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1.
Fish Shellfish Immunol ; 93: 597-611, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31400511

RESUMO

The transcription factor, activator protein-1 (AP-1), is a dimeric protein and a downstream member of the mitogen-activated protein kinase (MAPK) signaling pathway. It regulates a wide array of functions including, cell proliferation, survival, differentiation, response to UV-irradiation, immune responses, and inflammatory conditions. AP-1 belongs to the basic leucine zipper (bZIP) protein family, which consists of members from Jun, Fos, Maf, and ATF subfamilies. In the present study, c-Jun and c-Fos homologs were identified from a transcriptome database of Liza haematocheila and designated as Lhc-Jun and Lhc-Fos. In both sequences, the signature bZIP domain was identified and also the DNA binding sites, dimerization sites, as well as the phosphorylation sites, were found to be highly conserved through evolution. Tissue distribution analysis revealed that both Lhc-Jun and Lhc-Fos transcripts were ubiquitously expressed in all examined tissues of healthy mullets. In order to determine the transcriptional modulations of Lhc-Jun and Lhc-Fos, challenge experiments were carried out using LPS, poly I:C, and L. garvieae. The qRT-PCR analysis revealed significant upregulation of Lhc-Jun and Lhc-Fos in blood, gill, liver, and spleen. This is the first study that explores the correlation between UV-irradiation and AP-1 ortholog expression in teleosts. Also, this is the first time that the functional characterization of the teleost c-Fos ortholog has been carried out. Sub-cellular localization of Lhc-Jun and Lhc-Fos was observed in the nucleus. AP-1-Luc reporter assays revealed significant higher luciferase activities in both Lhc-Jun and Lhc-Fos proteins compared to mock controls. These results strongly suggest that Lhc-Jun and Lhc-Fos might play a significant role in Liza haematocheila immunity by regulating AP-1 promoter sequences in immune and stress-related genes.


Assuntos
Doenças dos Peixes/imunologia , Peixes/genética , Peixes/imunologia , Regulação da Expressão Gênica/imunologia , Imunidade Inata/genética , Fator de Transcrição AP-1/genética , Fator de Transcrição AP-1/imunologia , Sequência de Aminoácidos , Animais , Proteínas de Peixes/química , Proteínas de Peixes/genética , Proteínas de Peixes/imunologia , Perfilação da Expressão Gênica/veterinária , Infecções por Bactérias Gram-Positivas/imunologia , Infecções por Bactérias Gram-Positivas/veterinária , Lactococcus/fisiologia , Lipopolissacarídeos/farmacologia , Filogenia , Poli I-C/farmacologia , Proteínas Proto-Oncogênicas c-fos/genética , Proteínas Proto-Oncogênicas c-fos/imunologia , Proteínas Proto-Oncogênicas c-jun/genética , Proteínas Proto-Oncogênicas c-jun/imunologia , Alinhamento de Sequência/veterinária , Fator de Transcrição AP-1/química
2.
Front Immunol ; 9: 2761, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30559741

RESUMO

LC3-associated phagocytosis (LAP) is an emerging non-canonical autophagy process that bridges signaling from pattern-recognition receptors (PRRs) to autophagic machinery. LAP formation results in incorporation of lipidated LC3 into phagosomal membrane (termed LAPosome). Increasing evidence reveals that LAP functions as an innate defense mechanism against fungal pathogens. However, the molecular mechanism involved and the consequence of LAP in regulating anti-fungal immune response remain largely unexplored. Here we show that Histoplasma capsulatum is taken into LAPosome upon phagocytosis by macrophages. Interaction of H. capsulatum with Dectin-1 activates Syk and triggers subsequent NADPH oxidase-mediated reactive oxygen species (ROS) response that is involved in LAP induction. Inhibiting LAP induction by silencing LC3α/ß or treatment with ROS inhibitor impairs the activation of MAPKs-AP-1 pathway, thereby reduces macrophage proinflammatory cytokine response to H. capsulatum. Additionally, we unravel the importance of NLRX1 in fungus-induced LAP. NLRX1 facilitates LAP by interacting with TUFM which associates with autophagic proteins ATG5-ATG12 for LAPosome formation. Macrophages from Nlrx1 -/- mice or TUFM-silenced cells exhibit reduced LAP induction and LAP-mediated MAPKs-AP-1 activation for cytokine response to H. capsulatum. Furthermore, inhibiting ROS production in Nlrx1 -/- macrophages almost completely abolishes H. capsulatum-induced LC3 conversion, indicating that both Dectin-1/Syk/ROS-dependent pathway and NLRX1-TUFM complex-dependent pathway collaboratively contribute to LAP induction. Our findings reveal new pathways underlying LAP induction by H. capsulatum for macrophage cytokine response.


Assuntos
Citocinas/metabolismo , Histoplasma/imunologia , Macrófagos/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Proteínas Mitocondriais/metabolismo , Fagocitose/fisiologia , Animais , Autofagia/imunologia , Autofagia/fisiologia , Proteína 12 Relacionada à Autofagia/imunologia , Proteína 12 Relacionada à Autofagia/metabolismo , Proteína 5 Relacionada à Autofagia/imunologia , Proteína 5 Relacionada à Autofagia/metabolismo , Citocinas/imunologia , Histoplasmose/imunologia , Histoplasmose/metabolismo , Histoplasmose/microbiologia , Lectinas Tipo C/imunologia , Lectinas Tipo C/metabolismo , Macrófagos/imunologia , Macrófagos/microbiologia , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Associadas aos Microtúbulos/imunologia , Proteínas Mitocondriais/imunologia , Proteínas Quinases Ativadas por Mitógeno/imunologia , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NADPH Oxidases/imunologia , NADPH Oxidases/metabolismo , Fagocitose/imunologia , Fagossomos/imunologia , Fagossomos/metabolismo , Fagossomos/microbiologia , Espécies Reativas de Oxigênio/imunologia , Espécies Reativas de Oxigênio/metabolismo , Fator de Transcrição AP-1/imunologia , Fator de Transcrição AP-1/metabolismo
3.
Vet Microbiol ; 227: 82-89, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30473357

