Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 7 de 7
Filtrar
Mais filtros








Base de dados
Intervalo de ano de publicação
2.
Arthritis Rheumatol ; 73(12): 2206-2218, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34423919

RESUMO

OBJECTIVE: To investigate the role of PF-06650833, a highly potent and selective small-molecule inhibitor of interleukin-1-associated kinase 4 (IRAK4), in autoimmune pathophysiology in vitro, in vivo, and in the clinical setting. METHODS: Rheumatoid arthritis (RA) inflammatory pathophysiology was modeled in vitro through 1) stimulation of primary human macrophages with anti-citrullinated protein antibody immune complexes (ICs), 2) RA fibroblast-like synoviocyte (FLS) cultures stimulated with Toll-like receptor (TLR) ligands, as well as 3) additional human primary cell cocultures exposed to inflammatory stimuli. Systemic lupus erythematosus (SLE) pathophysiology was simulated in human neutrophils, dendritic cells, B cells, and peripheral blood mononuclear cells stimulated with TLR ligands and SLE patient ICs. PF-06650833 was evaluated in vivo in the rat collagen-induced arthritis (CIA) model and the mouse pristane-induced and MRL/lpr models of lupus. Finally, RNA sequencing data generated with whole blood samples from a phase I multiple-ascending-dose clinical trial of PF-06650833 were used to test in vivo human pharmacology. RESULTS: In vitro, PF-06650833 inhibited human primary cell inflammatory responses to physiologically relevant stimuli generated with RA and SLE patient plasma. In vivo, PF-06650833 reduced circulating autoantibody levels in the pristane-induced and MRL/lpr murine models of lupus and protected against CIA in rats. In a phase I clinical trial (NCT02485769), PF-06650833 demonstrated in vivo pharmacologic action pertinent to SLE by reducing whole blood interferon gene signature expression in healthy volunteers. CONCLUSION: These data demonstrate that inhibition of IRAK4 kinase activity can reduce levels of inflammation markers in humans and provide confidence in the rationale for clinical development of IRAK4 inhibitors for rheumatologic indications.


Assuntos
Artrite Experimental/tratamento farmacológico , Quinases Associadas a Receptores de Interleucina-1/antagonistas & inibidores , Isoquinolinas/uso terapêutico , Lactamas/uso terapêutico , Macrófagos/efeitos dos fármacos , Doenças Reumáticas/tratamento farmacológico , Sinoviócitos/efeitos dos fármacos , Animais , Artrite Experimental/imunologia , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Modelos Animais de Doenças , Humanos , Inflamação/tratamento farmacológico , Inflamação/imunologia , Isoquinolinas/farmacologia , Lactamas/farmacologia , Leucócitos Mononucleares/imunologia , Macrófagos/imunologia , Camundongos , Ratos , Doenças Reumáticas/imunologia , Sinoviócitos/imunologia
3.
ACS Chem Biol ; 14(6): 1235-1242, 2019 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-31082193

RESUMO

PF-06651600 was developed as an irreversible inhibitor of JAK3 with selectivity over the other three JAK isoforms. A high level of selectivity toward JAK3 is achieved by the covalent interaction of PF-06651600 with a unique cysteine residue (Cys-909) in the catalytic domain of JAK3, which is replaced by a serine residue in the other JAK isoforms. Importantly, 10 other kinases in the kinome have a cysteine at the equivalent position of Cys-909 in JAK3. Five of those kinases belong to the TEC kinase family including BTK, BMX, ITK, RLK, and TEC and are also inhibited by PF-06651600. Preclinical data demonstrate that inhibition of the cytolytic function of CD8+ T cells and NK cells by PF-06651600 is driven by the inhibition of TEC kinases. On the basis of the underlying pathophysiology of inflammatory diseases such as rheumatoid arthritis, inflammatory bowel disease, alopecia areata, and vitiligo, the dual activity of PF-06651600 toward JAK3 and the TEC kinase family may provide a beneficial inhibitory profile for therapeutic intervention.


