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1.
J Immunol ; 186(1): 563-75, 2011 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-21131419

RESUMO

Heat shock protein 90 (Hsp90) is a molecular chaperone involved in folding and stabilizing multiple intracellular proteins that have roles in cell activation and proliferation. Many Hsp90 client proteins in tumor cells are mutated or overexpressed oncogenic proteins driving cancer cell growth, leading to the acceptance of Hsp90 as a potential therapeutic target for cancer. Because several signal transduction molecules that are dependent on Hsp90 function are also involved in activation of innate and adaptive cells of the immune system, we investigated the mechanism by which inhibiting Hsp90 leads to therapeutic efficacy in rodent models of inflammation and autoimmunity. EC144, a synthetic Hsp90 inhibitor, blocked LPS-induced TLR4 signaling in RAW 264.7 cells by inhibiting activation of ERK1/2, MEK1/2, JNK, and p38 MAPK but not NF-κB. Ex vivo LPS-stimulated CD11b(+) peritoneal exudate cells from EC144-treated mice were blocked from phosphorylating tumor progression locus 2, MEK1/2, and ERK1/2. Consequently, EC144-treated mice were resistant to LPS administration and had suppressed systemic TNF-α release. Inhibiting Hsp90 also blocked in vitro CD4(+) T cell proliferation in mouse and human MLRs. In vivo, semitherapeutic administration of EC144 blocked disease development in rat collagen-induced arthritis by suppressing the inflammatory response. In a mouse collagen-induced arthritis model, EC144 also suppressed disease development, which correlated with a suppressed Ag-specific Ab response and a block in activation of Ag-specific CD4(+) T cells. Our results describe mechanisms by which blocking Hsp90 function may be applicable to treatment of autoimmune diseases involving inflammation and activation of the adaptive immune response.


Assuntos
Imunidade Adaptativa/efeitos dos fármacos , Doenças Autoimunes/tratamento farmacológico , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Imunidade Inata/efeitos dos fármacos , Imunossupressores/farmacologia , Mediadores da Inflamação/farmacologia , Pirimidinas/farmacologia , Pirróis/farmacologia , Animais , Doenças Autoimunes/imunologia , Doenças Autoimunes/metabolismo , Linhagem Celular , Linhagem Celular Transformada , Cristalografia por Raios X , Modelos Animais de Doenças , Feminino , Humanos , Imunossupressores/química , Imunossupressores/uso terapêutico , Inflamação/tratamento farmacológico , Inflamação/imunologia , Inflamação/metabolismo , Mediadores da Inflamação/síntese química , Mediadores da Inflamação/uso terapêutico , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos DBA , Pirimidinas/síntese química , Pirimidinas/uso terapêutico , Pirróis/síntese química , Pirróis/uso terapêutico , Ratos
2.
J Allergy Clin Immunol ; 121(2): 441-447.e5, 2008 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-17949802

RESUMO

BACKGROUND: A human Fcgamma-Fcepsilon fusion protein (GE2) designed to inhibit FcepsilonRI signaling by coaggregating FcepsilonRI with the inhibitory receptor FcgammaRIIB has been shown to inhibit mast cell activation and block cutaneous anaphylaxis. A critical issue remained as to whether the mechanism of GE2 inhibition is competition for IgE binding or inhibitory signaling through FcgammaRIIB. OBJECTIVE: Our aim was to define the in vitro and in vivo mechanism of action of a mouse homolog of GE2 (mGE) and to assess the potential of human GE2 (hGE2) for therapeutic administration. METHODS: The in vitro activity of mGE on mediator release and signaling pathways was characterized in IgE-sensitized bone marrow-derived mast cells (BMMCs). The in vivo activity of mGE was examined in mouse passive cutaneous and passive systemic anaphylaxis models, and the therapeutic activity of hGE2 was evaluated in Ascaris suum-sensitized cynomolgus monkeys. RESULTS: mGE inhibited release of histamine and cytokines by BMMCs from wild-type mice but not by BMMCs from FcgammaRIIB-deficient mice. In mice mGE blocked IgE-dependent anaphylaxis mediated by mast cells with sustained efficacy. In BMMCs mGE decreased spleen tyrosine kinase and extracellular signal-regulated kinases 1/2 phosphorylation and induced FcgammaRIIB phosphorylation and the subsequent recruitment of SH2 domain-containing inositol polyphosphate 5' phosphatase (SHIP) 1 and SH2 domain-containing protein tyrosine phosphatase (SHP) 1/2 phosphatases. When administered therapeutically, hGE2 protected sensitized monkeys from local anaphylaxis for 3 weeks. CONCLUSION: mGE-mediated inhibition of mast cell activation is associated with inhibitory signaling through FcgammaRIIB that results from activation of SHIP-1 and SHP-1/2 phosphatases.


