , Elementos de Resposta/genética , Animais , Regulação da Expressão Gênica , Ribonucleoproteínas Nucleares Heterogêneas/metabolismo , Humanos , Imunidade Inata , Camundongos , RNA Longo não Codificante/metabolismo , RNA Interferente Pequeno/genética , Células U937
4.
Mol Cancer Res ; 9(9): 1175-86, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21875933

RESUMO

Macrophage-stimulating protein (MSP) is a plasminogen-related growth factor and ligand for the receptor tyrosine kinase RON. The MSP/RON system promotes wound healing and invasive tumor growth and suppresses proinflammatory immune response. MSP binding to RON requires proteolytic conversion of the inactive single-chain form (pro-MSP) into the disulfide-linked α/ß heterodimer. The pro-MSP cleavage sequence (Ser-Lys-Leu-Arg(483)↓Val(484)) closely matches the substrate recognition sequences of hepsin, a type II transmembrane serine protease, that is overexpressed in several cancers. Here, we show that recombinant hepsin cleaves pro-MSP at the consensus site Arg(483)-Val(484) with superior efficiency compared with the known activators MT-SP1 and hepatocyte growth factor activator (HGFA). At least 50% of pro-MSP was processed within 1 hour at a hepsin concentration of 2.4 nmol/L and at a molar enzyme to substrate ratio of 1:500. An uncleavable single-chain variant of MSP weakly bound to a RON-Fc fusion protein, whereas hepsin-cleaved MSP bound with a K(D) of 10.3 nmol/L, suggesting that the high-affinity binding site in MSP ß-chain was properly formed. LNCaP prostate cancer cells overexpressing hepsin on the cell surface efficiently activated pro-MSP, which was blocked by a specific anti-hepsin antibody. Incubation of pro-MSP with hepsin led to robust RON-mediated phosphorylation of mitogen-activated protein kinase, ribosomal S6 protein, and Akt in human A2780 ovarian carcinoma cells stably expressing RON protein. In macrophages, pro-MSP with hepsin induced chemotaxis and attenuated lipopolysaccharide-dependent production of nitric oxide. These findings suggest that the MSP/RON signaling pathway may be regulated by hepsin in tissue homeostasis and in disease pathologies, such as in cancer and immune disorders.


Assuntos
Neoplasias Ovarianas/metabolismo , Neoplasias da Próstata/metabolismo , Precursores de Proteínas/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Serina Endopeptidases/metabolismo , Linhagem Celular Tumoral , Feminino , Humanos , Macrófagos/metabolismo , Masculino , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Precursores de Proteínas/genética , Proteólise , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores Proteína Tirosina Quinases/genética , Proteínas Recombinantes de Fusão/metabolismo , Serina Endopeptidases/genética , Transdução de Sinais
5.
J Biol Chem ; 286(37): 32762-74, 2011 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-21784853

RESUMO

Although the signal transduction mechanisms of the receptor tyrosine kinase MET are well defined, less is known about its close relative RON. MET initiates intracellular signaling by autophosphorylation on specific cytoplasmic tyrosines that form docking sites for the adaptor proteins Grb2 and Gab1. Grb2 binds directly and is essential for all of the biological activities of MET. Gab1 docks either directly or indirectly via Grb2 and controls only a subset of MET functions. Because MET and RON possess similar adaptor binding sites, it was anticipated that their adaptor interactions would be conserved. Here we show that in contrast to MET, RON relies primarily on Gab1 for signal transmission. Surprisingly, disruption of the Grb2 docking site of RON or Grb2 depletion augments activity, whereas enhancement of Grb2 binding attenuates Gab1 recruitment and signaling. Hence, RON and MET differ in their adaptor interactions; furthermore, Grb2 performs a novel antagonistic role in the context of RON signaling.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteína Adaptadora GRB2/metabolismo , Fosfoproteínas/metabolismo , Proteínas Proto-Oncogênicas c-met/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Transdução de Sinais/fisiologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Sítios de Ligação , Linhagem Celular Tumoral , Proteína Adaptadora GRB2/genética , Células HEK293 , Humanos , Camundongos , Células NIH 3T3 , Fosfoproteínas/genética , Fosforilação/fisiologia , Proteínas Proto-Oncogênicas c-met/genética , Receptores Proteína Tirosina Quinases/genética
6.
Genome Res ; 13(10): 2265-70, 2003 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-12975309

RESUMO

A large-scale effort, termed the Secreted Protein Discovery Initiative (SPDI), was undertaken to identify novel secreted and transmembrane proteins. In the first of several approaches, a biological signal sequence trap in yeast cells was utilized to identify cDNA clones encoding putative secreted proteins. A second strategy utilized various algorithms that recognize features such as the hydrophobic properties of signal sequences to identify putative proteins encoded by expressed sequence tags (ESTs) from human cDNA libraries. A third approach surveyed ESTs for protein sequence similarity to a set of known receptors and their ligands with the BLAST algorithm. Finally, both signal-sequence prediction algorithms and BLAST were used to identify single exons of potential genes from within human genomic sequence. The isolation of full-length cDNA clones for each of these candidate genes resulted in the identification of >1000 novel proteins. A total of 256 of these cDNAs are still novel, including variants and novel genes, per the most recent GenBank release version. The success of this large-scale effort was assessed by a bioinformatics analysis of the proteins through predictions of protein domains, subcellular localizations, and possible functional roles. The SPDI collection should facilitate efforts to better understand intercellular communication, may lead to new understandings of human diseases, and provides potential opportunities for the development of therapeutics.


