Activation of Human Monocytes for Enhanced Production of Interleukin 8 During Transendothelial Migration in Vitro

Interleukin-8 (IL-8) is a chemokine for polymorphonuclear leukocytes (PMNs) and lymphocytes, which promotes the extravasation of these inflammatory cells. In this study, we investigated IL-8 synthesis induced by the adhesive interaction between monocytes and endothelial cells during transmigration and the capacity of transmigrated monocytes to produce IL-8. Cocultured human monocytes and human umbilical vein endothelial cell (HUVEC) monolayers induced the synefgistic production of IL-8, compared with cultures of either monocytes or HUVEC monolayers alone. Coculture-induced IL-8 production almost doubled after HUVECs were stimulated with IL-1. The induced IL-8 mRNA expression was consistent with the protein data, indicating the de novo synthesis of IL-8 by the coculture. Monoclonal antibodies (mAbs) against IL-8 inhibited the transendothelial chemotactic activity of the supernatants for PMNs by 55%. Immunohistochemistry revealed that both adherent and transmigrated monocytes and unstimulated HUVECs expressed IL-8 protein, whereas nonadherent monocytes did little. Transmigrated monocytes spontaneously secreted a 3.8-fold greater amount of IL-8 than the initial monocytes. Coculture-induced IL-8 production was inhibited about 30% by polyclonal Abs against IL-, IL-1, or tumor necrosis factor , while it was not affected by mAbs against intercellular adhesion molecule 1 or vascular cell adhesion molecule 1. The results suggested that adhesive interaction during the transmigration of monocytes through HUVEC monolayers activates both cell types to produce IL-8 and that transmigrated monocytes are capable of producing ample IL-8.     

Dynamics of gastrin-producing cells in the rat after truncal vagotomy. Evaluation by double immunostaining for bromodeoxyuridine and little gastrin.

The mechanism of hyperplasia of gastrin-producing cells (G-cells) in the rat antral mucosa after truncal vagotomy was studied using double immunostaining for bromodeoxyuridine (BrdU) and little gastrin (G17). With single labeling of BrdU, a few G-cells (less than 1%) showed positive immunostaining for BrdU in the nucleus throughout the experimental period in both vagotomized rats and those given a sham operation. The labeled cells in both groups demonstrated a linear increase of BrdU labeling in an identical number of cells for each experimental time-point. The labeling index of the G-cells increased rapidly from day 2 to day 6 and attained a maximum level of 44.0% on day 10 in the vagotomized group after cumulative labeling. Even in this group, however, many G-cells showed no BrdU immunoreactivity throughout the experimental period. These cells did not replicate during the experimental period, but showed an intense reaction product for G17 in their cytoplasm after vagotomy. The present study indicates that the most important factor involved in G-cell hyperplasia observed after truncal vagotomy is the activation of pre-existing G-cells to synthesize and release hormone, together with the rapid maturation of progenitor cells to mature G-cells.     

Loss of Hrs in the Central Nervous System Causes Accumulation of Ubiquitinated Proteins and Neurodegeneration

The endosomal sorting complex required for transport (ESCRT) proteins form multimolecular complexes that control multivesicular body formation, endosomal sorting, and transport ubiquitinated membrane proteins (including cell-surface receptors) to the endosomes for degradation. There is accumulating evidence that endosomal dysfunction is linked to neural cell degeneration in vitro, but little is known about the relationship between neural disorders and ESCRT proteins in vivo. Here we specifically deleted the hrs gene, ESCRT-0, in the neurons of mice by crossing loxP-flanked hrs mice with transgenic mice expressing the synapsin-I Cre protein (SynI-cre). Histological analyses revealed that both apoptosis and a loss of hippocampal CA3 pyramidal neurons occurred in the hrs^flox/flox;SynI-cre mice. Notably, the hrs^flox/flox;SynI-cre mice accumulated ubiquitinated proteins, such as glutamate receptors and an autophagy-regulating protein, p62. These molecules are particularly prominent in the hippocampal CA3 neurons and cerebral cortex with advancing age. Accordingly, we found that both locomotor activity and learning ability were severely reduced in the hrs^flox/flox;SynI-cre mice. These data suggest that Hrs plays an important role in neural cell survival in vivo and provide an animal model for neurodegenerative diseases that are known to be commonly affected by the generation of proteinaceous aggregates.     

A case of small polypoid esophageal carcinoma with multidirectional differentiation, including neuroendocrine, squamous, ciliated glandular, and sarcomatous components

A small composite esophageal carcinoma measuring 1.5 x 1.4 x 1.0 cm is described. The tumor had a polypoid elevation with a superficial extension. Histologic examination revealed invasion of the submucosal layer and multidirectional differentiation, including neuroendocrine, squamous, ciliated glandular, and sarcomatous components. The neuroendocrine component was strongly positive for chromogranin and formed the bulk of the polypoid tumor. The squamous cell carcinoma exhibited a superficial extension. The adenocarcinoma was located in a small region of the tumor and contained ciliated glandular cells. The spindle cell sarcomatous component, which was positive for alpha-smooth muscle actin and negative for cytokeratin, exhibited no specific mesenchymal differentiation. Each component was found in 60%, 10%, 5%, and 25% of the tumor, respectively. Cases of small composite esophageal carcinoma containing various carcinomatous and sarcomatous components are extremely rare.     