RESUMO

Porcine reproductive and respiratory syndrome virus (PRRSV) infection which caused severe reproductive failure and respiratory disorders in swine is accompanied with severe nervous symptoms. Our previous studies demonstrated that microglia, the resident innate immune cells in central nervous system (CNS), could support PRRSV infection and replication in vitro. And PRRSV infection led to the increased expressions of large amounts of proinflammatory cytokines and chemokines which contributed to neuropathogenesis of PRRSV. Interleukin-1ß (IL-1ß) is one of the increased proinflammatory cytokines, which possesses diverse functions in immune response upon virus infection, including activation of innate immune and modulation of adaptive immune responses. Importantly, considerable evidences indicated that 1L-1ß is involved in neuronal injury. Here, we demonstrated that PRRSV infection up-regulated IL-1ß expression at both the mRNA and protein levels in microglia in a dose-dependent manner. Myeloid differentiation primary response gene 88 (MyD88), extracellular signal-regulated kinase1/2 (ERK) and activator protein 1 (AP-1) were involved in PRRSV induced IL-1ß production in microglia. Moreover, NOD-like receptor protein 3 (NLRP3) inflammasome is activated by PRRSV in microglia, which is required for IL-1ß secretion. Taken together, our data indicated that PRRSV infection could induce IL-1ß up-regulation, which was likely mediated by MyD88/ERK/AP-1 and NLRP3 inflammasome. These findings will provide new insights into the molecular mechanisms of IL-1ß production and some implications for neuropathogenesis of PRRSV.


Assuntos
MAP Quinases Reguladas por Sinal Extracelular/genética , Interleucina-1beta/genética , Microglia/imunologia , Microglia/virologia , Fator 88 de Diferenciação Mieloide/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Vírus da Síndrome Respiratória e Reprodutiva Suína/imunologia , Fator de Transcrição AP-1/genética , Animais , Quimiocinas/genética , Quimiocinas/imunologia , Citocinas/genética , Citocinas/imunologia , MAP Quinases Reguladas por Sinal Extracelular/imunologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Inflamassomos/genética , Inflamassomos/imunologia , Interleucina-1beta/imunologia , Fator 88 de Diferenciação Mieloide/imunologia , Fator 88 de Diferenciação Mieloide/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Fosforilação , Síndrome Respiratória e Reprodutiva Suína/imunologia , Síndrome Respiratória e Reprodutiva Suína/patologia , Síndrome Respiratória e Reprodutiva Suína/virologia , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Suínos , Fator de Transcrição AP-1/imunologia , Fator de Transcrição AP-1/metabolismo , Regulação para Cima
4.
Front Immunol ; 9: 1927, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30214442

RESUMO

The scaffold proteins CARMA1-3 (encoded by the genes CARD11, -14 and -10) and CARD9 play major roles in signaling downstream of receptors with immunoreceptor tyrosine activation motifs (ITAMs), G-protein coupled receptors (GPCR) and receptor tyrosine kinases (RTK). These receptors trigger the formation of oligomeric CARMA/CARD-BCL10-MALT1 (CBM) complexes via kinases of the PKC family. The CBM in turn regulates gene expression by the activation of NF-κB and AP-1 transcription factors and controls transcript stability. The paracaspase MALT1 is the only CBM component having an enzymatic (proteolytic) activity and has therefore recently gained attention as a potential drug target. Here we review recent advances in the understanding of the molecular function of the protease MALT1 and summarize how MALT1 scaffold and protease function contribute to the transmission of CBM signals. Finally, we will highlight how dysregulation of MALT1 function can cause pathologies such as immunodeficiency, autoimmunity, psoriasis, and cancer.


Assuntos
Doenças Autoimunes/imunologia , Proteínas Adaptadoras de Sinalização CARD/imunologia , Imunodeficiência de Variável Comum/imunologia , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/imunologia , Proteínas de Neoplasias/imunologia , Neoplasias/imunologia , Transdução de Sinais/imunologia , Doenças Autoimunes/terapia , Imunodeficiência de Variável Comum/patologia , Imunodeficiência de Variável Comum/terapia , Humanos , NF-kappa B/imunologia , Neoplasias/patologia , Neoplasias/terapia , Fator de Transcrição AP-1/imunologia
5.
J Virol ; 92(19)2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-30021895

