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1.
Am J Pathol ; 181(5): 1693-701, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22960075

RESUMO

Nonalcoholic fatty liver disease is an increasingly prevalent spectrum of conditions characterized by excess fat deposition within hepatocytes. Affected hepatocytes are known to be highly susceptible to ischemic insults, responding to injury with increased cell death, and commensurate liver dysfunction. Numerous clinical circumstances lead to hepatic ischemia. Mechanistically, specific means of reducing hepatic vulnerability to ischemia are of increasing clinical importance. In this study, we demonstrate that the glucagon-like peptide-1 receptor agonist Exendin 4 (Ex4) protects hepatocytes from ischemia reperfusion injury by mitigating necrosis and apoptosis. Importantly, this effect is more pronounced in steatotic livers, with significantly reducing cell death and facilitating the initiation of lipolysis. Ex4 treatment leads to increased lipid droplet fission, and phosphorylation of perilipin and hormone sensitive lipase - all hallmarks of lipolysis. Importantly, the protective effects of Ex4 are seen after a short course of perioperative treatment, potentially making this clinically relevant. Thus, we conclude that Ex4 has a role in protecting lean and fatty livers from ischemic injury. The rapidity of the effect and the clinical availability of Ex4 make this an attractive new therapeutic approach for treating fatty livers at the time of an ischemic insult.


Assuntos
Fígado Gorduroso/tratamento farmacológico , Fígado Gorduroso/prevenção & controle , Lipólise/efeitos dos fármacos , Peptídeos/farmacologia , Receptores de Glucagon/agonistas , Traumatismo por Reperfusão/prevenção & controle , Magreza/patologia , Peçonhas/farmacologia , Células 3T3-L1 , Adiposidade/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Proteínas de Transporte/metabolismo , Linhagem Celular Tumoral , Exenatida , Fígado Gorduroso/patologia , Receptor do Peptídeo Semelhante ao Glucagon 1 , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Hepatócitos/patologia , Humanos , Fígado/efeitos dos fármacos , Fígado/enzimologia , Fígado/patologia , Fígado/ultraestrutura , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Necrose , Peptídeos/uso terapêutico , Perilipina-1 , Fosfoproteínas/metabolismo , Fosforilação/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Substâncias Protetoras/uso terapêutico , Receptores de Glucagon/metabolismo , Traumatismo por Reperfusão/complicações , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/patologia , Esterol Esterase/metabolismo , Magreza/complicações , Peçonhas/uso terapêutico
2.
Innate Immun ; 18(2): 294-306, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21733977

RESUMO

Rotavirus (RV), a leading cause of diarrhea, primarily infects intestinal epithelial cells (IEC). Rotavirus-infected IEC produce IFN-ß and express hundreds of IFN-dependent genes. We thus hypothesized that type 1 IFN plays a key role in helping IEC limit RV replication and/or protect against cell death. To test this hypothesis, we examined IEC (HT29 cells) infected with RV (MOI 1) ± neutralizing antibodies to IFN-α/ß via microscopy and SDS-PAGE immunoblotting. We hypothesized that neutralization of IFN would be clearly detrimental to RV-infected IEC. Rather, we observed that blockade of IFN function rescued IEC from the apoptotic cell death that otherwise would have occurred 24-48 h following exposure to RV. This resistance to cell death correlated with reduced levels of viral replication at early time points (< 8 h) following infection and eventuated in reduced production of virions. The reduction in RV replication that resulted from IFN neutralization correlated with, and could be recapitulated by, blockade of IFN-induced protein kinase R (PKR) activation, suggesting involvement of this kinase. Interestingly, pharmacologic blockade of caspase activity ablated RV-induced apoptosis and dramatically increased viral protein synthesis, suggesting that IFN-induced apoptosis helps to control RV infection. These results suggest non-mutually exclusive possibilities that IFN signaling is usurped by RV to promote early replication and induction of cell death may be a means by which IFN signaling possibly clears RV from the intestine.


