Induction and activation of the aryl hydrocarbon receptor by IL-4 in B cells

It is widely known that IL-4 and IL-13 act on various kinds of cells, including B cells, resulting in enhancement of proliferation, class switching to IgE and expression of several surface proteins. These functions are important for the recognition of the various antigens in B cells and are known to be involved in the pathogenesis of allergic diseases. However, it has not been known whether IL-4/IL-13 is involved in the metabolism of various kinds of xenobiotics including 2,3,7,8-tetra-chlorodibenzo-p-dioxin (TCDD), and it remains undetermined whether TCDD, an environmental pollutant, influences IgE production in B cells, exaggerating allergic reactions. We identified IL-4- or IL-13-inducible genes in a human Burkitt lymphoma cell line, DND-39, using microarray technology, in which the AHR gene was included. The AHR gene product, the aryl hydrocarbon receptor (AhR), was induced by IL-4 in both mouse and human B cells in a STAT6-dependent manner. IL-4 alone had the ability to translocate the induced AhR to the nuclei. TCDD, a ligand for AhR, rapidly degraded the induced AhR by the proteasomal pathway, although IL-4-activated AhR sustained its expression. AhR activated by IL-4 caused expression of a xenobiotic-metabolizing gene, CYP1A1, and TCDD synergistically acted on the induction of this gene by IL-4. However, the induction of AhR had no effect on IgE synthesis or CD23 expression. These results indicate that the metabolism of xenobiotics would be a novel biological function of IL-4 and IL-13 in B cells, whereas TCDD is not involved in IgE synthesis in B cells.     

No difference in serum leptin concentrations between urban-dwelling Austronesians and Non-Austronesians in Papua New Guinea.

Pacific Islands populations can be broadly divided into Austronesians (AN) and Non-Austronesians (NAN); obesity and type 2 diabetes are prevalent in the former, although leptin levels in both groups have seldom been investigated. Thirty-seven (20 male and 17 female) adult pairs, matched by age and percent body fat, from AN-speaking Balopa and NAN-speaking Huli, all of whom migrated to settle in Port Moresby, the capital of Papua New Guinea, were selected for comparison of their serum leptin concentrations. The Balopa did not differ significantly from the Huli in age (30.5 +/- 9.7 and 30.0 +/- 8.7 years for males, 33.7 +/- 8.9 and 34.1 +/- 7.5 years for females, respectively) or percent body fat (19.4 +/- 5.6 and 18.8 +/- 4.6 for males, 34.1 +/- 6.2 and 33.3 +/- 5.0 for females), although the BMI of females was lower in the Balopa (26.4 +/- 4.9) than in the Huli (29.7 +/- 4.7) (P = 0.02). In both ethnic groups, females had markedly higher leptin concentrations than males, but there was no significant inter-group difference in males (3.5 +/- 2.6 and 3.1 +/- 4.7 ng/ml, P = 0.14) or females (22.7 +/- 12.9 and 19.7 +/- 11.9 ng/ml, P = 0.40), after controlling for lifestyle factors and serum lipids. Multiple regression analysis revealed that significant predictors of leptin concentration were % body fat (beta = 0.58), sex (male, 0; female, 1; beta = 0.27), and smoker status (non-smoker, 0; smoker, 1; beta = -0.15) (R(2) = 0.80), implying that the leptin concentration was primarily determined by lifestyle-derived body fatness. In conclusion, the NAN populations do not endogenously differ in leptin status from the AN populations, who have been recognized as a typical group with a "thrifty" genotype.     

Role of N-methyl-D-aspartate receptors and the nitric oxide pathway in nociception/hyperalgesia elicited by protease-activated receptor-2 activation in mice and rats

Activation of the peripheral protease-activated receptor-2 (PAR-2) triggers nociceptive behaviour and thermal hyperalgesia in rats. The present study created a novel mouse model for PAR-2-triggered nociception, and then examined the roles of NMDA receptors and the nitric oxide (NO) pathway in nociceptive processing by PAR-2. Intraplantar administration of the PAR-2 agonist SLIGRL-NH(2) elicited nociceptive responses in mice, an effect being more specific in mast cell-depleted mice. This PAR-2-triggered nociception was abolished by the NMDA receptor antagonist MK-801, but not the neuronal NO synthase inhibitor 7-nitro indazole. In contrast, the PAR-2-triggered thermal hyperalgesia in rats was blocked by both agents. Our study thus provides a novel mouse model for PAR-2-mediated nociception, and suggests that NMDA receptors are involved in PAR-2-triggered nociception and hyperalgesia, while NO contributes only to the latter.     