RESUMO

Epstein-Barr virus (EBV) ZEBRA protein activates the EBV lytic cycle. Cellular AP-1 proteins with alanine-to-serine [AP-1(A/S)] substitutions homologous to ZEBRA(S186) assume some functions of EBV ZEBRA. These AP-1(A/S) mutants bind methylated EBV DNA and activate expression of some EBV genes. Here, we compare expression of 67 viral genes induced by ZEBRA versus expression induced by AP-1(A/S) proteins. AP-1(A/S) activated 24 genes to high levels and 15 genes to intermediate levels; activation of 28 genes by AP-1(A/S) was severely impaired. We show that AP-1(A/S) proteins are defective at stimulating viral lytic DNA replication. The impairment of expression of many late genes compared to that of ZEBRA is likely due to the inability of AP-1(A/S) proteins to promote viral DNA replication. However, even in the absence of detectable viral DNA replication, AP-1(A/S) proteins stimulated expression of a subgroup of late genes that encode viral structural proteins and immune modulators. In response to ZEBRA, expression of this subgroup of late genes was inhibited by phosphonoacetic acid (PAA), which is a potent viral replication inhibitor. However, when the lytic cycle was activated by AP-1(A/S), PAA did not reduce expression of this subgroup of late genes. We also provide genetic evidence, using the BMRF1 knockout bacmid, that these genes are true late genes in response to ZEBRA. AP-1(A/S) binds to the promoter region of at least one of these late genes, BDLF3, encoding an immune modulator.IMPORTANCE Mutant c-Jun and c-Fos proteins selectively activate expression of EBV lytic genes, including a subgroup of viral late genes, in the absence of viral DNA replication. These findings indicate that newly synthesized viral DNA is not invariably required for viral late gene expression. While viral DNA replication may be obligatory for late gene expression driven by viral transcription factors, it does not limit the ability of cellular transcription factors to activate expression of some viral late genes. Our results show that expression of all late genes may not be strictly dependent on viral lytic DNA replication. The c-Fos A151S mutation has been identified in a human cancer. c-Fos A151S in combination with wild-type c-Jun activates the EBV lytic cycle. Our data provide proof of principle that mutant cellular transcription factors could cause aberrant regulation of viral lytic cycle gene expression and play important roles in EBV-associated diseases.


Assuntos
Antígenos Virais/genética , DNA Viral/genética , Herpesvirus Humano 4/genética , Interações Hospedeiro-Patógeno , Glicoproteínas de Membrana/genética , Transativadores/genética , Fator de Transcrição AP-1/genética , Proteínas Virais/genética , Substituição de Aminoácidos , Antígenos Virais/imunologia , Antivirais/farmacologia , Sítios de Ligação , Linhagem Celular Tumoral , Metilação de DNA/efeitos dos fármacos , DNA Viral/imunologia , Regulação da Expressão Gênica , Células HEK293 , Herpesvirus Humano 4/efeitos dos fármacos , Herpesvirus Humano 4/imunologia , Humanos , Linfócitos/imunologia , Linfócitos/virologia , Glicoproteínas de Membrana/imunologia , Mutação , Ácido Fosfonoacéticos/farmacologia , Regiões Promotoras Genéticas , Ligação Proteica , Transdução de Sinais , Transativadores/imunologia , Fator de Transcrição AP-1/imunologia , Proteínas Virais/imunologia , Replicação Viral/efeitos dos fármacos
6.
Int J Mol Sci ; 19(7)2018 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-29933606

RESUMO

8-Hydroxydaidzein (8-HD) is a daidzein metabolite isolated from soybeans. This compound has been studied for its anti-proliferation, depigmentation, and antioxidant activities. However, the anti-inflammatory activities of 8-HD are not well-understood. Through its antioxidant effects in ABTS and DPPH assays, 8-HD reduces the production of sodium nitroprusside (SNP)-induced radical oxygen species (ROS). By triggering various Toll-like receptors (TLRs), 8-HD suppresses the inflammatory mediator nitric oxide (NO) without cytotoxicity. We examined the regulatory mechanism of 8-HD in lipopolysaccharide (LPS)-induced conditions. We found that 8-HD diminishes inflammatory gene expression (e.g., inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)-2, and tumor necrosis factor (TNF)-α) by regulating the transcriptional activities of nuclear factor (NF)-κB and activator protein 1 (AP-1). To find the potential targets of 8-HD, signaling pathways were investigated by immunoblotting analyses. These analyses revealed that 8-HD inhibits the activation of TAK1 and that phosphorylated levels of downstream molecules decrease in sequence. Together, our results demonstrate the antioxidant and anti-inflammatory actions of 8-HD and suggest its potential use in cosmetics or anti-inflammatory drugs.


Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Isoflavonas/farmacologia , Lipopolissacarídeos/antagonistas & inibidores , Animais , Anti-Inflamatórios/isolamento & purificação , Antioxidantes/isolamento & purificação , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/imunologia , Isoflavonas/isolamento & purificação , Lipopolissacarídeos/farmacologia , MAP Quinase Quinase Quinases/genética , MAP Quinase Quinase Quinases/imunologia , Ativação de Macrófagos/efeitos dos fármacos , Camundongos , NF-kappa B/antagonistas & inibidores , NF-kappa B/genética , NF-kappa B/imunologia , Óxido Nítrico Sintase Tipo II/antagonistas & inibidores , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/imunologia , Células RAW 264.7 , Transdução de Sinais , Soja/química , Fator de Transcrição AP-1/genética , Fator de Transcrição AP-1/imunologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
7.
Immunol Lett ; 194: 21-28, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29248490

RESUMO

T cell functions are regulated by multiple signaling cascades, including the MKK4-JNK (c-Jun NH2 terminal kinase) pathway. However, the mechanism regulating the MKK4-JNK axis in T cells remains unclear. Herein, we demonstrated that protein acetylation modulates JNK activity induced by T cell receptor (TCR) activation. The acetyltransferase, CREB-binding protein (CBP), is transported from the nucleus to the cytoplasm in response to TCR cross-linking. To investigate the role of CBP in TCR signaling, we overexpressed CBP in the cytoplasm of Jurkat cells, a human T lymphocyte line. Enforced expression of cytoplasmic CBP led to MKK4 acetylation and interfered with MKK4-mediated JNK phosphorylation. Insufficient JNK activity decreased the activity of the transcription factor, AP-1. In contrast, other transcription factors, NF-κB and NFAT, stimulated with anti-CD3 and anti-CD28 antibodies were activated normally in the presence of cytoplasmic-CBP. These results provide valuable insights into the role of acetylation in MKK4-JNK signaling in T cells.