Assuntos
Apoptose/efeitos dos fármacos , Células Epiteliais/imunologia , Interferon beta/biossíntese , Interferon beta/farmacologia , Rotavirus/imunologia , Transdução de Sinais/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos , 2-Aminopurina/farmacologia , Anticorpos Antivirais/farmacologia , Antimetabólitos/farmacologia , Western Blotting , Inibidores de Caspase , Ativação Enzimática/efeitos dos fármacos , Ensaio de Imunoadsorção Enzimática , Células Epiteliais/efeitos dos fármacos , Células HT29 , Humanos , Marcação In Situ das Extremidades Cortadas , Interferon beta/imunologia , Mucosa Intestinal/citologia , Mucosa Intestinal/virologia , Intestinos/virologia , Oligopeptídeos/farmacologia
3.
Eur J Immunol ; 40(12): 3528-34, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21072873

RESUMO

The fact that some TLR-based vaccine adjuvants maintain function in TLR-deficient hosts highlights that their mechanism of function remains incompletely understood. Thus, we examined the ability of flagellin to induce cytokines and elicit/promote murine antibody responses upon deletion of the flagellin receptors TLR5 and/or NLRC4 (also referred to as IPAF) using a prime/boost regimen. In TLR5-KO mice, flagellin failed to induce NF-κB-regulated cytokines such as keratinocyte-derived chemokine (CXCL1) but induced WT levels of the inflammasome cytokine IL-18 (IL-1F4). Conversely, in NLRC4-KO mice, flagellin induced keratinocyte-derived chemokine, but not IL-18, whereas TLR5/NLRC4-DKO lacked induction of all cytokines measured. Flagellin/ovalbumin treatment resulted in high-antibody titers to both flagellin and ovalbumin in WT, TLR5-KO and DKO mice but did not elicit antibodies to either in TLR5/NLRC4-DKO mice. Thus, flagellin's ability to elicit/promote humoral immunity requires a germ-line-encoded receptor capable of recognizing this molecule. Such promotion of adaptive immunity can be effectively driven by either TLR5-mediated activation of NF-κB or NLRC4-mediated activation of the inflammasome.


Assuntos
Proteínas Reguladoras de Apoptose/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Flagelina/administração & dosagem , Imunidade Humoral , Macrófagos/metabolismo , Receptor 5 Toll-Like/metabolismo , Animais , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/imunologia , Proteínas de Ligação ao Cálcio/genética , Proteínas de Ligação ao Cálcio/imunologia , Linhagem Celular , Quimiocina CXCL1/metabolismo , Flagelina/farmacologia , Interações Hospedeiro-Patógeno , Imunidade Humoral/genética , Imunidade Inata , Imunização , Inflamassomos , Interleucina-18/genética , Interleucina-18/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , NF-kappa B/genética , NF-kappa B/metabolismo , Transdução de Sinais , Receptor 5 Toll-Like/genética , Receptor 5 Toll-Like/imunologia
4.
Int Immunol ; 21(8): 991-1001, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19592420

RESUMO

Chemokine receptors (CCRs) are important co-stimulatory molecules found on many blood cells and associated with various diseases. The expression and function of CCRs on mast cells has been quite controversial. In this study, we report for the first time that murine bone marrow-derived mast cells (BMMC) express messenger RNA and protein for CCR1. BMMC cultured in the presence of murine recombinant stem cell factor and murine IL-3 expressed CCR1 after 5-6 weeks. We also report for the first time that mBMMC(CCR1+) cells endogenously express neurokinin receptor-1 and intercellular adhesion molecule-1. To examine the activity of CCR1 on these BMMC, we simultaneously stimulated two receptors: CCR1 by its ligand macrophage inflammatory protein-1alpha and the IgE receptor FcepsilonRI by antigen cross-linking. We found that co-stimulation enhanced BMMC degranulation compared with FcepsilonRI stimulation alone, as assessed by beta-hexosaminidase activity (85 versus 54%, P < 0.0001) and Ca(2+) influx (223 versus 183 nM, P < 0.05). We also observed significant increases in mast cell secretion of key growth factors, cytokines and chemokine mediators upon CCR1-FcepsilonRI co-stimulation. These factors include transforming growth factor beta-1, tumor necrosis factor-alpha and the cytokine IL-6. Taken together, our data indicate that CCR1 plays a key role in BMMC function. These findings contribute to our understanding of mechanisms for immune cell trafficking during inflammation.


Assuntos
Células da Medula Óssea/metabolismo , Interleucina-6/metabolismo , Mastócitos/metabolismo , Receptores CCR1/biossíntese , Fator de Crescimento Transformador beta1/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Animais , Células Cultivadas , Feminino , Molécula 1 de Adesão Intercelular/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Receptores CCR1/genética , Receptores CCR1/metabolismo , Receptores de IgE/metabolismo , Receptores da Neurocinina-1/metabolismo , Transdução de Sinais
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