RESUMO
Systemic lupus erythematosus is characterized by dysregulated activation of T and B cells and autoantibodies to nuclear antigens and, in some cases, lipid antigens. Liposomes with nonbilayer phospholipid arrangements induce a disease resembling human lupus in mice, including IgM and IgG antibodies against nonbilayer phospholipid arrangements. As the effect of these liposomes on the innate immune response is unknown and innate immune system activation is necessary for efficient antibody formation, we evaluated the effect of these liposomes on Toll-like receptor (TLR) signaling, cytokine production, proinflammatory gene expression, and T, NKT, dendritic, and B cells. Liposomes induce TLR-4- and, to a lesser extent, TLR-2/TLR-6-dependent signaling in TLR-expressing human embryonic kidney (HEK) cells and bone marrow-derived macrophages. Mice with the lupus-like disease had increased serum concentrations of proinflammatory cytokines, C3a and C5a; they also had more TLR-4-expressing splenocytes, a higher expression of genes associated with TRIF-dependent TLR-4-signaling and complement activation, and a lower expression of apoptosis-related genes, compared to healthy mice. The percentage of NKT and the percentage and activation of dendritic and B2 cells were also increased. Thus, TLR-4 and TLR-2/TLR-6 activation by nonbilayer phospholipid arrangements triggers an inflammatory response that could contribute to autoantibody production and the generation of a lupus-like disease in mice.
Assuntos
Lipossomos/farmacologia , Lúpus Eritematoso Sistêmico/imunologia , Receptor 2 Toll-Like/imunologia , Receptor 4 Toll-Like/imunologia , Receptor 6 Toll-Like/imunologia , Animais , Autoanticorpos/biossíntese , Autoanticorpos/sangue , Clorpromazina/farmacologia , Citocinas/biossíntese , Citocinas/sangue , Diglicerídeos/farmacologia , Modelos Animais de Doenças , Feminino , Flagelina/farmacologia , Regulação da Expressão Gênica , Células HEK293 , Humanos , Imunoglobulina G/biossíntese , Imunoglobulina G/sangue , Imunoglobulina M/biossíntese , Imunoglobulina M/sangue , Inflamação , Lipopolissacarídeos/farmacologia , Lipossomos/química , Lúpus Eritematoso Sistêmico/induzido quimicamente , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/patologia , Camundongos , Camundongos Endogâmicos BALB C , Oligopeptídeos/farmacologia , Ácidos Fosfatídicos/química , Ácidos Fosfatídicos/farmacologia , Fosfatidilcolinas/química , Fosfatidilcolinas/farmacologia , Fosfatidilserinas/química , Fosfatidilserinas/farmacologia , Receptor 2 Toll-Like/agonistas , Receptor 2 Toll-Like/genética , Receptor 4 Toll-Like/agonistas , Receptor 4 Toll-Like/genética , Receptor 6 Toll-Like/agonistas , Receptor 6 Toll-Like/genéticaAssuntos
Carcinoma de Células Escamosas/genética , Antígeno Nuclear de Célula em Proliferação/genética , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteína Supressora de Tumor p53/genética , Neoplasias do Colo do Útero/genética , Carcinoma de Células Escamosas/patologia , Colo do Útero/citologia , Colo do Útero/fisiologia , Células Epiteliais/citologia , Células Epiteliais/fisiologia , Feminino , Humanos , Invasividade Neoplásica , Valores de Referência , Neoplasias do Colo do Útero/patologiaRESUMO
We have shown increased cyclooxygenase-2 (COX-2) expression in rats with kidney failure. Increased angiotensin II concentration, hypertension, and renal mass reduction have been described during development of kidney failure. Thus we explored each of these mechanisms, because any one of them could be responsible for COX-2 induction. Kidney failure increased systolic blood pressure from 104 +/- 5 to 138 +/- 2 mmHg, urinary PGE(2) from 74 +/- 17 to 185 +/- 25 ng/24 h, and COX-2 expression from 0.06 +/- 0.04 to 0.17 +/- 0.03 arbitraty units (AU). Treatment of the rats with ramipril or losartan prevented the increase in blood pressure, urinary PGE(2), and COX-2 expression in the rats with kidney failure. Infusion of angiotensin II increased blood pressure from 101 +/- 6 to 132 +/- 6 mm Hg, urinary PGE(2) excretion from 62 +/- 15 to 155 +/- 17 ng/24 h, and COX-2 expression from 0.23 +/- 0.01 to 1.6 +/- 0.3 AU. When the angiotensin II-infused rats were treated with nitrendipine, blood pressure decreased from 132 +/- 6 to 115 +/- 2 mm Hg, and urinary PGE(2) excretion decreased from 152 +/- 18 to 97 +/- 12 ng/24 h, whereas COX-2 expression was 1.6 +/- 0.7 and 1.7 +/- 0.5 AU for rats with and without nitrendipine. Blood pressure of the rats with renal pole resection was similar to that in sham rats (97 +/- 7 and 91 +/- 4 mmHg, respectively), whereas COX-2 expression was increased in rats with renal pole resection, from 0.06 +/- 0.04 to 0.12 +/- 0.03 AU. We suggest that in kidney failure, the increase in angiotensin II concentration regulates COX-2 expression, thereby increasing prostaglandin synthesis, which contributes to the development of kidney failure.