Assuntos
MAP Quinase Quinase 4/imunologia , Sistema de Sinalização das MAP Quinases/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Transdução de Sinais/imunologia , Linfócitos T/imunologia , Acetilação , Humanos , Células Jurkat , Fragmentos de Peptídeos/imunologia , Sialoglicoproteínas/imunologia , Linfócitos T/citologia , Fator de Transcrição AP-1/imunologia
8.
J Biol Regul Homeost Agents ; 31(3): 543-548, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28952282

RESUMO

Adaptive immune response plays an important role against bacteria and parasites, a reaction that also involves mast cell (MC) activation which participates in innate and adaptive immunity. In allergic reactions there is a TH2 immune response with generation of allergen-specific IgE antibodies. In MCs, IgE cross-link FcRI high affinity receptor and activate tyrosine kinase proteins, leading to stimulation of NF-κB and AP-1 resulting in the release of a number of cytokines/chemokines and other compounds. Through their proteolytic pathways, MCs may process the antigen for presentation to CD4+ cells which release TH2 cytokines and growth factors, which play an important role in asthma, allergy, anaphylaxis and inflammation. Thus, MCs can contribute to adaptive immunity. MCs may also be activated though the TLR-dependent pathway which is controlled by several proteins including myeloid differentiation factor 88 (MyD88) which can be inhibited by interleukin (IL)-37. Here, we describe the participation of MCs in adaptive immunity and inflammation, an effect that may be inhibited by IL-37.


Assuntos
Imunidade Adaptativa , Imunomodulação , Mastócitos/imunologia , Alérgenos/imunologia , Animais , Humanos , Hipersensibilidade/imunologia , Imunoglobulina E/imunologia , Interleucina-1/imunologia , Peptídeos e Proteínas de Sinalização Intracelular/imunologia , Fator 88 de Diferenciação Mieloide/imunologia , NF-kappa B/imunologia , Células Th2/imunologia , Receptores Toll-Like/imunologia , Fator de Transcrição AP-1/imunologia
9.
Nat Commun ; 8(1): 301, 2017 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-28824171

RESUMO

T helper 17 (Th17) cell plasticity contributes to both immunity and autoimmunity; however, the factors that control lineage flexibility are mostly unknown. Here we show the activator protein-1 (AP-1) factor JunB is an essential regulator of Th17 cell identity. JunB activates expression of Th17 lineage-specifying genes and coordinately represses genes controlling Th1 and regulatory T-cell fate. JunB supports Th17 cell identity by regulating key AP-1 complex constituents. In particular, JunB limits the expression of the subset repressor IRF8, and impedes access of JunD to regulatory regions of alternative effector loci. Although dispensable for homeostatic Th17 cell development, JunB is required for induction and maintenance of Th17 effector responses in the inflammatory contexts of both acute infection and chronic autoimmunity in mice. Through regulatory network analysis, we show that JunB is a core regulator of global transcriptional programs that promote Th17 cell identity and restrict alternative CD4+ T-cell potential.AP-1 family transcription factors regulate CD4+ T helper cell differentiation. Here the authors show that the AP-1 member JunB is a nonredundant regulator of transcriptional programs that support Th17 cell identity and restrain alternative Th1 and Treg cell fates in inflammatory contexts of acute fungal infection and chronic autoimmunity.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Inflamação/imunologia , Células Th17/imunologia , Fatores de Transcrição/imunologia , Animais , Autoimunidade/genética , Autoimunidade/imunologia , Linfócitos T CD4-Positivos/metabolismo , Inflamação/genética , Inflamação/metabolismo , Fatores Reguladores de Interferon/genética , Fatores Reguladores de Interferon/imunologia , Fatores Reguladores de Interferon/metabolismo , Interleucina-17/genética , Interleucina-17/imunologia , Interleucina-17/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Proteínas Proto-Oncogênicas c-jun/genética , Proteínas Proto-Oncogênicas c-jun/imunologia , Proteínas Proto-Oncogênicas c-jun/metabolismo , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Células Th17/metabolismo , Fator de Transcrição AP-1/genética , Fator de Transcrição AP-1/imunologia , Fator de Transcrição AP-1/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
10.
Cell Death Dis ; 8(8): e3004, 2017 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-28817116

RESUMO

Tanshinones belong to a group of lipophilic constituents of Salvia miltiorrhiza Bunge (Danshen), which is widely used in traditional Chinese medicine. A deluge of studies demonstrated that tanshinones exert anti-inflammatory effects, but the underlying mechanisms remain unclear to date. This study investigated the anti-inflammatory effects and mechanisms of total tanshinones (TTN). TTN suppressed the expression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) and the secretion of TNF-α, IL-6, and IL-1ß in RAW264.7 cells, bone marrow-derived macrophages, and THP-1 cells. TTN attenuated the LPS-induced transcriptional activity of NF-κB and decreased IκB-α and IKK phosphorylation and NF-κB/p65 nuclear translocation. Furthermore, TTN inhibited the LPS-induced transcriptional activity of AP-1, which was induced by the reduction of JNK1/2, ERK1/2, and p38MAPK phosphorylation. TTN blocked LPS-induced Toll-like receptor 4 (TLR4) dimerization, which consequently decreased MyD88 recruitment and TAK1 phosphorylation. In addition, TTN pretreatment effectively inhibited xylene-induced ear edema and LPS-induced septic death and improved LPS-induced acute kidney injury in mice. TTN exerts anti-inflammatory effects in vitro and in vivo by blocking TLR4 dimerization to activate MyD88-TAK1-NF-κB/MAPK signaling cascades, which provide the molecular basis of the anti-inflammatory effect of Danshen and suggest that TTN is a potential agent for the treatment of inflammatory diseases.


