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1.
Circulation ; 129(23): 2414-25, 2014 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-24664276

RESUMO

BACKGROUND: Costimulatory cascades such as the CD40L-CD40 dyad enhance immune cell activation and inflammation during atherosclerosis. Here, we tested the hypothesis that CD40 directly modulates traits of the metabolic syndrome in diet-induced obesity in mice. METHODS AND RESULTS: To induce the metabolic syndrome, wild-type or CD40(-/-) mice consumed a high-fat diet for 20 weeks. Unexpectedly, CD40(-/-) mice exhibited increased weight gain, impaired insulin secretion, augmented accumulation of inflammatory cells in adipose tissue, and enhanced proinflammatory gene expression. This proinflammatory and adverse metabolic phenotype could be transplanted into wild-type mice by reconstitution with CD40-deficient lymphocytes, indicating a major role for CD40 in T or B cells in this context. Conversely, therapeutic activation of CD40 signaling by the stimulating antibody FGK45 abolished further weight gain during the study, lowered glucose levels, improved insulin sensitivity, and suppressed adipose tissue inflammation. Mechanistically, CD40 activation decreased the expression of proinflammatory cytokines in T cells but not in B cells or macrophages. Finally, repopulation of lymphocyte-free Rag1(-/-) mice with CD40(-/-) T cells provoked dysmetabolism and inflammation, corroborating a protective role of CD40 on T cells in the metabolic syndrome. Finally, levels of soluble CD40 showed a positive association with obesity in humans, suggesting clinical relevance of our findings. CONCLUSIONS: We present the surprising finding that CD40 deficiency on T cells aggravates whereas activation of CD40 signaling improves adipose tissue inflammation and its metabolic complications. Therefore, positive modulation of the CD40 pathway might describe a novel therapeutic concept against cardiometabolic disease.


Assuntos
Tecido Adiposo/imunologia , Aterosclerose/imunologia , Antígenos CD40/genética , Antígenos CD40/imunologia , Síndrome Metabólica/imunologia , Obesidade/imunologia , Adipócitos/imunologia , Adipócitos/metabolismo , Transferência Adotiva , Animais , Aterosclerose/genética , Aterosclerose/metabolismo , Ligante de CD40/imunologia , Ligante de CD40/metabolismo , Humanos , Inflamação/genética , Inflamação/imunologia , Inflamação/metabolismo , Resistência à Insulina/genética , Resistência à Insulina/imunologia , Ativação Linfocitária/imunologia , Masculino , Síndrome Metabólica/genética , Síndrome Metabólica/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obesidade/genética , Obesidade/metabolismo , Transdução de Sinais/imunologia , Linfócitos T/imunologia , Linfócitos T/metabolismo
2.
Gynecol Oncol ; 124(2): 236-43, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22044689

RESUMO

OBJECTIVE: The contribution of BRCA1 and BRCA2 mutations to ovarian cancer in Colombia has not yet been explored. Five founder mutations have been identified in two previous studies of breast cancer patients in the Bogota region [1,2]. It is important that the frequency of mutations be established among unselected cases of ovarian cancer in order to estimate the genetic burden of this cancer in Colombia and to plan genetic and preventive services. METHODS: We enrolled 100 unselected women with ovarian cancer from the Bogota region, and from northern and southern central regions of Colombia. A detailed family history was obtained from each patient and a blood sample was processed for DNA analysis. DNA quality was adequate for BRCA testing for 96 women. Mutations in BRCA1 and BRCA2 were sought using a Hispanic BRCA mutation testing panel. All mutations were confirmed by direct sequencing. RESULTS: Fifteen mutations were identified (two in BRCA2 and thirteen in BRCA1) representing 15.6% of the total (95% CI: 7.8% to 21.3%). Among the 15 mutation-positive families there were nine breast-ovarian cancer families, one gastric cancer family, one prostate cancer family, three uterine cancer families, and one family with no history of cancer. A single founder mutation in BRCA1 (3450del4) was seen in 11 patients. CONCLUSION: In summary, BRCA1 founder mutations are common in Colombian women with ovarian cancer. Approximately 11.5% of all ovarian cancer cases in the Bogota region are attributable to a single BRCA1 founder mutation.


Assuntos
Genes BRCA1 , Genes BRCA2 , Mutação em Linhagem Germinativa , Neoplasias Ovarianas/genética , Adolescente , Adulto , Idoso , Colômbia/epidemiologia , Análise Mutacional de DNA , Feminino , Predisposição Genética para Doença , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/epidemiologia , Prevalência , Adulto Jovem
3.
Circ Res ; 109(11): 1269-79, 2011 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-21998326

RESUMO

RATIONALE: CD40L figures prominently in chronic inflammatory diseases such as atherosclerosis. However, since CD40L potently regulates immune function and hemostasis by interaction with CD40 receptor and the platelet integrin GPIIb/IIIa, its global inhibition compromises host defense and generated thromboembolic complications in clinical trials. We recently reported that CD40L mediates atherogenesis independently of CD40 and proposed Mac-1 as an alternate receptor. OBJECTIVE: Here, we molecularly characterized the CD40L-Mac-1 interaction and tested whether its selective inhibition by a small peptide modulates inflammation and atherogenesis in vivo. METHODS AND RESULTS: CD40L concentration-dependently bound to Mac-1 I-domain in solid phase binding assays, and a high-affinity interaction was revealed by surface-plasmon-resonance analysis. We identified the motif EQLKKSKTL, an exposed loop between the α1 helix and the ß-sheet B, on Mac-1 as binding site for CD40L. A linear peptide mimicking this sequence, M7, specifically inhibited the interaction of CD40L and Mac-1. A cyclisized version optimized for in vivo use, cM7, decreased peritoneal inflammation and inflammatory cell recruitment in vivo. Finally, LDLr(-/-) mice treated with intraperitoneal injections of cM7 developed smaller, less inflamed atherosclerotic lesions featuring characteristics of stability. However, cM7 did not interfere with CD40L-CD40 binding in vitro and CD40L-GPIIb/IIIa-mediated thrombus formation in vivo. CONCLUSIONS: We present the novel finding that CD40L binds to the EQLKKSKTL motif on Mac-1 mediating leukocyte recruitment and atherogenesis. Specific inhibition of CD40L-Mac-1 binding may represent an attractive anti-inflammatory treatment strategy for atherosclerosis and other inflammatory conditions, potentially avoiding the unwanted immunologic and thrombotic effects of global inhibition of CD40L.


Assuntos
Aterosclerose/metabolismo , Ligante de CD40/metabolismo , Quimiotaxia de Leucócito/fisiologia , Antígeno de Macrófago 1/metabolismo , Trombose/etiologia , Motivos de Aminoácidos , Animais , Aterosclerose/genética , Aterosclerose/prevenção & controle , Tempo de Sangramento , Coagulação Sanguínea/efeitos dos fármacos , Coagulação Sanguínea/fisiologia , Células CHO , Células Cultivadas , Cricetinae , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Moleculares , Fragmentos de Peptídeos/farmacologia , Fragmentos de Peptídeos/uso terapêutico , Peptídeos Cíclicos/farmacologia , Peritonite/sangue , Peritonite/prevenção & controle , Conformação Proteica , Mapeamento de Interação de Proteínas , Estrutura Terciária de Proteína , Receptores de LDL/deficiência , Proteínas Recombinantes de Fusão/fisiologia , Ressonância de Plasmônio de Superfície
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