Assuntos
Mastócitos/efeitos dos fármacos , Monoéster Fosfórico Hidrolases/metabolismo , Proteínas Tirosina Fosfatases/metabolismo , Receptores de IgG/metabolismo , Proteínas Recombinantes de Fusão/farmacologia , Domínios de Homologia de src , Anafilaxia/prevenção & controle , Animais , Ascaris suum , Células da Medula Óssea/efeitos dos fármacos , Células Cultivadas , Ativação Enzimática/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Humanos , Imunização , Imunoglobulina E/metabolismo , Inositol Polifosfato 5-Fosfatases , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Macaca fascicularis , Camundongos , Camundongos Endogâmicos , Camundongos Knockout , Fosfatidilinositol-3,4,5-Trifosfato 5-Fosfatases , Monoéster Fosfórico Hidrolases/química , Isoformas de Proteínas/química , Isoformas de Proteínas/metabolismo , Proteínas Tirosina Fosfatases/química , Proteínas Tirosina Quinases/metabolismo , Receptores de IgE/metabolismo , Proteínas Recombinantes de Fusão/genética , Quinase Syk , Receptor 4 Toll-Like/metabolismo
3.
J Immunol ; 177(4): 2610-20, 2006 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-16888023

RESUMO

TNF-like weak inducer of apoptosis (TWEAK) is a TNF family member with pleiotropic effects on a variety of cell types, one of which is the induction of proinflammatory cytokines by synovial fibroblasts derived from rheumatoid arthritis (RA) patients. In this study, we report that the serum TWEAK level was dramatically elevated during mouse collagen-induced arthritis (CIA) and blocking TWEAK by a neutralizing mAb significantly reduced the clinical severity of CIA. Histological analyses also revealed that TWEAK inhibition diminished joint inflammation, synovial angiogenesis, as well as cartilage and bone erosion. Anti-TWEAK treatment proved efficacious when administered just before the disease onset but not during the priming phase of CIA. Consistent with this, TWEAK inhibition did not affect either cellular or humoral responses to collagen. In contrast, TWEAK inhibition significantly reduced serum levels of a panel of arthritogenic mediators, including chemokines such as MIP-1beta (CCL-4), lymphotactin (XCL-1), IFN-gamma-inducible protein 10 (IP-10) (CXCL-10), MCP-1 (CCL-2), and RANTES (CCL-5), as well as the matrix metalloprotease-9. Exploring the possible role of the TWEAK/Fn14 pathway in human RA pathogenesis, we showed that TWEAK can target human primary chondrocytes and osteoblast-like cells, in addition to synovial fibroblasts. We further demonstrated that TWEAK induced the production of matrix metalloproteases in human chondrocytes and potently inhibited chondrogenesis and osteogenesis using in vitro models. These results provide evidence for a novel cytokine pathway that contributes to joint tissue inflammation, angiogenesis, and damage, as well as may inhibit endogenous repair, suggesting that TWEAK may be a new therapeutic target for human RA.


Assuntos
Artrite Experimental/metabolismo , Artrite Experimental/patologia , Mediadores da Inflamação/fisiologia , Fatores de Necrose Tumoral/fisiologia , Animais , Apoptose/imunologia , Artrite Experimental/sangue , Células Cultivadas , Colágeno Tipo II/administração & dosagem , Citocina TWEAK , Adjuvante de Freund/administração & dosagem , Humanos , Mediadores da Inflamação/antagonistas & inibidores , Mediadores da Inflamação/sangue , Ligantes , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Receptores do Fator de Necrose Tumoral/metabolismo , Receptores do Fator de Necrose Tumoral/fisiologia , Receptor de TWEAK , Inibidores do Fator de Necrose Tumoral , Fatores de Necrose Tumoral/biossíntese , Fatores de Necrose Tumoral/sangue
4.
J Clin Invest ; 112(5): 755-67, 2003 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-12952924

RESUMO

In studies using genetically deficient mice, a role for the lymphotoxin (LT) system in the pathogenesis of experimental autoimmune encephalomyelitis (EAE) has remained controversial. Here, we have reassessed this conclusion by using a fusion protein decoy that blocks the LT pathway in vivo without evoking the developmental defects inherent in LT-deficient mice. We have found that inhibition of the LT pathway prevented disease in two models of EAE that do not rely on the administration of pertussis toxin. Surprisingly, disease attenuation was due to specific blockade of LTalphabeta binding rather than the binding of LIGHT to its receptors. In a third system that requires pertussis toxin, LT inhibition did not affect disease, as was observed when the same model was used with LT-deficient mice. Disease prevention in pertussis toxin-free models was associated with defects in T cell responses and migration. When the DO11.10 T cell transgenic system was used, inhibition of the LT pathway was shown to uncouple T cell priming from T cell recall responses. Therefore, it is hypothesized that the LT pathway and its ability to maintain lymphoid microenvironments is critical for sustaining late-phase T cell responses in multiple sclerosis.


Assuntos
Encefalomielite Autoimune Experimental/etiologia , Linfotoxina-alfa/fisiologia , Proteínas de Membrana/fisiologia , Fator de Necrose Tumoral alfa/fisiologia , Animais , Encéfalo/patologia , Modelos Animais de Doenças , Feminino , Leucócitos/fisiologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Ratos , Ratos Endogâmicos Lew , Linfócitos T/imunologia , Membro 14 da Superfamília de Ligantes de Fatores de Necrose Tumoral
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