Assuntos
/farmacologia , Anti-Inflamatórios/farmacologia , Edema/tratamento farmacológico , Fator 88 de Diferenciação Mieloide/imunologia , Salvia miltiorrhiza/química , Sepse/tratamento farmacológico , Receptor 4 Toll-Like/imunologia , /isolamento & purificação , Animais , Anti-Inflamatórios/isolamento & purificação , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/imunologia , Orelha , Edema/induzido quimicamente , Edema/genética , Edema/imunologia , Regulação da Expressão Gênica , Humanos , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Lipopolissacarídeos/farmacologia , Camundongos , Proteínas Quinases Ativadas por Mitógeno/genética , Proteínas Quinases Ativadas por Mitógeno/imunologia , Fator 88 de Diferenciação Mieloide/genética , Inibidor de NF-kappaB alfa/genética , Inibidor de NF-kappaB alfa/imunologia , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/imunologia , Multimerização Proteica , Células RAW 264.7 , Sepse/induzido quimicamente , Sepse/genética , Sepse/imunologia , Transdução de Sinais , Células THP-1 , Receptor 4 Toll-Like/antagonistas & inibidores , Receptor 4 Toll-Like/genética , Fator de Transcrição AP-1/genética , Fator de Transcrição AP-1/imunologia , Fator de Transcrição RelA/genética , Fator de Transcrição RelA/imunologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
11.
Cell Immunol ; 319: 10-16, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28750923

RESUMO

While IgE is considered the primary mediator of mast cell activation, IL-33 contributes substantially in asthma, allergic rhinitis, and atopic dermatitis. To develop effective treatments for allergic disease, it is important to understand the role of therapeutic agents on IL-33 activation. We examined the effect of Didox (3,4-dihydroxybenzohydroxamic acid), an antioxidant and ribonucleotide reductase (RNR) inhibitor, on IL-33-mediated mast cell activation. Didox suppressed IL-6, IL-13, TNF, and MIP-1α (CCL3) production in bone marrow derived mast cells following IL-33 activation. This suppression was observed in different genetic backgrounds and extended to peritoneal mast cells. The antioxidant N-acetylcysteine mimicked the suppression of Didox, albeit at a much higher dose, while the RNR inhibitor hydroxyurea had no effect. Didox substantially suppressed IL-33-mediated NFκB and AP-1 transcriptional activities. These results suggest that Didox attenuates IL-33-induced mast cell activation and should be further studied as a potential therapeutic agent for inflammatory diseases involving IL-33.


Assuntos
Regulação da Expressão Gênica/efeitos dos fármacos , Ácidos Hidroxâmicos/farmacologia , Imunossupressores/farmacologia , Interleucina-33/farmacologia , Mastócitos/efeitos dos fármacos , Acetilcisteína/farmacologia , Animais , Células da Medula Óssea/citologia , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/imunologia , Quimiocina CCL3/antagonistas & inibidores , Quimiocina CCL3/genética , Quimiocina CCL3/imunologia , Feminino , Regulação da Expressão Gênica/imunologia , Genes Reporter , Hidroxiureia/farmacologia , Interleucina-13/antagonistas & inibidores , Interleucina-13/genética , Interleucina-13/imunologia , Interleucina-33/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Luciferases/genética , Luciferases/imunologia , Masculino , Mastócitos/citologia , Mastócitos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/antagonistas & inibidores , NF-kappa B/genética , NF-kappa B/imunologia , Cultura Primária de Células , Transdução de Sinais , Fator de Transcrição AP-1/antagonistas & inibidores , Fator de Transcrição AP-1/genética , Fator de Transcrição AP-1/imunologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
12.
Int Immunopharmacol ; 48: 211-218, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28528205

RESUMO

Inflammation could be described as a physiological response of the body to tissue injury, pathogen invasion, and irritants. During the inflammatory phase, cells of both the innate as well as adaptive immune system are activated and recruited to the site of inflammation. These mediators are downstream targets for the transcription factors; activator protein-1 (AP1), nuclear factor kappa-light-chain-enhancer (NF-κB), signal transducers and activators of transcription factors (STAT1), as well as interferon regulatory factors (IRFs), which control the expression of most immunomodulatory genes. There is a significant increase in active p38 mitogen-activated protein kinase (p38MAK) immediately after lipopolysaccharide (LPS) stimulation, which results in the activation of AP-1 transcription factor and expression of proinflammatory cytokines, IL-12 and IL-23. We studied the novel mechanism of p38 MAPK activation through the formation of a heterotrimeric complex of Protein kinase C delta type (PKCδ), Toll-Interleukin 1 Receptor (TIR) Domain Containing Adaptor Protein (TIRAP), and p38 proteins. TIRAP serves as an adaptor molecule which brings PKCδ and p38 in close proximity. The complex facilitates the activation of p38MAPK by PKCδ. Therefore, we propose that disruption of the heterotrimeric complex may be a good strategy to dampen the inflammatory response. Structure-based design of small molecules or peptides targetting PKCδ-TIRAP or TIRAP-p38 interfaces would be beneficial for therapy in AP1 mediated inflammatory diseases.


