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1.
J Cell Sci ; 130(20): 3568-3577, 2017 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-28827407

RESUMO

The small GTPase Arl8b localizes primarily to lysosomes and is involved in lysosomal motility and fusion. Here, we show that Arl8b is required for lysosomal degradation of maternal proteins in the visceral yolk sac endoderm (VYSE), an apical cell layer of the visceral yolk sac, of mouse embryos. The VYSE actively takes up maternal materials from uterine fluid and degrades them in lysosomes to provide breakdown products to the embryo. Arl8b gene-trap mice (Arl8b-/- ) displayed decreased early embryo body size. The Arl8b-/-  VYSE exhibited defective endocytic trafficking to the lysosome and accumulation of maternal proteins such as albumin and immunoglobulin G in late endocytic organelles. Furthermore, Transthyretin-Cre;Arl8bflox/flox mice in which Arl8b was ablated specifically in the VYSE also showed decreased embryo body size, defects in trafficking to the lysosome and reduction of the free amino acid level in the embryos. Taken together, these results suggest that Arl8b mediates lysosomal degradation of maternal proteins in the VYSE, thereby contributing to mouse embryonic development.


Assuntos
Fatores de Ribosilação do ADP/fisiologia , Saco Vitelino/metabolismo , Animais , Embrião de Mamíferos/metabolismo , Endoderma , Feminino , Lisossomos/metabolismo , Camundongos Endogâmicos C57BL , Proteólise
2.
J Leukoc Biol ; 91(6): 967-76, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22422925

RESUMO

Recent evidences suggest that the extracts of plant products are able to modulate innate immune responses. A saponin GL and a chalcone ILG are representative components of Glycyrrhiza uralensis, which attenuate inflammatory responses mediated by TLRs. Here, we show that GL and ILG suppress different steps of the LPS sensor TLR4/MD-2 complex signaling at the receptor level. Extract of G. uralensis suppressed IL-6 and TNF-α production induced by lipid A moiety of LPS in RAW264.7 cells. Among various G. uralensis-related components of saponins and flavanones/chalcones, GL and ILG could suppress IL-6 production induced by lipid A in dose-dependent manners in RAW264.7 cells. Furthermore, elevation of plasma TNF-α in LPS-injected mice was attenuated by passive administration of GL or ILG. GL and ILG inhibited lipid A-induced NF-κB activation in Ba/F3 cells expressing TLR4/MD-2 and CD14 and BMMs. These components also inhibited activation of MAPKs, including JNK, p38, and ERK in BMMs. In addition, GL and ILG inhibited NF-κB activation and IL-6 production induced by paclitaxel, a nonbacterial TLR4 ligand. Interestingly, GL attenuated the formation of the LPS-TLR4/MD-2 complexes, resulting in inhibition of homodimerization of TLR4. Although ILG did not affect LPS binding to TLR4/MD-2, it could inhibit LPS-induced TLR4 homodimerization. These results imply that GL and ILG modulate the TLR4/MD-2 complex at the receptor level, leading to suppress LPS-induced activation of signaling cascades and cytokine production, but their effects are exerted at different steps of TLR4/MD-2 signaling.


Assuntos
Anti-Inflamatórios/farmacologia , Chalconas/farmacologia , Inibidores Enzimáticos/farmacologia , Ácido Glicirrízico/farmacologia , Lipopolissacarídeos/farmacologia , Antígeno 96 de Linfócito/imunologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Receptor 4 Toll-Like/imunologia , Animais , Anti-Inflamatórios/química , Linhagem Celular , Chalconas/química , Inibidores Enzimáticos/química , Glycyrrhiza uralensis/química , Ácido Glicirrízico/química , Interleucina-6/imunologia , Interleucina-6/metabolismo , Receptores de Lipopolissacarídeos/imunologia , Receptores de Lipopolissacarídeos/metabolismo , Antígeno 96 de Linfócito/metabolismo , Sistema de Sinalização das MAP Quinases/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Quinases de Proteína Quinase Ativadas por Mitógeno/imunologia , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , NF-kappa B/imunologia , NF-kappa B/metabolismo , Multimerização Proteica/efeitos dos fármacos , Multimerização Proteica/imunologia , Receptor 4 Toll-Like/metabolismo , Fator de Necrose Tumoral alfa/imunologia , Fator de Necrose Tumoral alfa/metabolismo
3.
Int Immunol ; 17(7): 827-36, 2005 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-15908446

RESUMO

SIGNR1, a member of a new family of mouse C-type lectins, is expressed at high levels in macrophages (Mphi) within the splenic marginal zone, lymph node medulla, and in some strains, in peritoneal cavity. We previously reported that SIGNR1 captures gram-negative bacteria, such as Escherichia coli and Salmonella typhimurium, as well as Candida albicans. We have now investigated the precise ligands and innate responses that involve SIGNR1. The interaction of SIGNR1 with FITC-dextran and E. coli was completely inhibited by LPS from E. coli and Salmonella minnesota. Using LPS from various types of rough mutants of Salmonella, we found that SIGNR1 primarily recognizes oligosaccharides in the non-reductive end of the LPS core region. In transfectants, expression of SIGNR1 enhanced the oligomerization of Toll-like receptor (TLR) 4 molecules as well as the degradation of IkappaB-alpha after stimulation with E. coli under low-serum conditions. The enhanced TLR4 oligomerization was inhibited by pre-treatment of the cells with anti-SIGNR1 mAb or with mannan. A physical association between SIGNR1 and the TLR4-MD-2 complex was also observed by immunoprecipitation. Finally, we found that transfection of SIGNR1 into the macrophage-like RAW264.7 cells resulted in significant augmentation of cytokine production. These results suggest that SIGNR1 associates with TLR4 to capture gram-negative bacteria and facilitate signal transduction to activate innate M responses.


Assuntos
Moléculas de Adesão Celular/imunologia , Escherichia coli/imunologia , Lectinas Tipo C/imunologia , Lipopolissacarídeos/imunologia , Macrófagos/imunologia , Glicoproteínas de Membrana/imunologia , Receptores de Superfície Celular/imunologia , Salmonella/imunologia , Transdução de Sinais/imunologia , Animais , Linhagem Celular , Citocinas/biossíntese , Feminino , Expressão Gênica , Lectinas Tipo C/genética , Lipopolissacarídeos/farmacologia , Ativação de Macrófagos/efeitos dos fármacos , Ativação de Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Transdução de Sinais/efeitos dos fármacos , Receptor 4 Toll-Like/imunologia
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