Assuntos
Janus Quinase 3/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirimidinas/farmacologia , Pirróis/farmacologia , Animais , Antígenos CD/imunologia , Antígenos de Diferenciação de Linfócitos T/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Humanos , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Lectinas Tipo C/antagonistas & inibidores , Lectinas Tipo C/imunologia , Camundongos
4.
PLoS One ; 11(5): e0155368, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27171494

RESUMO

The cytokine TWEAK and its cognate receptor Fn14 are members of the TNF/TNFR superfamily and are upregulated in tissue injury to mediate local tissue responses including inflammation and tissue remodeling. We found that in various models of kidney disease, Fn14 expression (mRNA and protein) is upregulated in the kidney. These models include: lupus nephritis mouse models (Nephrotoxic serum Transfer Nephritis and MRL.Faslpr/lpr), acute kidney injury models (Ischemia reperfusion injury and Folic acid injury), and a ZSF-1 diabetic nephropathy rat model. Fn14 expression levels correlate with disease severity as measured by disease histology. We have also shown for the first time the detection of soluble Fn14 (sFn14) in the urine and serum of mice. Importantly, we found the sFn14 levels are markedly increased in the diseased mice and are correlated with disease biomarkers including proteinuria and MCP-1. We have also detected sFn14 in human plasma and urine. Moreover, sFn14 levels, in urine are significantly increased in DN patients and correlated with proteinuria and MCP-1 levels. Thus our data not only confirm the up-regulation of Fn14/TWEAK pathway in kidney diseases, but also suggest a novel mechanism for its regulation by the generation of sFn14. The correlation of sFn14 levels and disease severity suggest that sFn14 may serve as a potential biomarker for both acute and chronic kidney diseases.


Assuntos
Nefropatias/metabolismo , Receptores do Fator de Necrose Tumoral/metabolismo , Injúria Renal Aguda/sangue , Injúria Renal Aguda/patologia , Injúria Renal Aguda/urina , Adulto , Animais , Cromatografia Líquida , Modelos Animais de Doenças , Ácido Fólico/metabolismo , Humanos , Rim/metabolismo , Rim/patologia , Nefrite Lúpica/sangue , Nefrite Lúpica/patologia , Nefrite Lúpica/urina , Masculino , Camundongos , Receptores do Fator de Necrose Tumoral/sangue , Traumatismo por Reperfusão/sangue , Traumatismo por Reperfusão/patologia , Traumatismo por Reperfusão/urina , Solubilidade , Receptor de TWEAK , Espectrometria de Massas em Tandem , Regulação para Cima
5.
J Exp Med ; 203(8): 1891-901, 2006 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-16831897

RESUMO

Type I interferons (IFNs) are pleiotropic cytokines with antiviral and immunomodulatory properties. The immunosuppressive actions of type I IFNs are poorly understood, but IFN-mediated suppression of TNFalpha production has been implicated in the regulation of inflammation and contributes to the effectiveness of type I IFNs in the treatment of certain autoimmune and inflammatory diseases. In this study, we investigated mechanisms by which type I IFNs suppress induction of TNFalpha production by immune complexes, Fc receptors, and Toll-like receptors. Suppression of TNFalpha production was mediated by induction and activation of the Axl receptor tyrosine kinase and downstream induction of Twist transcriptional repressors that bind to E box elements in the TNF promoter and suppress NF-kappaB-dependent transcription. Twist expression was activated by the Axl ligand Gas6 and by protein S and apoptotic cells. These results implicate Twist proteins in regulation of TNFalpha production by antiinflammatory factors and pathways, and provide a mechanism by which type I IFNs and Axl receptors suppress inflammatory cytokine production.


Assuntos
Inflamação/imunologia , Interferon-alfa/farmacologia , Proteínas Oncogênicas/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Proteína 1 Relacionada a Twist/metabolismo , Animais , Células Cultivadas , Citocinas/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Macrófagos/efeitos dos fármacos , Camundongos , Modelos Biológicos , Proteínas Oncogênicas/genética , Proteínas Proto-Oncogênicas , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores Proteína Tirosina Quinases/genética , Receptores Fc/metabolismo , Transdução de Sinais/efeitos dos fármacos , Receptor 2 Toll-Like/metabolismo , Receptor 4 Toll-Like/metabolismo , Fator de Necrose Tumoral alfa/biossíntese , Fator de Necrose Tumoral alfa/genética , Receptor Tirosina Quinase Axl
6.
J Immunol ; 172(10): 6476-81, 2004 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-15128840