Assuntos
Inflamação/imunologia , Glicoproteínas de Membrana/imunologia , Proteína Quinase C-delta/imunologia , Receptores de Interleucina-1/imunologia , Fator de Transcrição AP-1/imunologia , Proteínas Quinases p38 Ativadas por Mitógeno/imunologia , Animais , Inflamação/induzido quimicamente , Lipopolissacarídeos , Macrófagos/imunologia , Camundongos Endogâmicos C57BL
13.
Mol Immunol ; 87: 258-266, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28521278

RESUMO

CD4+ T-cell activation and its subsequent induction of CD154 (CD40 ligand, CD40L) expression are pivotal in shaping both the humoral and cellular immune responses. Scaffold protein JLP regulates signal transduction pathways and molecular trafficking inside cells, thus represents a critical component in maintaining cellular functions. Its role in regulating CD4+ T-cell activation and CD154 expression, however, is unclear. Here, we demonstrated expression of JLP in mouse tissues of lymph nodes, thymus, spleen, and also CD4+ T cells. Using CD4+ T cells from jlp-deficient and jlp-wild-type mice, we demonstrated that JLP-deficiency impaired T-cell proliferation, IL-2 production, and CD154 induction upon TCR stimulations, but had no impacts on the expression of other surface molecules such as CD25, CD69, and TCR. These observed impaired T-cell functions in the jlp-/- CD4+ T cells were associated with defective NF-AT activation and Ca2+ influx, but not the MAPK, NF-κB, as well as AP-1 signaling pathways. Our findings indicated that, for the first time, JLP plays a critical role in regulating CD4+ T cells response to TCR stimulation partly by mediating the activation of TCR-initiated Ca2+/NF-AT.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/imunologia , Linfócitos T CD4-Positivos/imunologia , Ligante de CD40/imunologia , Ativação Linfocitária/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Animais , Antígenos CD40/imunologia , Proliferação de Células/fisiologia , Interleucina-2/imunologia , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/imunologia , Transdução de Sinais/imunologia , Fator de Transcrição AP-1/imunologia
14.
Poult Sci ; 96(3): 723-730, 2017 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-28394395

RESUMO

The goal of this study was to determine whether nuclear factor-κB (NFκB) and activator protein 1 (AP-1) were the responsible transcription factors for the induction of proinflammatory cytokines in hen vaginal cells stimulated by different Toll-like receptor (TLR) ligands. Cultured vaginal cells were treated with or without poly I:C (TLR3 ligand; dsRNA virus), lipopolysaccharide (LPS) (TLR4 ligand; gram-negative bacteria), flagellin (TLR5 ligand; bacterial flagellum), R848 (TLR7 ligand; ssRNA virus), and CpG-oligodeoxynucleotide (CpG-ODN) (TLR21 ligand; bacteria and DNA virus) in the presence or absence of different doses of BAY11-7085 (NFκB inhibitor) and tanshinone IIA (AP-1 inhibitor). Then, gene expressions of IL1B, IL6, and CXCLi2 were examined by real-time PCR analysis. The results showed that the induction of the expression of IL1B, IL6 and CXCLi2 by poly I:C, LPS, and CpG-ODN were suppressed by Bay11-7085, but not by tanshinone IIA. IL1B expression was upregulated by flagellin and R848, and the increase in its expression was suppressed by Bay11-7085, but not by tanshinone. These results suggest that NFκB is the responsible transcription factor for the expression of proinflammatory cytokines and chemokines, including I IL1B, IL6, and CXCLi2 in response to the ligands of TLR3, 4, and 21, and IL1B in response to the ligands of TLR5 and 7 in the vaginal cells.


Assuntos
Galinhas/imunologia , Regulação da Expressão Gênica/efeitos dos fármacos , Imunossupressores/farmacologia , NF-kappa B/imunologia , Receptores Toll-Like/imunologia , Fator de Transcrição AP-1/imunologia , Animais , Proteínas Aviárias/genética , Proteínas Aviárias/imunologia , Células Cultivadas , Quimiocinas/metabolismo , Galinhas/genética , Citocinas/genética , Feminino , Ligantes , NF-kappa B/antagonistas & inibidores , Oviductos/microbiologia , Fator de Transcrição AP-1/antagonistas & inibidores , Vagina/citologia
15.
Virology ; 507: 170-178, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28448848

RESUMO

Transmissible gastroenteritis virus (TGEV) is a porcine enteric coronavirus which causes lethal severe watery diarrhea in piglets. The pathogenesis of TGEV is strongly associated with inflammation. In this study, we found that TGEV infection activates transcription factors NF-κB, IRF3 and AP-1 in a time- and dose-dependent manner in porcine kidney cells. Treatment with the NF-κB-specific inhibitor BAY11-7082 significantly decreased TGEV-induced proinflammatory cytokine production, but did not affect virus replication. Phosphorylation of NF-κB subunit p65 and proinflammatory cytokine production were greatly decreased after knockdown of retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) or its adaptors MAVS and STING, while only slight reduction was observed in cells following silencing of Toll-like receptor adaptors, MyD88 and TRIF. Furthermore, TGEV infection significantly upregulated mRNA expression of RIG-I and MDA5. Taken together, our results indicate that the RLR signaling pathway is involved in TGEV-induced inflammatory responses.


