RESUMEN
Matrix metalloproteinases (MMPs) are potential biomarkers for disease activity in inflammatory bowel disease (IBD). However, clinical trials targeting MMPs have not succeeded, likely due to poor understanding of the biological functions of individual MMPs. Here, we explore the role of MMP-19 in IBD pathology. Using a DSS-induced model of colitis, we show evidence for increased susceptibility of Mmp-19-deficient (Mmp-19(-/-)) mice to colitis. Absence of MMP-19 leads to significant disease progression, with reduced survival rates, severe tissue destruction, and elevated levels of pro-inflammatory modulators in the colon and plasma, and failure to resolve inflammation. There was a striking delay in neutrophil infiltration into the colon of Mmp-19(-/-) mice during the acute colitis, leading to persistent inflammation and poor recovery; this was rescued by reconstitution of irradiated Mmp-19(-/-) mice with wild-type bone marrow. Additionally, Mmp-19-deficient macrophages exhibited decreased migration in vivo and in vitro and the mucosal barrier appeared compromised. Finally, chemokine fractalkine (CX3CL1) was identified as a novel substrate of MMP-19, suggesting a link between insufficient processing of CX3CL1 and cell recruitment in the Mmp-19(-/-) mice. MMP-19 proves to be a critical factor in balanced host response to colonic pathogens, and for orchestrating appropriate innate immune response in colitis.
Asunto(s)
Quimiocina CX3CL1/metabolismo , Colitis/inmunología , Colon/inmunología , Enfermedades Inflamatorias del Intestino/inmunología , Mucosa Intestinal/inmunología , Macrófagos/inmunología , Metaloproteinasas de la Matriz Secretadas/metabolismo , Animales , Movimiento Celular , Células Cultivadas , Colitis/inducido químicamente , Citocinas/metabolismo , Sulfato de Dextran , Progresión de la Enfermedad , Humanos , Inmunidad Innata , Mediadores de Inflamación/metabolismo , Mucosa Intestinal/patología , Metaloproteinasas de la Matriz Secretadas/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Infiltración Neutrófila/genéticaRESUMEN
Chicken ghrelin has recently been isolated as a hormone which stimulates growth hormone and corticosterone secretion in chicken. Ghrelin mediates these actions in mammals by binding to the growth hormone secretagogue receptor (GHS-R). In this study, we describe the partial cloning of two chicken GHS-R (cGHS-R) isoforms: cGHS-R1a and cGHS-R1c. cGHS-R1a and cGHS-R1c cDNA show, respectively, 81 and 78% homology with the corresponding parts of the human GHS-R1a cDNA. In contrast to the human GHS-R1b isoform, which is truncated after transmembrane domain 5 (TM-5), the chicken GHS-R1c isoform lacks 16 amino acids in TM-6 suggesting that this isoform is not active in ghrelin signal transduction. The cystein residues, N-linked glycosylation sites and potential phosphorylation sites, found in the human GHS-R1a, were also conserved in both chicken isoforms. RT-PCR analysis demonstrated cGHS-R1a and cGHS-R1c mRNA expression in all tissues tested, except liver and pancreas, with highest levels in the pituitary and the hypothalamus. Intermediate levels of expression were detected, in descending order, in the ovary, telencephalon, heart, adrenal gland, cerebellum, and optic lobes whereas low expression was detected in the brainstem, lung, kidney, proventriculus, duodenum, and colon. Very low expression was found in skin, stomach, and muscle. cGHS-R1c was expressed in lower amounts than cGHS-R1a in all analysed tissues. Administration of 1 microM chicken ghrelin to pituitaries in vitro resulted in a down-regulation of both cGHS-R isoforms within 15 min, whereas after 1h levels returned to control values. Growth hormone and corticosterone down-regulated cGHS-R1a and cGHS-R1c mRNA expression within 60 min of exposure, whereas growth hormone-releasing factor 1-29 (1 microM) only reduced cGHS-R1a mRNA expression after 60min. Thyrotropin-releasing hormone (1 microM) did not alter cGHS-R expression.
Asunto(s)
Pollos/metabolismo , Hipotálamo/metabolismo , Adenohipófisis/metabolismo , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Pollos/genética , Clonación Molecular , ADN Complementario/análisis , Regulación de la Expresión Génica , Datos de Secuencia Molecular , Isoformas de Proteínas/clasificación , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , ARN Mensajero/análisis , Receptores Acoplados a Proteínas G/clasificación , Receptores de Ghrelina , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Alineación de Secuencia , Homología de Secuencia de Ácido Nucleico , Distribución TisularRESUMEN
We devised an achievement motive questionnaire (Elizur 1979, 1986; Shye 1978a) based on a facet definition of achievement motive. We then administered it to 165 women and 362 men employed by a large industrial corporation in Hungary in order to examine achievement motivation. Although we found significant differences in the frequency of responses to the achievement motive items, the basic structure of the achievement motive domain was similar for women and men. We detected no special tendency for women to score higher than men on affective responses. These results support the view that gender differences in achievement motive are rooted in socialization processes rather than in basic differences between women and men.