Assuntos
Moléculas de Adesão Celular Neuronais , Biologia Computacional/métodos , Proteínas de Membrana/genética , Proteínas/genética , Proteínas/metabolismo , Proteínas Ligadas por GPI , Biblioteca Gênica , Humanos , Dados de Sequência Molecular , Valor Preditivo dos Testes , Sinais Direcionadores de Proteínas/genética
7.
J Biol Chem ; 278(3): 1910-4, 2003 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-12417590

RESUMO

Interleukin (IL)-17 is a pro-inflammatory cytokine that is produced by activated T cells. Despite increasing evidence that high levels of IL-17 are associated with several chronic inflammatory diseases including rheumatoid arthritis, psoriasis, and multiple sclerosis, the regulation of its expression is not well characterized. We observe that IL-17 production is increased in response to the recently described cytokine IL-23. We present evidence that murine IL-23, which is produced by activated dendritic cells, acts on memory T cells, resulting in elevated IL-17 secretion. IL-23 also induced expression of the related cytokine IL-17F. IL-23 is a heterodimeric cytokine and shares a subunit, p40, with IL-12. In contrast to IL-23, IL-12 had only marginal effects on IL-17 production. These data suggest that during a secondary immune response, IL-23 can promote an activation state with features distinct from the well characterized Th1 and Th2 profiles.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Interleucina-17/biossíntese , Interleucinas/fisiologia , Ativação Linfocitária/fisiologia , Animais , Linfócitos T CD4-Positivos/citologia , Células Cultivadas , Interleucina-17/genética , Interleucina-23 , Subunidade p19 da Interleucina-23 , Camundongos , Camundongos Endogâmicos C57BL , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
8.
J Biol Chem ; 277(19): 17281-90, 2002 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-11877390

RESUMO

The angiopoietin family of secreted factors is functionally defined by the C-terminal fibrinogen (FBN)-like domain, which mediates binding to the Tie2 receptor and thereby facilitates a cascade of events ultimately regulating blood vessel formation. By screening expressed sequence tag data bases for homologies to a consensus FBN-like motive, we have identified ANGPTL3, a liver-specific, secreted factor consisting of an N-terminal coiled-coil domain and the C-terminal FBN-like domain. Co-immunoprecipitation experiments, however, failed to detect binding of ANGPTL3 to the Tie2 receptor. A molecular model of the FBN-like domain of ANGPTL3 was generated and predicted potential binding to integrins. This hypothesis was experimentally confirmed by the finding that recombinant ANGPTL3 bound to alpha(v)beta(3) and induced integrin alpha(v)beta(3)-dependent haptotactic endothelial cell adhesion and migration and stimulated signal transduction pathways characteristic for integrin activation, including phosphorylation of Akt, mitogen-activated protein kinase, and focal adhesion kinase. When tested in the rat corneal assay, ANGPTL3 strongly induced angiogenesis with comparable magnitude as observed for vascular endothelial growth factor-A. Moreover, the C-terminal FBN-like domain alone was sufficient to induce endothelial cell adhesion and in vivo angiogenesis. Taken together, our data demonstrate that ANGPTL3 is the first member of the angiopoietin-like family of secreted factors binding to integrin alpha(v)beta(3) and suggest a possible role in the regulation of angiogenesis.


Assuntos
Endotélio/citologia , Substâncias de Crescimento/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular , Receptores de Vitronectina/metabolismo , Sequência de Aminoácidos , Angiopoietina-2 , Proteínas Semelhantes a Angiopoietina , Angiopoietinas , Animais , Adesão Celular , Linhagem Celular , Movimento Celular , Células Cultivadas , Clonagem Molecular , Córnea/metabolismo , Fibrinogênio/metabolismo , Quinase 1 de Adesão Focal , Proteína-Tirosina Quinases de Adesão Focal , Humanos , Sistema de Sinalização das MAP Quinases , Camundongos , Dados de Sequência Molecular , Neovascularização Fisiológica , Testes de Precipitina , Ligação Proteica , Estrutura Terciária de Proteína , Proteínas Tirosina Quinases/metabolismo , Proteínas/metabolismo , Ratos , Proteínas Recombinantes/metabolismo , Homologia de Sequência de Aminoácidos , Transfecção
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