Assuntos
Gastroenterite Suína Transmissível/imunologia , Gastroenterite Suína Transmissível/virologia , NF-kappa B/imunologia , Vírus da Gastroenterite Transmissível/fisiologia , Animais , Citocinas/genética , Citocinas/imunologia , Proteína DEAD-box 58/genética , Proteína DEAD-box 58/imunologia , Gastroenterite Suína Transmissível/genética , Helicase IFIH1 Induzida por Interferon/genética , Helicase IFIH1 Induzida por Interferon/imunologia , NF-kappa B/genética , Fosforilação , Transdução de Sinais , Suínos , Fator de Transcrição AP-1/genética , Fator de Transcrição AP-1/imunologia , Vírus da Gastroenterite Transmissível/genética
16.
J Immunol ; 198(9): 3605-3614, 2017 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-28298526

RESUMO

Activation of proinflammatory macrophages is associated with the inflammatory state of rheumatoid arthritis. Their polarization and activation are controlled by transcription factors such as NF-κB and the AP-1 transcription factor member c-Fos. Surprisingly, little is known about the role of the AP-1 transcription factor c-Jun in macrophage activation. In this study, we show that mRNA and protein levels of c-Jun are increased in macrophages following pro- or anti-inflammatory stimulations. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment cluster analyses of microarray data using wild-type and c-Jun-deleted macrophages highlight the central function of c-Jun in macrophages, in particular for immune responses, IL production, and hypoxia pathways. Mice deficient for c-Jun in macrophages show an amelioration of inflammation and bone destruction in the serum-induced arthritis model. In vivo and in vitro gene profiling, together with chromatin immunoprecipitation analysis of macrophages, revealed direct activation of the proinflammatory factor cyclooxygenase-2 and indirect inhibition of the anti-inflammatory factor arginase-1 by c-Jun. Thus, c-Jun regulates the activation state of macrophages and promotes arthritis via differentially regulating cyclooxygenase-2 and arginase-1 levels.


Assuntos
Arginase/metabolismo , Artrite/imunologia , Ciclo-Oxigenase 2/metabolismo , Inflamação/imunologia , Macrófagos/imunologia , Proteínas Proto-Oncogênicas c-jun/metabolismo , Fator de Transcrição AP-1/metabolismo , Animais , Arginase/imunologia , Células Cultivadas , Análise por Conglomerados , Ciclo-Oxigenase 2/imunologia , Feminino , Lipopolissacarídeos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , NF-kappa B/metabolismo , Proteínas Proto-Oncogênicas c-jun/genética , Fator de Transcrição AP-1/imunologia , Regulação para Cima
17.
Sci Rep ; 7: 42191, 2017 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-28169350

RESUMO

Chloroquine (CQ) is widely used as an anti-inflammatory therapeutic for rheumatic diseases. Although its modes of action on the innate immune system are well described, there is still insufficient knowledge about its direct effects on the adaptive immune system. Thus, we evaluated the influence of CQ on activation parameters of human CD4+ T-cells. CQ directly suppressed proliferation, metabolic activity and cytokine secretion of T-cells following anti-CD3/anti-CD28 activation. In contrast, CQ showed no effect on up-regulation of T-cell activation markers. CQ inhibited activation of all T helper cell subsets, although IL-4 and IL-13 secretion by Th2 cells were less influenced compared to other Th-specific cytokines. Up to 10 µM, CQ did not reduce cell viability, suggesting specific suppressive effects on T-cells. These properties of CQ were fully reversible in re-stimulation experiments. Analyses of intracellular signaling showed that CQ specifically inhibited autophagic flux and additionally activation of AP-1 by reducing phosphorylation of c-JUN. This effect was mediated by inhibition of JNK catalytic activity. In summary, we characterized selective and reversible immunomodulatory effects of CQ on human CD4+ T-cells. These findings provide new insights into the biological actions of JNK/AP-1 signaling in T-cells and may help to expand the therapeutic spectrum of CQ.


Assuntos
Antirreumáticos/farmacologia , Linhagem da Célula/efeitos dos fármacos , Cloroquina/farmacologia , Transdução de Sinais/efeitos dos fármacos , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Fator de Transcrição AP-1/imunologia , Anticorpos/farmacologia , Antígenos CD28/antagonistas & inibidores , Antígenos CD28/genética , Antígenos CD28/imunologia , Complexo CD3/antagonistas & inibidores , Complexo CD3/genética , Complexo CD3/imunologia , Linhagem da Célula/imunologia , Relação Dose-Resposta a Droga , Regulação da Expressão Gênica/imunologia , Humanos , Imunofenotipagem , Interleucina-13/genética , Interleucina-13/imunologia , Interleucina-4/genética , Interleucina-4/imunologia , Ativação Linfocitária/efeitos dos fármacos , MAP Quinase Quinase 4/genética , MAP Quinase Quinase 4/imunologia , Cultura Primária de Células , Transdução de Sinais/imunologia , Linfócitos T Auxiliares-Indutores/citologia , Linfócitos T Auxiliares-Indutores/imunologia , Equilíbrio Th1-Th2/efeitos dos fármacos , Fator de Transcrição AP-1/genética
18.
J Agric Food Chem ; 65(18): 3647-3658, 2017 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-28122452

RESUMO

Octacosanol has multiple biological functions. In this study, the anti-inflammatory effect and molecular mechanism of octacosanol were evaluated by using dextran sulfate sodium (DSS)-induced ulcerative colitis model in mice and lipopolysaccharide (LPS)-stimulated mouse macrophage RAW264.7 cells. The colitis mouse model was induced by 3.0% DSS in 8-week ICR mice and octacosanol orally administered with 100 mg/kg/day. The results showed that octacosanol significantly improved the health status of mice and reduced DSS-induced pathological damage in the colonic tissues. Octacosanol obviously inhibited the mRNA and protein expression levels of pro-inflammatory factors of colonic tissues. In vitro, octacosanol administration significantly reduced the expression of mRNA or protein of pro-inflammatory cytokines and the phosphorylation of c-Jun N-terminal kinase and p38, and it also partly prevented LPS-induced translocations of NF-κB and AP-1. Octacosanol has anti-inflammatory effect, and its molecular mechanism may be involved in downregulating the expression of inflammatory factors and blocking of MAPK/NF-κB/AP-1 signaling pathway.


