RESUMO
A patient with a 17-year history of plaque psoriasis accompanied by type 2 diabetes mellitus discontinued cyclosporine and steroid ointment given for treatment of psoriasis because she was dissatisfied with the effects of the drugs. After sitagliptin, a dipeptidyl peptidase-IV (DPP-IV) inhibitor, was administered for control of blood glucose, psoriatic skin lesions were gradually diminished, although HbA1c did not improve. Three months after the administration of sitagliptin, infiltration, scales and erythema on all psoriatic plaques disappeared, leaving pigmentation on flat skin. DPP-IV in serum degrades the incretin hormones which stimulate ß-cell insulin secretion. DPP-IV inhibitors, as incretin enhancers, cause an increase in glucose-dependent insulin secretion, and are applied for the treatment of diabetes mellitus. DPP-IV is also expressed on T cells as CD26, a surface antigen which plays an important role in activating T cells. As helper T cells are involved in the pathogenesis of psoriasis, it is possible that DPP-IV inhibitors improve psoriatic skin lesions by inhibiting T cell activation, independently of glycemic control. DPP-IV inhibitors could be an alternative for the treatment of psoriasis.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Hipoglicemiantes/uso terapêutico , Psoríase/tratamento farmacológico , Pirazinas/uso terapêutico , Triazóis/uso terapêutico , Adulto , Diabetes Mellitus Tipo 2/complicações , Feminino , Humanos , Psoríase/complicações , Fosfato de Sitagliptina , Linfócitos T/efeitos dos fármacos , Resultado do TratamentoRESUMO
We determined the effect of 17beta-estradiol on tumor necrosis factor alpha (TNF-alpha)-induced cytotoxicity in human peripheral T lymphocytes (T cells) using lactate dehydrogenase assay. Treatment with 17beta-estradiol (1-100 nM) for 24 h showed dose-dependent reduction of TNF-alpha-induced cytotoxicity in T cells. To further evaluate the mechanism of 17beta-estradiol on TNF-alpha-induced cytotoxicity in T cells, we identified estrogen receptor (ER) protein in T cells using immunocytochemistry and used the pure ER antagonist ICI 172,780. ERalpha immunoreactivity was clearly observed in T cells. ERbeta immunoreactivity was also detected in some T cells. ICI 172,780 (10(-7) M) alone did not affect cytotoxicity in T cells, however, ICI 172,780 (10(-7) M) completely abolished 17beta-estradiol cytoprotective effects in T cells. TNF-alpha tended to increase nuclear factor kappaB (NF-kappaB) protein levels in nuclear extracts but it did not reach statistical significance by Western blotting. In contrast, NF-kappaB protein levels in nuclear extracts followed by TNF-alpha with 17beta-estradiol treatment were significantly increased compared with NF-kappaB protein levels in untreated group. NF-kappaB blocker pyrrolidinedithiocarbamate (PDTC) (10(-4) M) alone did not affect cytotoxicity in T cells. In contrast, PDTC (10(-4) M) completely abolished 17beta-estradiol cytoprotective effects in T cells. Caspase -3/-7 activity was significantly increased followed by TNF-alpha, and 17beta-estradiol treatment significantly reduced the increment. The present studies suggest the protective effect of 17beta-estradiol on TNF-alpha-induced cytotoxicity through ERs in T cells and that NF-kappaB activation and caspase suppression may be involved in the mechanism.
Assuntos
Citotoxicidade Imunológica/efeitos dos fármacos , Estradiol/farmacologia , Prolina/análogos & derivados , Linfócitos T/imunologia , Fator de Necrose Tumoral alfa/farmacologia , Adulto , Caspase 3 , Caspases/análise , Caspases/metabolismo , Células Cultivadas , Antagonistas de Estrogênios/farmacologia , Moduladores de Receptor Estrogênico/farmacologia , Receptor alfa de Estrogênio/análise , Receptor beta de Estrogênio/análise , Feminino , Humanos , Imuno-Histoquímica/métodos , L-Lactato Desidrogenase/análise , NF-kappa B/antagonistas & inibidores , NF-kappa B/metabolismo , Prolina/farmacologia , Linfócitos T/química , Linfócitos T/efeitos dos fármacos , Tiocarbamatos/farmacologiaAssuntos
Artrite Juvenil/complicações , Neurite (Inflamação)/etiologia , Adolescente , Artrite Juvenil/diagnóstico , Artrite Juvenil/tratamento farmacológico , Quimioterapia Combinada , Eritema/tratamento farmacológico , Eritema/etiologia , Feminino , Humanos , Metotrexato/uso terapêutico , Metilprednisolona/administração & dosagem , Neurite (Inflamação)/tratamento farmacológico , Prednisolona/uso terapêutico , Pulsoterapia , Resultado do Tratamento , Vasculite/complicações , Vasculite/tratamento farmacológicoAssuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/imunologia , Hipersensibilidade a Drogas/diagnóstico , Hipoglicemiantes/efeitos adversos , Insulina/efeitos adversos , Hipersensibilidade a Drogas/prevenção & controle , Feminino , Humanos , Insulina/análogos & derivados , Insulina Aspart , Pessoa de Meia-IdadeRESUMO
OBJECTIVE: We have previously reported the characterization and regulation of interleukin-1 (IL-1) receptors utilizing [125I]IL-1 binding assay in male C57BL/6 mice and the mouse AtT-20 pituitary tumor cells. In the present study, we examine IL-1 receptors using an immunoblotting method to further characterize the mechanisms regulating the interactions of IL-1 receptors with endotoxin, lipopolysaccharide (LPS). METHODS: We established Western blotting for IL-1 receptors using AtT-20 mouse pituitary tumor cells. RESULTS: Several bands were seen; however, only the 105-kD band was neutralized with a 5-fold excess of IL-1 receptor- blocking peptides, suggesting that this band is specific for IL-1 receptors. Next, we investigated the effect of LPS and IL-1beta on IL-1 receptors. Treatment of AtT-20 cells with 0.01 microg/ml of LPS did not affect IL-1 receptors. In contrast, 1 microg/ml of LPS significantly increased IL-1 receptors in AtT-20 cells compared with the control group. In addition, [125I]IL-1beta binding was markedly increased followed by 1 microg/ml of LPS. In contrast, 1 nM recombinant human IL-1beta significantly decreased IL-1 receptors in AtT-20 cells compared with the control group although treatment of AtT-20 cells with 0.01 nM IL-1beta did not affect IL-1 receptors. LPS (0.1 and 1 microg/ml) did not affect IL-1beta concentrations in the medium of AtT-20 cell culture. IL-1beta concentrations in the homogenates from AtT-20 cells were significantly decreased after 1 microg/ml of LPS treatment but not after 0.01 microg/ml LPS. CONCLUSIONS: These data demonstrate that LPS and IL-1beta differentially modulate IL-1 receptors in AtT-20 cells and LPS-induced modulation of IL-1 receptors may provide a novel mechanism for the actions of LPS to alter pituitary function during endotoxemia. Additional in vivo studies are necessary to determine the physiological relevance of this in vitro phenomenon.