Menstrual- and gender-dependent variations in circulating IL-1 agonists, antagonists, and binding proteins.

This study tested the hypotheses that sex-related differences in circulating binding proteins for interleukin- 1beta (IL- 1beta ) exist and that these binding proteins affect immunoassays for IL-1beta and IL-1Ra. 125I-labeled IL-1beta was added to human plasma samples, then chromatographed. The percentages of total radioactivity eluting in a high-molecular-weight peak were 21.0 + 0.8 for men (n = 6), 19.1+/-0.9 for follicular phase women (n = 6), and 18.0+/-0.8 in luteal phase women (n = 6; men vs. women, P = 0.032; follicular vs. luteal, P = 0.035), and correlated with plasma sIL-1RII concentrations (r = 0.647, P = 0.007). Plasma IL-1beta immunoreactivity did not correspond to concurrent cellular secretion rates due, in part, to interference in the IL-1beta assay by sIL-1RII. Correspondence between plasma IL-1Ra levels and cellular secretion rates was observed only after serial dilutions of the samples. These results indicate that plasma IL-1beta binding capacity differs between men and women and that sIL-1RII is a major contributing factor. Furthermore, relating plasma IL-1 isoform immunoreactivity to functional measures (tracer binding) or concurrent release by isolated cells can lead to insights about assay interferences that may exist in plasma.

Gender differences in IL-1 alpha, IL-1 beta, and IL-1 receptor antagonist secretion from mononuclear cells and urinary excretion.

Previous studies have reported increased secretion of IL-1-like activity from mononuclear cells and increased circulating levels during the luteal phase of the menstrual cycle. In this investigation, specific RIAs for the agonists IL-1 alpha and IL-beta as well as IL-1 receptor antagonist (IL-1Ra) were used to determine whether differential IL-1 secretory patterns exist between men and women or between phases of the menstrual cycle. Mononuclear cells were isolated from six men and five women at 4-h intervals from 8 am to 8 pm, with the women studied once in midfollicular phase and once in midluteal phase. In the absence of any intentional stimulation, significant differences in secretion were observed between groups (p < 0.03) for all three species of IL-1: women's cells isolated during the luteal phase secreted 5- to 10-fold more than cells from men, and women's cells isolated during the follicular phase secreted 13- to 28-fold more than cells from men. In addition, total 24-h urine samples were collected in intervals with end points coinciding with the blood samples. Urinary excretion correlated with cellular secretion for IL-beta and IL-1Ra (p = 0.024 and 0.028, respectively), indicating that the in vitro results may correspond to differential processes occurring in vivo. Although greater absolute amounts of each species of IL-1 were secreted during the follicular phase, the ratio of agonist to antagonist secreted was greater in the luteal phase (p < 0.05), in agreement with previous studies of bioactivity. These results indicate that the regulation of IL-1 secretion is fundamentally different in women compared with men and alludes to the possibility that IL-1 may serve different biologic functions in women than men.

Are events after endotoxemia related to circulating phospholipase A2?

OBJECTIVE: The authors sought to determine whether the signs and symptoms of endotoxemia were related to the endotoxin-stimulated increase in circulating phospholipase A2 (PLA2) activity. BACKGROUND: Because hypotension and pulmonary injury have been associated with elevated PLA2 activity in septic shock and PLA2 levels are reduced with the administration of glucocorticoids, the PLA2 response to endotoxin was investigated in volunteers pretreated with and without hydrocortisone. METHODS: Carefully screened human subjects were studied under four conditions: (1) saline, (2) hydrocortisone, (3) endotoxin, and (4) hydrocortisone administration before endotoxin exposure. Pulse rate, blood pressure, temperature, and symptoms of endotoxemia were serially measured. Plasma for tumor necrosis factor concentrations and PLA2 activity was obtained. RESULTS: After lipopolysaccharide, pulse rate and tumor necrosis factor concentrations rose at 1 to 2 hours; temperature increased maximally at 4 hours. PLA2 activity reached peak levels at 24 hours. With hydrocortisone pretreatment, a 50% reduction in the concentrations of tumor necrosis factor and PLA2 occurred. Significant correlations between other variables and PLA2 activity were not observed. The enzyme identified by monoclonal antibody was the secreted nonpancreatic PLA2 (SNP-PLA2). CONCLUSIONS: The results of this study suggest that elevations in circulating SNP-PLA2 activity and systemic events associated with intravenous endotoxin administration are unrelated.

Hematologic and immunomodulatory effects of an interleukin-1 receptor antagonist coinfusion during low-dose endotoxemia in healthy humans.

