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1.
Cytokine ; 14(5): 272-82, 2001 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-11444907

RESUMO

Tumour necrosis factor (TNF)-alpha and interleukin (IL-)1beta, essential players in the pathogenesis of immuno-inflammatory diseases, are strongly induced in monocytes by direct contact with stimulated T lymphocytes. The present study shows that the latter mechanism is inhibited by interferon (IFN)-beta. In co-cultures of autologous T lymphocytes and monocytes stimulated by phytohaemagglutinin (PHA), IFN-beta inhibited the production of TNF-alpha and IL-1beta by 88 and 98%, respectively, whereas the simultaneous production of IL-1 receptor antagonist (IL-1Ra), was enhanced two-fold. The latter effects of IFN-beta were independent of modulations in IFN-gamma, IL-4 and IL-10 production. When monocytes were activated by plasma membranes of stimulated T cells, IFN-beta slightly inhibited the production of TNF-alpha and IL-1beta, while enhancing 1.5-fold that of IL-1Ra. The latter effect correlated with the persistence of high steady-state levels of IL-1Ra mRNA after 24 h of activation. Membranes isolated from T lymphocytes that had been stimulated in the presence of IFN-beta displayed a 80% decrease in their capacity to induce the production of IL-1beta and TNF-alpha in monocytes, whereas IL-1Ra induction was decreased by only 32%. These results demonstrate that IFN-beta modulates contact-mediated activation of monocytes by acting on both T lymphocytes and monocytes, decreasing the ability of T lymphocytes to induce TNF-alpha and IL-1beta production in monocytes and directly enhancing the production of IL-1Ra in the latter cells.


Assuntos
Interferon beta/farmacologia , Interleucina-1/biossíntese , Monócitos/imunologia , Linfócitos T/imunologia , Fator de Necrose Tumoral alfa/biossíntese , Membrana Celular/metabolismo , Células Cultivadas , Humanos , Interferon gama/biossíntese , Proteína Antagonista do Receptor de Interleucina 1 , Interleucina-1/genética , Interleucina-10/biossíntese , Interleucina-4/biossíntese , Ativação Linfocitária , Proteínas de Membrana/metabolismo , Modelos Imunológicos , Estabilidade de RNA , Sialoglicoproteínas/biossíntese , Sialoglicoproteínas/genética , Linfócitos T/efeitos dos fármacos
2.
Blood ; 97(8): 2381-9, 2001 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-11290601

RESUMO

Tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta), essential components in the pathogenesis of immunoinflammatory diseases, are strongly induced in monocytes by direct contact with stimulated T lymphocytes. This study demonstrates that adult human serum (HS) but not fetal calf or cord blood serum displays inhibitory activity toward the contact-mediated activation of monocytes by stimulated T cells, decreasing the production of both TNF-alpha and IL-1beta. Fractionation of HS and N-terminal microsequencing as well as electroelution of material subjected to preparative electrophoresis revealed that apolipoprotein A-I (apo A-I), a "negative" acute-phase protein, was the inhibitory factor. Functional assays and flow cytometry analyses show that high-density lipoprotein (HDL)-associated apo A-I inhibits contact-mediated activation of monocytes by binding to stimulated T cells, thus inhibiting TNF-alpha and IL-1beta production at both protein and messenger RNA levels. Furthermore, apo A-I inhibits monocyte inflammatory functions in peripheral blood mononuclear cells activated by either specific antigens or lectins without affecting cell proliferation. These results demonstrate a new anti-inflammatory activity of HDL-associated apo A-I that might have modulating functions in nonseptic conditions. Therefore, because HDL has been shown to bind and neutralize lipopolysaccharide, HDL appears to play an important part in modulating both acute and chronic inflammation. The novel anti-inflammatory function of apo A-I reported here might lead to new therapeutic approaches in inflammatory diseases such as rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, and atherosclerosis.


Assuntos
Apolipoproteína A-I/farmacologia , Comunicação Celular/efeitos dos fármacos , Interleucina-1/biossíntese , Lipoproteínas HDL/fisiologia , Monócitos/efeitos dos fármacos , Linfócitos T/fisiologia , Fator de Necrose Tumoral alfa/biossíntese , Reação de Fase Aguda , Adulto , Animais , Apolipoproteína A-I/isolamento & purificação , Bovinos , Depressão Química , Desenho de Fármacos , Sangue Fetal , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Recém-Nascido , Inflamação , Interleucina-1/genética , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Lipoproteínas HDL/isolamento & purificação , Camundongos , Monócitos/metabolismo , RNA Mensageiro/biossíntese , Acetato de Tetradecanoilforbol/farmacologia , Células Tumorais Cultivadas , Fator de Necrose Tumoral alfa/genética
3.
EMBO J ; 17(7): 1919-29, 1998 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-9524115

RESUMO

Polarized expression of most epithelial plasma membrane proteins is achieved by selective transport from the Golgi apparatus or from endosomes to a specific cell surface domain. In Madin-Darby canine kidney (MDCK) cells, basolateral sorting generally depends on distinct cytoplasmic targeting determinants. Inactivation of these signals often resulted in apical expression, suggesting that apical transport of transmembrane proteins occurs either by default or is mediated by widely distributed characteristics of membrane glycoproteins. We tested the hypothesis of N-linked carbohydrates acting as apical targeting signals using three different membrane proteins. The first two are normally not glycosylated and the third one is a glycoprotein. In all three cases, N-linked carbohydrates were clearly able to mediate apical targeting and transport. Cell surface transport of proteins containing cytoplasmic basolateral targeting determinants was not significantly affected by N-linked sugars. In the absence of glycosylation and a basolateral sorting signal, the reporter proteins accumulated in the Golgi complex of MDCK as well as CHO cells, indicating that efficient transport from the Golgi apparatus to the cell surface is signal-mediated in polarized and non-polarized cells.


Assuntos
Polaridade Celular/fisiologia , Complexo de Golgi/metabolismo , Lectinas de Ligação a Manose , Proteínas de Membrana/metabolismo , Oligossacarídeos , Animais , Transporte Biológico , Células CHO , Linhagem Celular , Membrana Celular , Cricetinae , Cães , Glicosilação/efeitos dos fármacos , Proteínas de Membrana/genética , Ocludina , Receptores Fc/genética , Receptores Fc/metabolismo , Receptores de LDL/genética , Proteínas Recombinantes de Fusão , Tunicamicina/farmacologia
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