PLASMA CELL GRANULOMA OF THE LUNG WITH EXTRAPULMONAL EXTENSION

A rare case of plasma cell granuloma of the lung in a 5-year-old girl showing extrapulmonal extension to the adjoining thoracic wall was reported. Intrapulmonal and thoracic wall granulomas revealed the same histopathologic features; proliferation of plasma cells and fibrous connective tissue. Although slightly atypical plasma cells were observed among many mature ones, immunohistochemical examination revealed polyclonal proliferation, confirming their inflammatory nature. Cellular components of fibrous connective tissue were identified as fibroblastic cells and myofibroblasts by electron microscopy. The present case and literature suggested the importance of the fact that "infiltrative" plasma cell granuloma had a tendency to occur in children. ACTA PATHOL. JPN. 35: 933–944, 1985.     

DETECTION OF HBsAg IN THE PANCREAS

Hepatitis B surface antigen (HBsAg) has been reported to be present in other organs than the liver.^3,9 So far as our knowledge is concerned, however, any report of cases dealing with pancreatic diseases induced by hepatitis B virus (HBV) has not been described in the English and Japanese literature. We report an autopsy case with a pancreatic lesion characterized by damage of both exocrine and endocrine epithelial cells with inflammatory response, which were immunohistochemically found to be positive for HBsAg, and electron-microscopically to possess core-like particles In the nucleus and cytoplasm.     

A common mutation in methylenetetrahydrofolate reductase gene among the Japanese population

Summary Hyperhomocysteinemia has been reported as an independent risk factor for atherosclerotic cerebrovascular and coronary heart diseases. 5,10-Methylenetetrahydrofolate reductase (MTHFR) is one of the enzymes responsible for hyperhomocysteinemia. The C to T transition of the MTHFR gene at nucleotide position 677 results in decreasing the enzymatic activity and increasing the plasma homocysteine level. We studied the distribution of the MTHFR gene mutation among the Japanese population. The subjects were 129 Japanese males (aged 40–59 years). The allele frequency of the mutation was 0.38. The frequencies of the three genotypes were as follows: +/+, 11%; +/–, 54%; –/–, 35% (+ and – indicate the presence and absence of the mutation, respectively). We also studied the frequency of the MTHFR gene mutation in the middle-aged Japanese males with hypertension to investigate the possibility that this mutation is related to essential hypertension. The normotensive and hypertensive subjects were identical in the distribution of the mutated allele and the frequencies of the three genotypes. Furthermore, the prevalence of hypertension in each genotype group was same, although the mean diastolic pressure of the group with homozygous mutation was significantly higher than that of other groups (p<0.05).     

Bronchial hyperresponsiveness and airway inflammation in adolescents with asymptomatic childhood asthma

BACKGROUND: About 70% of childhood asthmatics become free of asthma-related symptoms during adolescence. Little is known about bronchial hyperresponsiveness (BHR) and airway inflammation in young adults with "outgrown" childhood asthma. METHODS: We studied 61 nonsmoking medical students (18 intermittent mild asthmatics, 23 students with outgrown childhood asthma but free of asthma-related symptoms for 10 years (asymptomatic asthmatics) and 20 healthy students). BHR and lung function were measured, and induced sputum samples analyzed for eosinophil count, eosinophilic cationic protein (ECP), granulocyte-macrophage colony stimulating factor (GM-CSF), and tumor necrosis factor-alpha (TNF-alpha). RESULTS: BHR was still present in most asymptomatic asthmatics, but it was milder compared with healthy students. Only three subjects with previous asthma had no BHR and no signs of airway inflammation. Percentages of eosinophil, and ECP, TNF-alpha and GM-CSF concentrations in induced sputum of mild asthmatics and asymptomatic asthma groups were higher than in the healthy group. In asymptomatic asthmatics group, the duration of asthma, sputum eosinophil percentage, and the level of TNF-alpha in sputum correlated significantly with BHR. CONCLUSIONS: Only a few subjects with longstanding asymptomatic asthma could be considered as cured; most asymptomatic asthmatics continued to exhibit BHR and signs of airway inflammation. The outcome of childhood asthma and BHR was associated with the degree of airway inflammation and the duration of childhood asthma.     

Long-term follow up studies of bronchial asthma in children. II. Prognosis and complications, treatment and allergic evaluations

A questionnaire on the prognosis of bronchial asthma was sent in 1988 to 1592 patients (1038 males, 554 females) averaging 20 years of age after 12 years' follow up. We reported on the prognosis and risk factors associated with asthmatic children in part I. The relation between prognosis and other allergic complications, treatment and laboratory data were investigated in this study. Eosinophil counts of more than 1000/mm3 and/or total serum IgE levels of more than 500 IU/ml (100 IU/ml in infants) indicated poor prognosis. However, the prognosis was not affected either by the allergens themselves or by the number of allergens determined by skin test and RAST. The prognosis was worse for patients with multiple allergic complications than for those without complications. Treatment may after the natural course of childhood asthma, but it has been difficult to evaluate the effect of each regimen over a long period. We compared the effect of hyposensitization (specific immunization) and non-bronchodilator antiasthmatic drugs (NBAAD), and found that hyposensitization alone gave better results than NBAAD and its combination. We had better results from hyposensitization over a period of 1 to 5 years than for less than 1 year or more than 5 years. We conclude that asthmatic children with risk factors should be kept under strict environmental control and given suitable therapeutic regimens to avoid the development of allergic diseases, the slow down of "allergic march", and to avoid intractable asthma.