Assuntos
Colite/tratamento farmacológico , Colite/imunologia , Álcoois Graxos/administração & dosagem , Macrófagos/efeitos dos fármacos , Oryza/química , Extratos Vegetais/administração & dosagem , Animais , Colite/genética , Modelos Animais de Doenças , Feminino , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/genética , Proteínas Quinases JNK Ativadas por Mitógeno/imunologia , Macrófagos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos ICR , NF-kappa B/genética , NF-kappa B/imunologia , Transdução de Sinais/efeitos dos fármacos , Fator de Transcrição AP-1/genética , Fator de Transcrição AP-1/imunologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Proteínas Quinases p38 Ativadas por Mitógeno/imunologia
19.
Cytokine ; 91: 57-64, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28011397

RESUMO

Pseudolysimachion rotundum var. subintegrum is utilized as a traditional herbal remedy to treat cough, bronchitis, and asthma in Korea, Russia, China, and Europe. Here, we show that 3-methoxy-catalposide, a novel iridoide glycoside isolated from P. rotundum var. subintegrum has the anti-inflammatory activity in lipopolysaccharide (LPS)-stimulated macrophages. The chemical structure of 3-methoxy-catalposide was determined by NMR, optical rotation and HRESIMS. In in vitro experiment, RAW264.7 cells were treated with 3-methoxy-catalposide for 2h before exposure to LPS for different times. Inflammatory gene and protein expressions were assayed using RT-PCR and ELISA. Activities of signal proteins were examined using western analysis. Our results demonstrated that 3-methoxy-catalposide significantly inhibits the expression of cyclooxygenase (COX)-2 and inducible nitric oxide synthase (iNOS) in RAW264.7 cells stimulated by LPS, thereby suppressing the release of prostaglandin E2 (PGE2) and nitric oxide (NO). Moreover, 3-methoxy-catalposide markedly reduced the LPS-induced expression of pro-inflammatory genes, such as interleukin (IL)-6, IL-1ß, and TNF-α. Further, 3-methoxy-catalposide inhibited both LPS-induced activation of three MAP kinases (ERK 1/2, JNK, and p38) and the nuclear translocation of NF-κB and AP-1. These results support that 3-methoxy-catalposide may be a promising candidate for inflammation treatment.


Assuntos
MAP Quinases Reguladas por Sinal Extracelular/imunologia , Glucosídeos Iridoides/farmacologia , Lipopolissacarídeos/toxicidade , Macrófagos/imunologia , Monocinas/imunologia , Animais , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/imunologia , Inflamação/patologia , Macrófagos/patologia , Camundongos , NF-kappa B/imunologia , Células RAW 264.7 , Fator de Transcrição AP-1/imunologia
20.
J Biol Chem ; 291(45): 23628-23644, 2016 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-27650495

RESUMO

Glucocorticoids are commonly used to treat inflammatory disorders. The glucocorticoid receptor (GR) can tether to inflammatory transcription factor complexes, such as NFκB and AP-1, and trans-repress the transcription of cytokines, chemokines, and adhesion molecules. In contrast, aldosterone and the mineralocorticoid receptor (MR) primarily promote cardiovascular inflammation by incompletely understood mechanisms. Although MR has been shown to weakly repress NFκB, its role in modulating AP-1 has not been established. Here, the effects of GR and MR on NFκB and AP-1 signaling were directly compared using a variety of ligands, two different AP-1 consensus sequences, GR and MR DNA-binding domain mutants, and siRNA knockdown or overexpression of core AP-1 family members. Both GR and MR repressed an NFκB reporter without influencing p65 or p50 binding to DNA. Likewise, neither GR nor MR affected AP-1 binding, but repression or activation of AP-1 reporters occurred in a ligand-, AP-1 consensus sequence-, and AP-1 family member-specific manner. Notably, aldosterone interactions with both GR and MR demonstrated a potential to activate AP-1. DNA-binding domain mutations that eliminated the ability of GR and MR to cis-activate a hormone response element-driven reporter variably affected the strength and polarity of these responses. Importantly, MR modulation of NFκB and AP-1 signaling was consistent with a trans-mechanism, and AP-1 effects were confirmed for specific gene targets in primary human cells. Steroid nuclear receptor trans-effects on inflammatory signaling are context-dependent and influenced by nuclear receptor conformation, DNA sequence, and the expression of heterologous binding partners. Aldosterone activation of AP-1 may contribute to its proinflammatory effects in the vasculature.


Assuntos
NF-kappa B/imunologia , Receptores de Glucocorticoides/imunologia , Receptores de Mineralocorticoides/imunologia , Transdução de Sinais , Fator de Transcrição AP-1/imunologia , Sequência de Aminoácidos , Sequência de Bases , DNA/química , Expressão Gênica , Regulação da Expressão Gênica , Células HEK293 , Humanos , Inflamação/genética , Inflamação/imunologia , Mutação , Domínios Proteicos , Receptores de Glucocorticoides/química , Receptores de Glucocorticoides/genética , Receptores de Mineralocorticoides/química , Receptores de Mineralocorticoides/genética
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