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1.
Cell Death Dis ; 9(5): 500, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29703889

RESUMO

Necroptosis, a form of regulated necrotic cell death, is mediated by receptor interacting protein 1 (RIPK1), RIPK3, and mixed lineage kinase domain-like protein (MLKL). However, the mechanism by which necroptosis promotes inflammation is still unclear. Here we report that the expression of cytokines is robustly upregulated in a cell-autonomous manner during necroptosis induced by tumor necrosis factor alpha (TNFα). We demonstrate that TNFα-induced necroptosis leads to two waves of cytokine production. The first wave, more transient and weaker than the second, is in response to TNFα alone; whereas the second wave depends upon the necroptotic signaling. We show that necroptosis promotes the transcription of TNFα-target genes in a cell-intrinsic manner. The activation of both NF-κB and p38 by the necroptotic machinery, RIPK1, RIPK3, and MLKL, is involved in mediating the robust induction of cytokine expression in the second wave. In contrast, necroptosis induced by direct oligomerization of MLKL promotes cytokine production at much lower levels than that of necroptosis induced with TNFα. Thus, we conclude that TNFα-induced necroptosis signaling events mediated by RIPK1 and RIPK3 activation, in addition to the MLKL oligomerization, promotes the expression of cytokines involving multiple intracellular signaling mechanisms including NF-κB pathway and p38. These findings reveal that the necroptotic cell death machinery mounts an immune response by promoting cell-autonomous production of cytokines. Our study provides insights into the mechanism by which necroptosis promotes inflammation in human diseases.


Assuntos
Quimiocina CXCL1/genética , Regulação da Expressão Gênica/imunologia , Necrose/genética , Proteínas Quinases/genética , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Apoptose/imunologia , Linhagem Celular , Quimiocina CXCL1/agonistas , Quimiocina CXCL1/imunologia , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/imunologia , Células HEK293 , Células HT29 , Humanos , Camundongos , Necrose/imunologia , Isoformas de Proteínas/agonistas , Isoformas de Proteínas/genética , Isoformas de Proteínas/imunologia , Proteínas Quinases/imunologia , Multimerização Proteica , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/imunologia , Proteína Serina-Treonina Quinases de Interação com Receptores/imunologia , Transdução de Sinais , Fator de Transcrição RelA/antagonistas & inibidores , Fator de Transcrição RelA/genética , Fator de Transcrição RelA/imunologia , Fator de Necrose Tumoral alfa/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Proteínas Quinases p38 Ativadas por Mitógeno/imunologia
2.
Basic Clin Pharmacol Toxicol ; 119(6): 540-547, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27194111

RESUMO

The compound 5-fluorouracil (5-FU) is used in cancer chemotherapy and is known to cause diarrhoea. We recently reported that chemokine (C-X-C motif) ligand 1 (CXCL1) and neutrophils in the colonic mucosa were markedly increased by the administration of 5-FU in mice. Curcumin has anti-inflammatory, antitumour and antioxidant properties. Therefore, we examined the effect of curcumin on 5-FU-induced diarrhoea development and CXCL1 and CXCL2 up-regulation in the colon. Mice were given 5-FU (50 mg/kg, i.p.) daily for 4 days. Curcumin (100 or 300 mg/kg, p.o.) was administered on the day before the first administration of 5-FU and administered 30 min. before the administration of 5-FU. Gene expression levels of CXCL1 and CXCL2 in the colon were examined by real-time RT-PCR. Curcumin reduced the 5-FU-induced diarrhoea development. Under this condition, the CXCL1 and CXCL2 gene up-regulated by 5-FU administration was inhibited by curcumin. The gene expression of CXCL1 and CXCL2 was also enhanced by 5-FU application in vitro. The 5-FU-induced up-regulated CXCL1 and CXCL2 gene expressions were inhibited by curcumin, Bay-117082 and bortezomib, nuclear factor kappa B (NF-κB) inhibitors, C646, a p300/cyclic adenosine monophosphate response element-binding protein-histone acetyltransferase (HAT) inhibitor. In conclusion, these findings suggested that curcumin prevented the development of diarrhoea by inhibiting NF-κB and HAT activation.


Assuntos
Antimetabólitos Antineoplásicos/efeitos adversos , Antioxidantes/uso terapêutico , Colo Descendente/efeitos dos fármacos , Curcumina/uso terapêutico , Diarreia/prevenção & controle , Suplementos Nutricionais , Fluoruracila/efeitos adversos , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/farmacologia , Anti-Inflamatórios não Esteroides/uso terapêutico , Antimetabólitos Antineoplásicos/química , Antimetabólitos Antineoplásicos/farmacologia , Antioxidantes/administração & dosagem , Antioxidantes/farmacologia , Quimiocina CXCL1/agonistas , Quimiocina CXCL1/antagonistas & inibidores , Quimiocina CXCL1/genética , Quimiocina CXCL1/metabolismo , Quimiocina CXCL2/agonistas , Quimiocina CXCL2/antagonistas & inibidores , Quimiocina CXCL2/genética , Quimiocina CXCL2/metabolismo , Colo Descendente/imunologia , Colo Descendente/metabolismo , Colo Descendente/fisiopatologia , Curcumina/administração & dosagem , Curcumina/farmacologia , Diarreia/induzido quimicamente , Diarreia/metabolismo , Diarreia/fisiopatologia , Proteína p300 Associada a E1A/agonistas , Proteína p300 Associada a E1A/antagonistas & inibidores , Proteína p300 Associada a E1A/metabolismo , Inibidores Enzimáticos/farmacologia , Fluoruracila/antagonistas & inibidores , Fluoruracila/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/fisiopatologia , Masculino , Camundongos Endogâmicos C57BL , NF-kappa B/agonistas , NF-kappa B/antagonistas & inibidores , NF-kappa B/metabolismo , Índice de Gravidade de Doença , Técnicas de Cultura de Tecidos
3.
Mol Med Rep ; 12(1): 1279-85, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25760831

