Hidehiro Mori

Peritoneal Fluid lnterleukin‐1β and Tumor Necrosis Factor in Patients With Benign Gynecologic Disease

ABSTRACT: The levels of interleukin 1β (IL‐1β) and tumor necrosis factor (TNF) in peritoneal fluid (PF‐IL‐1β and PF‐TNF) and production of IL‐1β and TNF by peritoneal macrophages were determined in patients with benign gynecologic disease. The level of PF‐IL‐1β was elevated in the acute pelvic inflammatory disease (PID) and stages I and II endometriosis (E I/II) groups compared with the normal pelvis group, but not in the myoma of the uterus, ovarian cyst, and postinflammatory pelvic adhesion groups. The level of PF‐TNF was elevated in the PID, EI/II and stages III and IV endometriosis (EIII/IV) groups. There was no correlation between the levels of PF‐IL‐β and PF‐TNF. Neither the level of PF‐IL‐β nor that of PF‐TNF was correlated with the concentration of peritoneal macrophages. Peritoneal macrophages produced IL‐1β and TNF in vitro in the absence of stimulants. The levels of PF‐IL‐1β and PF‐TNF are presumably linked to the activation of peritoneal macrophages.

Expression of interleukin-1 (IL-1) beta messenger ribonucleic acid (mRNA) and IL-1 receptor antagonist mRNA in peritoneal macrophages from patients with endometriosis

OBJECTIVE To investigate the expression of interleukin-1 (IL-1) beta messenger ribonucleic acid (mRNA) and IL-1 receptor antagonist (IL-1ra) mRNA in peritoneal macrophages. DESIGN, SETTING Peritoneal fluid (PF) samples were collected from patients who underwent laparoscopy or laparotomy. Northern blot analysis was performed at the reproductive research laboratory. PATIENTS Twenty-six patients with endometriosis, 10 patients with postinflammatory pelvic adhesion, and 12 control women with normal pelvis. MAIN OUTCOME MEASURE Polyadenylated RNA isolated from peritoneal macrophages was analyzed on Northern blots by using synthetic oligonucleotide probes. RESULTS The level of IL-1 beta mRNA expression was elevated in the group with stage I endometriosis, whereas the increased expression of IL-1ra mRNA was observed in the group with stages III and IV endometriosis. The level of IL-1 beta mRNA showed a positive correlation with that of IL-1 beta in PF and a negative correlation with the level of IL-1ra mRNA. CONCLUSIONS Our results suggest that peritoneal macrophages express IL-1ra mRNA rather than IL-1 beta mRNA with the progress of endometriosis and that peritoneal macrophages may secrete IL-1ra protein that modulates the effects of IL-1.

Danazol Suppresses the Production of Interleukin-1β and Tumor Necrosis Factor by Human Monocytes

ABSTRACT: The effects of estradiol (E2), progesterone (P), and danazol on the production of interleukin‐1β (IL‐1β) and tumor necrosis factor (TNF) by OK‐432 (a streptococcal preparation)‐stimulated monocytes were examined. E2 and P at physiologic concentrations enhanced IL‐1β and TNF production by monocytes from donors with lower control levels (without steroids added) of IL‐1β and TNF. However, E2 and P at physiologic concentrations did not affect IL‐1β and TNF production by monocytes from donors with higher control levels of IL‐1β and TNF. Danazol inhibited IL‐1β and TNF production by monocytes in a dose‐dependent manner from not only donors with lower control levels of IL‐1β and TNF but also donors with higher control levels of IL‐1β and TNF. Danazol at a concentration of 10−6 M significantly suppressed IL‐1β and TNF production in the presence of E2 and/or P at concentrations giving peak responses of IL‐1β production. These findings suggest possible new mechanisms of action for danazol in the treatment of endometriosis and infertility associated with immune abnormalities.

Inhibitory effects of non-steroidal anti-inflammatory drugs, piroxicam and indomethacin on 4-nitroquinoline 1-oxide-induced tongue carcinogenesis in male ACIN rats

The effects of the non-steroidal anti-inflammatory drugs (NSAIDs), piroxicam and indomethacin on 4-nitroquinoline 1-oxide-(4-NQO)-induced tongue carcinogenesis in male ACI/N rats were examined. Rats were given 4-NQO (10 ppm) in the drinking water for 12 weeks and followed by either diet containing 150 ppm piroxicam or the drinking water containing 10 ppm indomethacin for 24 weeks. The incidence of tongue neoplasms (squamous cell papilloma and carcinoma) in rats given 4-NQO plus piroxicam (4/13, 31%) and those given 4-NQO plus indomethacin (3/13, 23%) were significantly lower than that of animals given 4-NQO alone (12/17, 71%) (P less than 0.05 and P less than 0.005). Rats given piroxicam or indomethacin alone had no neoplasms in the tongue. Thus, piroxicam and indomethacin significantly inhibited the development of tongue neoplasms in male ACI/N rats.

Localization of Bax and Bcl-2 proteins, regulators of programmed cell death, in the human central nervous system

Bax and Bcl-2 proteins are identified as regulating molecules for programmed cell death. In the central nervous system, programmed cell death or apoptosis is considered to be an important phenomenon that is related to neuron vulnerability to a variety of toxic effects, including ischaemic insult. In this study, localization of Bax and Bcl-2 proteins was investigated in the human central nervous system using autopsy cases without any neurological disorder. Results were compared with findings in the rat. Most neurons in human cerebral cortex, basal ganglia and brain stem were positive for both Bax and Bcl-2 proteins, whereas Purkinje cells in cerebellum and neurons in hippocampal CA1, CA2 and CA3 regions were positive for Bax but negative or weakly positive for Bcl-2. Glial cells examined in all sections were negative for both proteins. Choroid plexus, ependymal cells and arachnoid villi showed positive reactivity for both proteins. A possible relationship between the localization of Bax or Bcl-2 proteins and the cell vulnerability in central nervous system is discussed.

Enhancing effects of estrogens on endometrial carcinogenesis initiated by N-methyl-N-nitrosourea in ICR mice

The present study was undertaken to examine the effects of estrogens, such as estrone (E1), 17β‐estradiol (E2) and estriol (E3), on endometrial Carcinogenesis initiated by N‐methyl‐N‐nitrosourea (MNU) in mice. A total of 120 female ICR mice received MNU solution (1 mg/100 g body wt.) and normal saline at 10 weeks of age into their left and right uterine corpora, respectively. One week later, they were divided into four groups and treated as follows: Group 1 (30 mice) was given 25 ppm E1‐containing diet; Group 2 (30 mice) was fed 5 ppm E2‐containing diet; Group 3 (30 mice) was given 25 ppm E3‐containing diet; and Group 4 (30 mice) was fed the basal diet alone. At the termination of the experiment (Week 30), all surviving animals were autopsied and histopathological examinations revealed that endometrial adenocarcinomas had developed in all groups. The incidence of adenocarcinomas in the MNU‐treated uterine corpus in Group 1 (25 ppm E1‐feeding, 9/23, 39%) was significantly higher than that in Group 4 (basal diet, 3/26, 12%, P<0.05). Also, the incidences of adenocarcinomas in the MNU‐treated uterine corpus in Groups 2 (5 ppm E2‐feeding, 8/24, 33%) and 3 (25 ppm E3‐feeding, 7/26, 28%) were higher than in Group 4, but the difference was not statistically significant. Feeding of diet containing E1, E2 and E3 increased the incidences of the preneoplastic endometrial lesions (atypical, adenomatous or cystic glandular hyperplasia). In the uterine cervix, small numbers of squmous cell carcinomas, dysplasias or hyperplasias were occasionally found in all groups. These results indicate enhancing effects of the above three types of estrogens on the endometrial carcinogenesis induced by MNU in ICR mice.

