RESUMO
Germline mutations in STK11, which encodes the tumor suppressor liver kinase B1 (LKB1), promote Peutz-Jeghers syndrome (PJS), a cancer predisposition syndrome characterized by the development of gastrointestinal (GI) polyps. Here, we report that heterozygous deletion of Stk11 in T cells (LThet mice) is sufficient to promote GI polyposis. Polyps from LThet mice, Stk11+/- mice, and human PJS patients display hallmarks of chronic inflammation, marked by inflammatory immune-cell infiltration, signal transducer and activator of transcription 3 (STAT3) activation, and increased expression of inflammatory factors associated with cancer progression [interleukin 6 (IL-6), IL-11, and CXCL2]. Targeting either T cells, IL-6, or STAT3 signaling reduced polyp growth in Stk11+/- animals. Our results identify LKB1-mediated inflammation as a tissue-extrinsic regulator of intestinal polyposis in PJS, suggesting possible therapeutic approaches by targeting deregulated inflammation in this disease.
Assuntos
Pólipos Adenomatosos/genética , Síndrome de Peutz-Jeghers/genética , Proteínas Serina-Treonina Quinases/genética , Neoplasias Gástricas/genética , Linfócitos T/imunologia , Proteínas Quinases Ativadas por AMP , Pólipos Adenomatosos/imunologia , Pólipos Adenomatosos/patologia , Animais , Quimiocina CXCL2/genética , Deleção de Genes , Expressão Gênica , Humanos , Inflamação/genética , Inflamação/imunologia , Inflamação/patologia , Interleucina-11/genética , Interleucina-6/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Síndrome de Peutz-Jeghers/imunologia , Síndrome de Peutz-Jeghers/patologia , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Neoplasias Gástricas/imunologia , Neoplasias Gástricas/patologiaRESUMO
Toxemia of pregnancy is characterized by a combination of at least two of the following clinical symptoms: hypertension, edema, and proteinuria. In three successive trials over three consecutive years, the dietary intakes of a selected number of young pregnant women attending a Maternal and Infant Care Clinic at Tuskegee Institute were evaluated for protein, amino acids, and total calories. Women with toxemia were identified, and women without toxemia served as controls. The toxemic group generally consumed more protein than the controls, but values were statistically significant only in the first trial. However, all essential amino acids were consumed in significantly greater amounts by the toxemic group. Protein and essential amino acids were consumed in adequate amounts (at least two-thirds of the RDA) by both groups but in amounts smaller than the national average. Non-essential amino acids were also consumed in adequate amounts, with the toxemic group consuming larger quantities than the controls. Caloric intakes were adequate for young pregnant women. The relationships of glucosuria and of toxemia to protein and amino acid intake were similar and were opposite to the relationship of anemia to protein and amino acid intake. Meats and grains contributed the greatest quantity of protein and amino acids to the diet in all groups. Data seem to imply that any relationship of protein and amino acids with toxemia of pregnancy is a complex one involving several possibly interrelated nutritional parameters.