Expression of EGF, EGF-receptor, p53, v-erb B and ras p21 in colorectal neoplasms by immunostaining paraffin-embedded tissues

Immunohistochemical studies were performed to clarify the significance of the expression or overexpression of epidermal growth factor (EGF), EGF-receptor (EGFR), p53, v- erb B, ras p21 in 23 cases each of tubular adenoma and adenocarcinoma. The expression of EGF, EGFR, p53, v- erb B, and ras p21 in paraffin-embedded tissues, from 46 patients with colorectal tumors (adenoma: 23 cases; 14 mild dysplasia, six moderate dysplasia, three severe dysplasia, adenocarcinoma: 23 cases; 17 well differentiated, two moderately differentiated, three poorly differentiated, one mucinous carcinoma was analyzed immunohistochemically using anti-EGF, EGFR, p53, v- erb B and ras p21 antibodies. The EGF and ras p21 tended to express more strongly in carcinoma cases than in the adenoma cases, and in severe and moderate dysplasia than in mild dysplasia (EGF: stained positive in five adenomas [21.74%] and 17 adenocarcinomas [73.91%]; ras p21: stained positive in six adenomas [26.09%] and 14 adenocarcinomas [60.87%]. The EGFR stained positive in two adenomas (8.70%) and two adenocarcinomas (8.70%). The p53 and v- erb B showed positive staining only in the carcinoma cases (p53: stained positive in four cases [17.39%]; v- erb B: stained positive in eight cases [34.78%]). This study suggests that these factors seem to have some role in the progression of colon neoplasms. It suggests that genetic alteration is not always equal to the overexpression of protein products, but that it reflects them well, and that the staining makes some contribution to differential diagnosis in colorectal neoplasms.     

Epithelioid leiomyosarcoma of the external deep soft tissue

Epithelioid leiomyosarcoma in the external deep soft tissue is extremely rare. Most epithelioid leiomyosarcomas occur in the uterus. We present a case of epithelioid leiomyosarcoma occurring in the muscle of the thigh of a 78-year-old man. Histologically, the tumor predominantly consisted of round or polygonal cells arranged in sheets with a focal spindle cell component. Immunohistochemical analysis revealed that the tumor cells expressed vimentin, alpha-smooth muscle actin, and alpha-sarcomeric actin. The tumor was negative for desmin, S100 protein, glial fibrillary acidic protein, pan-keratin, epithelial membrane antigen, CAM 5.2, HMB-45, leukocyte common antigen, factor VIII-associated antigen, and CD34. Electron microscopically, some tumor cells contained abundant actin-type filaments in their cytoplasm.     

Gonadotropin-releasing-hormone (gn-rh) receptor in the reproductive-tract tumor - physiological-role and signal-transduction pathway

Gonadotropin-releasing hormoen (Gn-RH) analogs have been used in the therapy of the endocrine-dependent cancers including the repductive tract-originated tumors. Gn-RH receptor and its transmembrane signaling pathways have been demonstrated in a high proportion of these tumors. The demonstration of existence of receptors for a hormone can better predict hormonal dependency, and might be a first step towards an effective hormonal treatment. These findings suggest the merit of further therapeutic investigations of Gn-RH analogs alone or in combination with traditional therapies in the management of Gn-RH receptor-positive tumors.     

A new membrane-attack complex/perforin (MACPF) domain lethal toxin from the nematocyst venom of the Okinawan sea anemone Actineria villosa.

The Okinawan sea anemone Actineria villosa causes severe cases of stinging. We isolated the 60 kDa A. villosa toxin (AvTX-60A) as the major toxin from the isolated nematocysts of this species. AvTX-60A showed fatal toxicity to mice with intraperitoneal injection at a minimum lethal dose of less than 250 microg/kg. The N-terminal amino acid sequence was determined and the corresponding cDNA encoding AvTX-60A was sequenced. The deduced amino acid sequence of AvTX-60A showed high similarity with PsTX-60A, which had been isolated as one of the major toxins from the venomous sea anemone Phyllodiscus semoni. These sea anemone toxins are new members of the family of proteins containing membrane-attack complex/perforin (MACPF) domains, best known in pore forming proteins such as perforin. These are the first examples of MACPF domain proteins as toxins for prey acquisition or repelling predators in nature.