Effects of genetic and pharmacological inhibition of TNF-alpha in the regulation of inflammation in macrophages.
Pharmacol Res
; 60(4): 332-40, 2009 Oct.
Article
em En
| MEDLINE
| ID: mdl-19450684
ABSTRACT
Tumour necrosis factor-alpha (TNF-alpha) is an inflammatory cytokine produced by circulating monocytes and resident macrophages during acute inflammation and is responsible for a diverse range of signalling events within cells, leading to necrosis or apoptosis. The biologic activities of TNF are mediated by two receptors TNFR1 and TNFR2, although a lot of studies demonstrated that most of the biological activities of TNF-alpha are mediated through TNFR1. In the present study, we want to evaluate the role of TNF-alpha on regulation of in vitro models of inflammation. In particular we used peritoneal macrophages, from TNF-alphaR1 knock out and TNF-alphaR1 wild-type mice, stimulated with LPS 10 microg/ml and IFN-gamma 100 U/ml. Our results showed that the deletion of TNF-alphaR1 gene significantly reduced the degree of (i) MAPK activation, (ii) IkappaB-alpha degradation, (iii) phosphorylation of Ser536 on the NF-kappaB subunit p65 and (iv) iNOS and COX-2 expression. In addition, to confirm the pivotal role of TNF-alpha on regulation of peritoneal macrophages inflammation, we have also investigated the protective effects of infliximab, a TNF-alpha chimeric mouse/human IgG1 antibody against TNF-alpha. As shown in the present study, the cell incubation with infliximab (0.1 microg/ml, 1 microg/ml and 10 microg/ml) significantly leads to a concentration-dependent inhibition of the inflammatory mediators above described. In conclusion, our study demonstrates that pharmacological and genetic inhibition of the TNF/TNFR1 binding reduce the degree of macrophages inflammation caused by LPS/IFN-gamma stimulation.
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1
Base de dados:
MEDLINE
Assunto principal:
Fator de Necrose Tumoral alfa
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Receptores Tipo I de Fatores de Necrose Tumoral
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Macrófagos
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Anti-Inflamatórios
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Anticorpos Monoclonais
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Ano de publicação:
2009
Tipo de documento:
Article