RESUMO

Since bacterial invasion into host cells is a critical step in the infection process and the predominance of multiple-antibiotic-resistant Klebsiella (K.) pneumoniae strains, using molecular agents to interfere with K. pneumoniae invasion is an attractive approach for the prevention of infection and suppress the immune inflammatory response. In previous studies by our group, high-mobility group nucleosome-binding domain 2 (HMGN2) protein was shown to exhibit anti-bacterial activity in vitro. The objective of the present study was to investigate the effects of HMGN2 protein on the invasion of K. pneumoniae 03183 in vivo. The results showed that pre-treatment with 128 µg/ml HMGN2 significantly reduced K. pneumoniae 03183 invasion into mouse lungs and increased the mRNA expression of CXCL1 and LCN2 within 2 h. Immunohistochemical staining showed that F-actin expression was significantly decreased, and fluorescence microscopy and western blot analysis further demonstrated that HMGN2 significantly blocked K. pneumoniae 03183-induced actin polymerization. These changes implied that HMGN2 may provide protection against K. pneumoniae 03183 infection in vivo.


Assuntos
Antibacterianos/farmacologia , Proteína HMGN2/farmacologia , Infecções por Klebsiella/tratamento farmacológico , Klebsiella pneumoniae/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Pneumonia Bacteriana/tratamento farmacológico , Actinas/genética , Actinas/imunologia , Proteínas de Fase Aguda/agonistas , Proteínas de Fase Aguda/genética , Proteínas de Fase Aguda/imunologia , Animais , Antibacterianos/biossíntese , Quimiocina CXCL1/agonistas , Quimiocina CXCL1/genética , Quimiocina CXCL1/imunologia , Feminino , Expressão Gênica , Proteína HMGN2/biossíntese , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Humanos , Infecções por Klebsiella/imunologia , Infecções por Klebsiella/microbiologia , Infecções por Klebsiella/patologia , Klebsiella pneumoniae/fisiologia , Lipocalina-2 , Lipocalinas/agonistas , Lipocalinas/genética , Lipocalinas/imunologia , Pulmão/microbiologia , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Oncogênicas/agonistas , Proteínas Oncogênicas/genética , Proteínas Oncogênicas/imunologia , Pneumonia Bacteriana/imunologia , Pneumonia Bacteriana/microbiologia , Pneumonia Bacteriana/patologia , RNA Mensageiro/genética , RNA Mensageiro/imunologia , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/farmacologia
4.
J Diabetes Res ; 2014: 187153, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24672802

RESUMO

Adipocytes release immune mediators that contribute to diabetes-associated inflammatory processes. As the stress protein heat shock protein 60 (Hsp60) induces proinflammatory adipocyte activities, we hypothesized that adipocytes of diabetes-predisposed mice exhibit an increased proinflammatory reactivity to Hsp60. Preadipocytes and mature adipocytes from nonobese diabetic (NOD), New Zealand obese (NZO), and C57BL/6J mice were analyzed for Hsp60 binding, Hsp60-activated signaling pathways, and Hsp60-induced release of the chemokine CXCL-1 (KC), interleukin 6 (IL-6), and macrophage chemoattractant protein-1 (MCP-1). Hsp60 showed specific binding to (pre-)adipocytes of NOD, NZO, and C57BL/6J mice. Hsp60 binding involved conserved binding structure(s) and Hsp60 epitopes and was strongest to NZO mouse-derived mature adipocytes. Hsp60 exposure induced KC, IL-6, and MCP-1 release from (pre-)adipocytes of all mouse strains with a pronounced increase of IL-6 release from NZO mouse-derived adipocytes. Compared to NOD and C57BL/6J mouse derived cells, Hsp60-induced formation of IL-6, KC, and MCP-1 from NZO mouse-derived (pre-)adipocytes strongly depended on NF κ B-activation. Increased Hsp60 binding and Hsp60-induced IL-6 release by mature adipocytes of NZO mice suggest that enhanced adipocyte reactivity to the stress signal Hsp60 contributes to inflammatory processes underlying diabetes associated with obesity and insulin resistance.


Assuntos
Adipócitos/metabolismo , Chaperonina 60/metabolismo , Citocinas/metabolismo , Sistema de Sinalização das MAP Quinases , Proteínas Mitocondriais/metabolismo , Obesidade/metabolismo , Paniculite/metabolismo , Regulação para Cima , Adipócitos/imunologia , Adipócitos/patologia , Adipogenia , Animais , Células Cultivadas , Chaperonina 60/genética , Quimiocina CCL2/agonistas , Quimiocina CCL2/biossíntese , Quimiocina CCL2/metabolismo , Quimiocina CXCL1/agonistas , Quimiocina CXCL1/biossíntese , Quimiocina CXCL1/metabolismo , Citocinas/agonistas , Citocinas/biossíntese , Feminino , Interleucina-6/agonistas , Interleucina-6/biossíntese , Interleucina-6/metabolismo , Gordura Intra-Abdominal/imunologia , Gordura Intra-Abdominal/metabolismo , Gordura Intra-Abdominal/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos Obesos , Proteínas Mitocondriais/genética , NF-kappa B/agonistas , NF-kappa B/metabolismo , Obesidade/imunologia , Obesidade/patologia , Paniculite/imunologia , Paniculite/patologia , Proteínas Recombinantes/metabolismo
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