RESUMO

Interleukin-10 is a predominantly anti-inflammatory cytokine that inhibits macrophage and dendritic cell function, but can acquire proinflammatory activity during immune responses. We investigated whether type I IFNs, which are elevated during infections and in autoimmune diseases, modulate the activity of IL-10. Priming of primary human macrophages with low concentrations of IFN-alpha diminished the ability of IL-10 to suppress TNF-alpha production. IFN-alpha conferred a proinflammatory gain of function on IL-10, leading to IL-10 activation of expression of IFN-gamma-inducible, STAT1-dependent genes such as IFN regulatory factor 1, IFN-gamma-inducible protein-10 (CXCL10), and monokine induced by IFN-gamma (CXCL9). IFN-alpha priming resulted in greatly enhanced STAT1 activation in response to IL-10, and STAT1 was required for IL-10 activation of IFN-gamma-inducible protein-10 and monokine induced by IFN-gamma expression in IFN-alpha-primed cells. In control, unprimed cells, IL-10 activation of STAT1 was suppressed by constitutive activity of protein kinase C and Src homology 2 domain-containing phosphatase 1. These results demonstrate that type I IFNs regulate the balance between IL-10 anti- and proinflammatory activity, and provide insight into molecular mechanisms that regulate IL-10 function. Gain of IL-10 proinflammatory functions may contribute to its pathogenic role in autoimmune diseases characterized by elevated type I IFN levels, such as systemic lupus erythematosus.


Assuntos
Mediadores da Inflamação/fisiologia , Interferon-alfa/imunologia , Interleucina-10/fisiologia , Lúpus Eritematoso Sistêmico/imunologia , Animais , Células Cultivadas , Proteínas de Ligação a DNA/antagonistas & inibidores , Proteínas de Ligação a DNA/deficiência , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Sinergismo Farmacológico , Humanos , Mediadores da Inflamação/antagonistas & inibidores , Interferon-alfa/farmacologia , Interleucina-10/antagonistas & inibidores , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Lúpus Eritematoso Sistêmico/genética , Ativação de Macrófagos/imunologia , Fator Estimulador de Colônias de Macrófagos/farmacologia , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Camundongos Knockout , Camundongos Mutantes , Proteína Quinase C/metabolismo , Proteína Quinase C/fisiologia , Proteína Quinase C-delta , Proteína Fosfatase 1 , Proteínas Tirosina Fosfatases/metabolismo , Proteínas Tirosina Fosfatases/fisiologia , Fator de Transcrição STAT1 , Transativadores/antagonistas & inibidores , Transativadores/deficiência , Transativadores/genética , Transativadores/metabolismo , Regulação para Cima/imunologia
7.
J Immunol ; 171(10): 5034-41, 2003 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-14607900

RESUMO

One important mechanism of cross-regulation by opposing cytokines is inhibition of signal transduction, including inhibition of Janus kinase-STAT signaling by suppressors of cytokine signaling. We investigated whether IFN-gamma, a major activator of macrophages, inhibited the activity of IL-10, an important deactivator. Preactivation of macrophages with IFN-gamma inhibited two key anti-inflammatory functions of IL-10, the suppression of cytokine production and of MHC class II expression. Gene expression profiling showed that IFN-gamma broadly suppressed the ability of IL-10 to induce or repress gene expression. Although IFN-gamma induced expression of suppressor of cytokine signaling proteins, IL-10 signal transduction was not suppressed and IL-10 activation of Janus kinases and Stat3 was preserved. Instead, IFN-gamma switched the balance of IL-10 STAT activation from Stat3 to Stat1, with concomitant activation of inflammatory gene expression. IL-10 activation of Stat1 required the simultaneous presence of IFN-gamma. These results demonstrate that IFN-gamma operates a switch that rapidly regulates STAT activation by IL-10 and alters macrophage responses to IL-10. Dynamic regulation of the activation of different STATs by the same cytokine provides a mechanism by which cells can integrate and balance signals delivered by opposing cytokines, and extends our understanding of cross-regulation by opposing cytokines to include reprogramming of signaling and alteration of function.


Assuntos
Interferon gama/farmacologia , Interleucina-10/metabolismo , Interleucina-10/fisiologia , Transdução de Sinais/imunologia , Adjuvantes Imunológicos/farmacologia , Adjuvantes Imunológicos/fisiologia , Linhagem Celular , Células Cultivadas , Proteínas de Ligação a DNA/biossíntese , Proteínas de Ligação a DNA/metabolismo , Proteínas de Ligação a DNA/fisiologia , Sinergismo Farmacológico , Regulação da Expressão Gênica/imunologia , Humanos , Mediadores da Inflamação/antagonistas & inibidores , Mediadores da Inflamação/fisiologia , Interferon gama/fisiologia , Interleucina-10/antagonistas & inibidores , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Ativação de Macrófagos/imunologia , Fator de Transcrição STAT1 , Fator de Transcrição STAT3 , Transativadores/biossíntese , Transativadores/metabolismo , Transativadores/fisiologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/biossíntese , Regulação para Cima/imunologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA