Kiyoshi Sakamoto

Elevation of circulating interleukin 6 after surgery: Factors influencing the serum level

To investigate the effect of surgical trauma and other factors on the postoperative elevation of serum interleukin 6 (IL-6), we examined changes in IL-6 concentration after major thoracoabdominal surgery. Serum IL-6 levels reached the maximum concentration on the first postoperative day in all 38 patients, with peak ranging from 1400.8 +/- 383.4 pg/ml (mean +/- SEM) to 29.8 +/- 3.8 among six groups who underwent surgery at different sites. The IL-6 peak was significantly correlated with surgical trauma as defined by the operation length and the volume of blood loss during surgery (r = 0.554, P < 0.01 and r = 0.427, P < 0.01, respectively). The peak concentration of serum IL-6 in patients undergoing esophagectomy was significantly higher than in those undergoing pancreaticoduodenectomy (P < 0.05), despite a similar degree of surgical trauma defined by the operation length and volume of blood loss during surgery. Peak IL-6 concentration observed in a patient who underwent esophagectomy was about 100-fold greater in fluid drained from the thorax than in the peripheral blood. IL-6 mRNA was demonstrated in leukocytes from thoracic and abdominal exudate at 6, 24 and 48 h after surgery. In contrast, IL-6 mRNA could not be detected in leukocytes from the peripheral blood. Similar findings were also observed for interleukin 8 (IL-8). However, interleukin 1 beta (IL-1 beta) and tumour necrosis factor-alpha (TNF-alpha) were detected only once after surgery in the drainage fluid.(ABSTRACT TRUNCATED AT 250 WORDS)

Inhibition of stress-induced gastric injury in the rat by glutathione

Glutathione metabolism occurs via interorgan cycles in which hepatic synthesis of reduced glutathione and its transfer to extrahepatic tissues play an important role. To elucidate the physiologic significance of the cycles and tissue thiol status during stress-induced gastric mucosal injury, dynamic aspects of glutathione metabolism were analyzed in rats that were treated with water-immersion restraint. This treatment induced gastric mucosal lesion with concomitant decrease in the levels of perchloric acid-soluble thiols in various tissues, particularly in the liver and stomach. During the treatment, glutathione levels markedly decreased in the liver but not in other tissues. Depletion of hepatic glutathione by buthionine sulfoximine, a specific inhibitor for gamma-glutamyl cysteine synthetase, markedly decreased hepatic glutathione levels and increased the gastric injury. Intraperitoneal injection of reduced glutathione significantly increased plasma levels of glutathione and inhibited the occurrence of gastric injury without affecting intracellular glutathione levels. These results indicate that extracellular glutathione and its interorgan metabolism might play a critical role in the protection of gastric mucosa particularly when animals were challenged with various stress.

Group II phospholipase A2 is increased in peritoneal and pleural effusions in patients with various types of cancer

Serum levels of group II phospholipase A2 (PLA2) have been reported to be associated with stage of disease in cancer patients. These levels are also related to the malignant potential in tissues, and are an important prognostic factor. We radioimmunoassayed group II PLA2 levels in pleural and peritoneal effusions from patients with various cancers. We also investigated the production of group II PLA2 in cells in effusions from cancer patients by Northern blotting, immunocytochemistry and in situ hybridization. Immunoreactive group II PLA2 levels were significantly higher in effusions from 47 patients with various cancers, compared with those in sera and cirrhotic ascites. There was no significant correlation between group II PLA2 levels in effusions and those in sera. Group II PLA2 mRNA was expressed at a high level in cells from effusions, by Northern blot analysis, but not in those cells from blood. The localization of group II PLA2 protein and mRNA was intense in carcinoma cells and CD68‐positive macrophages, determined by immunocytochemistry and in situ hybridization. In addition, IL‐6 and IL‐8 levels were significantly higher in effusions, in comparison with those in sera from patients, suggesting that cancer cells and macrophages produce group II PLA2 by IL‐6. These group II PLA2 levels are apparently significantly increased in effusions, and the carcinoma cells and macrophages produce group II PLA2, as noted in effusions from patients with various cancers. Int. J. Cancer 74:245‐250, 1997.

Increased expression of membrane-associated phospholipase A2 shows malignant potential of human breast cancer cells

Background. Recently, the authors reported that membrane‐associated phospholipase A2 (M‐PLA2) was one of the acute phase reactants and increased in serum of patients with various malignant tumors.

Evaluation of Serum CA125 Values in Healthy Individuals and Pregnant Women

CA125 is an antigenic determinant associated with human epithelial ovarian carcinoma. This study was undertaken to evaluate the distribution of serum CA125 levels and the effect of smoking on these levels among healthy individuals and clarify the relation of maternal serum CA125 level and pregnancy. Among 552 healthy individuals, the distribution of serum CA125 values was demonstrated to resemble logarithmic normal distribution. Analysis of variance about age and sex revealed apparent elevation of values for women under 49 years of age in comparison with those for women over 50 years of age and men. Values for these two groups were 143 units/ml for the former and 32 units/ml for the latter, with a 99.7% confidence limit. These values exclude 99.3% of the former and 99.7% of the latter. Serum CA125 values were not affected by smoking. The measurement of serum CA125 levels in 71 pregnant women disclosed a significant elevation during the first trimester in comparison with non-pregnant women under 49 years of age. These results indicate that CA125 values must be deliberatively evaluated in young women, especially during first trimester of pregnancy.

Clinical Significance of Serum CA125 Values in Patients with Cancers of the Digestive System

A study of 347 patients with gastrointestinal diseases revealed elevation of CA125 in sera of 63% of patients with pancreatic carcinoma, 46% of patients with carcinoma of the biliary tract, 40% of patients with liver carcinoma and 11–37% of patients with other carcinomas. All of the patients with acute pancreatitis, chronic pancreatitis, cholelithiasis, and peptic ulcer had normal CA125 values, but 35% of patients with liver cirrhosis and 10% of patients with chronic active hepatitis had elevated values. Patients with disseminated carcinomas had significantly higher levels than patients with localized carcinomas. CA125 did not significantly correlate with CA19–9 or carcino-embryonic antigen in patients with pancreatic carcinoma. Ninety-seven percent of patients with pancreatic carcinoma were defined as being positive when both serum CA125 and CA19–9 were evaluated. These results indicate that CA125 is useful for differentiating pancreatic carcinoma from chronic pancreatitis, especially when supplemented with CA19–9.

The ratio of neutrophils to lymphocytes and the phenotypes of neutrophils in patients with early gastric cancer

Abstract We examined 55 patients (40 male, 15 female) who were diagnosed from 1987 to 1991 as having early gastric cancer (EGC) stage I according to the general rules of classification of the Japanese Research Society for Gastric Cancer. Of the 55 patients, 42 (30 male, 12 female) were alive in April 1992. The prognosis correlated well with the ratio of neutrophils to lymphocytes (N/L ratio) but not with the total number of white blood cells in the peripheral blood. The patients were divided into two groups according to their N/L ratio. Of the 29 patients with an N/L ratio less than 2, 27 were alive in 1992, whereas only 15 of the 26 patients with an N/L ratio of 2 or more were alive (χ2 analysis, P = 0.0022). We further examined the phenotypes of neutrophils from 29 other patients with EGC at the time of diagnosis before surgical operation. These patients were divided into two groups: 17 patients with a low N/L ratio (less than 2) and 12 patients with a high N/L ratio (2 or more). CD10 and CD35 expressions on neutrophils from the patients with a low N/L ratio were lower than those from the patients with a high N/L ratio. The N/L ratio correlated well with both CD10 and CD35 expression, whereas no correlation was observed between the numbers of neutrophils and the expression of these phenotypes. The respiratory burst of neutrophils from the patients with a high N/L ratio was higher than that of neutrophils from the patients with a low N/L ratio, though there was no correlation in the phagocytic activity between both groups. It was thus suggested that the heterogeneity of neutrophils is, at least partly, related to the prognosis of patients with EGC.

Elevation of serum group II phospholipase A2 levels in patients with advanced cancer

To investigate the role of group II phospholipase A2 (M-PLA2) in cancer, we examined M-PLA2 serum levels in 170 pre-operative patients with various cancers and found elevated levels in 49% of them. M-PLA2 serum levels were significantly higher in patients with tumor stages T2-4, N1, M1 and stages II to IV than in T1, N0, M0 and stage I tumors, respectively. In all nine post-operative patients tested, M-PLA2 decreased 14 days after tumor resection and reduced to normal levels in 4 patients. Six of 16 carcinoma cell lines (37.5%) spontaneously secreted M-PLA2 into the culture supernatant despite the absence of IL-6 and IL-1 in 5 of the 6 lines. These results demonstrate that M-PLA2 produced by cancer cells may contribute, at least in part, to the elevation of serum M-PLA2 levels observed in cancer patients.

Interleukin-8 is constitutively and commonly produced by various human carcinoma cell lines

SummaryWe examined the production of interleukin-8 and interleukin-6 by 30 human carcinoma cell lines. Serum levels of interleukin-8 were measured in 14 patients with hepatocellular carcinoma by enzyme-linked immunosorbent assay and Northern blotting. Furthermore, serum interleukin-8 was also investigated in a nude mouse bearing a tumor of the HuH7 hepatoma cell line producing interleukin-8. Of the 30 cell lines, 29 (96.7%) constitutively produced interleukin-8, and 19 of the 29 (65.5%) were high producers (>1 ng/ml culture supernatant). Among the high producers, 4 cell lines released both interleukin-8 and interleukin-6. Interleukin-6 was constitutively produced by 17 of the 30 (56.7%) cell lines, 4 of which (23.5%) were high producers (>1 ng/ml). By Northern blot analysis, mRNAs of interleukin-8 and interleukin-6 were detected in producing cell lines. Of 14 patients with hepatocellular carcinoma, 4 (28.5%) showed increased levels of serum interleukin-8. Furthermore, inoculation of the HuH7 hepatoma cell line which produced the highest amount of interleukin-8 into a nude mouse resulted in tumor production accompanied by an elevated level of human interleukin-8 (646 pg/ml) in the peripheral blood. Thus, interleukin-8 is constitutively and commonly produced by various carcinoma cell lines. The production of interleukin-8 by carcinoma cells may be related to the elevation of serum interleukin-8 in patients with hepatocellular carcinoma. Finally, these cell lines may be valuable for studying the relationship between interleukin-8 and cancer.

Leukemia inhibitory factor induces apoptosis and proliferation of human carcinoma cells through different oncogene pathways

Leukemia inhibitory factor (LIF) affects the growth of carcinoma cells, and we thus analyzed its underlying mechanisms. Carcinoma cells constitutively express LIF mRNA, and 23 lines (92.0%) and all (100%) of 25 lines express LIF receptor mRNAs of LIFRβ and gp130, respectively. Exogenous addition of LIF promoted significant cell proliferation in 4 lines (MCF‐7, ZR‐75‐1, Hs‐700T and Panc‐1) and suppressed cell growth in 3 lines (AZ‐521, GBK‐1 and HT‐29). LIF significantly induced an immediate early response of genes c‐fos and junB 3 hr after stimulation, but not of c‐jun during the process of proliferation of MCF‐7 and Hs‐700T cells, with maximum levels at 30–60 min. The cell‐cycle‐related gene cyclin E was also induced in MCF‐7 and Hs‐700T cells, whereas cyclinA, cdk2, c‐myc, c‐myb and p53 mRNAs were not induced. On the other hand, LIF inhibited growth and increased the rate of cell death of AZ‐521 and GBK‐1 cells. LIF increased the number of TUNEL‐positive cells in AZ‐521 cells and DNA fragmentation in AZ‐521 and GBK‐1 cells. LIF induced apoptosis related genes c‐myc and ICE during suppression of cell growth, but p53, p21, c‐fos, cyclin A and cyclin E were not induced. Our results suggest that LIF is linked to cell proliferation and apoptosis in some human carcinoma cell lines. It is considered that this is related to differences in signal transduction and induction of oncogenes. Int. J. Cancer 72:687–695, 1997.