Inhibitory effect of 5-hydroxy-4-(2-phenyl-(E)-ethenyl)-2(5H)-furanone, a novel synthesized retinoid, on azoxymethane-induced intestinal carcinogenesis in rats

Modifying effects of 5-hydroxy-4-(2-phenyl-(E)-ethenyl)-2(5H)-furanone, a novel synthesized retinoid (KYN-54), on intestinal carcinogenesis were examined in a rat model using azoxymethane (AOM). A total of ninety male F344 rats, 6 weeks old, were divided into 4 groups. Group 1 (20 rats) was fed a diet containing KYN-54 at a concentration of 0.02% for 3 weeks, during which time 2 s.c. injections of azoxymethane (15 mg/kg) were applied and then kept on a basal diet until the end of the experiment (1 year). Group 2 (30 rats) was given azoxymethane as in group 1 and fed the basal diet throughout, without synthetic retinoid exposure. Group 3 (20 rats) was administered KYN-54 at the commencement of the experiment, but not given the carcinogen. Group 4 (20 rats) received a basal diet alone throughout the experiment and served as a control. Intestinal tumors were seen in groups 1 and 2, their incidence and average number in group 1 (74%, 1.07 +/- 0.87) being significantly less than in group 2 (39%, 0.56 +/- 0.78) (P < 0.02 and P < 0.05, respectively). These results suggest that the synthetic retinoid might be a promising chemopreventive agent for intestinal neoplasia.

Decrease in interferon-γ production by peripheral blood mononuclear cells in patients with uterine cervical cancer

The interferon-γ (IFN-γ) productivity of peripheral blood mononuclear cells (PBMCs) was examined in 30 patients with uterine cervical cancer. The patients under 50 years of age had decreased IFN-γ production compared with the age-matched controls. The IFN-γ productivity in the patients over 50 years of age was decreased as well as in the age-matched controls. The proportion of monocytes in PBMCs did not correlate with the IFN-γ productivity. The prostaglandin E2 (PGE2) productivity of PBMCs increased with the progress of cancer. PGE2 inhibited the IFN-γ production by PBMCs, and the sensitivity of PBMCs to PGE2 was increased in the patients and controls over 60 years of age. The addition of indomethacin resulted in an increase in IFN-γ production by PBMCs. These results suggest that the increased production of PGE2 and/or increased sensitivity to PGE2 are responsible for the decreased IFN-γ production in patients with cervical cancer.

Extra-adrenal pheochromocytoma-ganglioneuroma. A case report.

A case of rare extra-adrenal tumor composed of pheochromocytoma-ganglioneuroma which developed in a 48-year-old Japanese male is reported. Histologically, the tumor contained equal proportion of two distinct patterns, pheochromocytoma and ganglioneuroma. Immunohistochemical examination revealed that pheochromocytoma cells were positive for Leu-7 and ganglion cells in ganglioneuroma were positive for vasoactive intestinal peptide (VIP), respectively. Neuron specific enolase (NSE) was positive in the neoplastic cells of both components, and S-100 protein was also positive in fibers around ganglion cells. Ultrastructural examination revealed that neurosecretory granules were present in the neoplastic cells.

Estrogen binding sites in peripheral blood monocytes and effects of danazol on their sites in vitro

1. This study was designed to investigate the presence of estrogen type I (high affinity, low capacity) and type II (low affinity, high capacity) binding sites in human peripheral blood monocytes and the effects of danazol on these sites. 2. These two types of estrogen binding sites existed in human peripheral blood monocytes. 3. Danazol bound to these sites in high concentration (10(-6) M, clinical serum concentration during danazol therapy) and decreased the number of both sites. 4. It is suggested that danazol has an anti-estrogenic action to the monocytes through the competition and suppression of estrogen binding sites as seen in the estrogen target organ.