Endotoxin is a component of gram-negative bacteria that causes hematologic and immunologic changes through its induction of cytokines. Interleukin-1 receptor antagonist (IL-1Ra) is a naturally occurring inhibitor of IL-1 that competes with IL-1 for occupancy of cell-surface receptors but possesses no agonist activity. We investigated the ability of human recombinant IL-1Ra to block the effects of low-dose endotoxin. Fourteen healthy male volunteers between 18 and 30 years old were injected intravenously with 3 ng/kg Escherichia coli endotoxin. Concurrent with the injections, nine volunteers received a 3-hour continuous intravenous infusion of IL-1Ra. The other five subjects were given a 3-hour infusion of saline. Volunteers injected with endotoxin experienced a threefold increase in circulating neutrophils over baseline. This neutrophilia was significantly reduced by 48% in subjects administered endotoxin plus IL-1Ra (P = .0253). Ex vivo mitogen-induced peripheral blood mononuclear cell proliferation decreased by greater than 60% at 3 and 6 hours after endotoxin injection (P = .0053). This endotoxin-induced reduction in mitogen response was reversed in subjects coinjected with IL-1Ra (P = .0253). Endotoxin-induced symptoms, fever, and tachycardia were unaffected by IL-1Ra. IL-1 appears to be an important mediator in endotoxemia because some of its hematologic and immunomodulatory effects can be blocked by IL-1Ra.

Intravenous endotoxin suppresses the cytokine response of peripheral blood mononuclear cells of healthy humans.

When administered parenterally, endotoxin stimulates the synthesis of IL-1, TNF-alpha, and IL-6. However, this initial injection induces tolerance; a second injection of endotoxin results in lower levels of circulating cytokines. In our study, five healthy male volunteers between the ages of 18 and 30 were injected with Escherichia coli endotoxin. Four subjects received only saline. Immediately before the injection and 3, 6, and 24 h afterward, PBMC were isolated and stimulated in vitro with endotoxin, IL-1, or toxic shock syndrome toxin-1. Inasmuch as CD14+ monocytes are the primary source of the cytokines induced by these stimuli, results are expressed as cytokine production per 10(6) CD14+ cells. Six h after endotoxin injection, endotoxin-stimulated CD14+ cells synthesized 66% less IL-1 beta (p < 0.01), 47% less TNF-alpha (p < 0.001), 56% less IL-6 (p < 0.01), and 49% less IL-8 (p < 0.01) than cells obtained before the injection. This suppression was not specific for endotoxin; IL-1 beta-induced IL-1 alpha and TNF-alpha were reduced by 84% (p = 0.01) and 68% (p < 0.001), respectively. A decrease in cytokine synthesis was also observed using toxic shock syndrome toxin-1 as a stimulus: 57% for IL-1 beta (p = 0.06), 70% for TNF-alpha (p < 0.01), 56% for IL-6 (p < 0.05), and 71% for IL-8 (p = 0.001). When data were expressed as cytokine production per 10(6) PBMC, cells isolated 3 h after endotoxin injection synthesized significantly less stimulus-induced IL-1, TNF-alpha, IL-6, and IL-8 than did PBMC from saline-injected controls. We conclude that endotoxin tolerance is due, in part, to changes in the stimulus-induced cytokine response of circulating CD14+ cells.

Balance of synovial fluid IL-1 beta and IL-1 receptor antagonist and recovery from Lyme arthritis.

Borrelia burgdorferi, the causative agent of Lyme disease, is a potent inducer of interleukin-1 beta (IL-1 beta), a cytokine implicated in the pathogenesis of inflammatory arthritis. The balance between IL-1 and the IL-1 receptor antagonist (IL-1ra), a naturally occurring inhibitor of IL-1, might influence disease expression. To explore this possibility, we have done a retrospective study that compared the clinical course of Lyme arthritis in 83 patients with concentrations of IL-1 beta and IL-1ra in the patients' synovial fluid. Patients with high concentrations of IL-1ra and low concentrations of IL-1 beta had rapid resolution of attacks of arthritis, whereas patients with the reverse pattern of cytokine concentrations had long intervals to recovery. Thus, the balance between synovial fluid IL-1 beta and IL-1ra concentrations relates to the time to recovery from an episode of Lyme arthritis.

Translocation (9;22) is associated with extremely poor prognosis in intensively treated children with acute lymphoblastic leukemia.

The prognostic implications of t(9;22)(q34;q11) were assessed at a median follow-up of 3.5 years in 434 children receiving intensive treatment for acute lymphoblastic leukemia (ALL). Four-year event-free and overall survivals were 81% and 88%, respectively, in 419 children lacking t(9;22), but were 0% and 20%, respectively, in 15 children with t(9;22) (P less than .001). Poor outcome for children with t(9;22)-positive ALL was particularly notable because we have reported improved survival in other historically poor prognosis ALL cytogenetic categories when treated with similarly intensive therapy. We recommend that very intensive treatment approaches, including bone marrow transplantation in first remission, be considered for all children with t(9;22)-positive ALL.

Effects of fasting on luteinizing hormone dynamics in the male rat.

It is well known that reproductive function is impaired in humans and animals when nutrient intake is inadequate. Fasting, one of the most severe nutritional insults, has been used experimentally to identify the major effects of nutritional deficiencies on reproductive processes. In the rat, circulating reproductive hormone concentrations are reduced during fasting. Although decreased luteinizing hormone-releasing hormone (LHRH) secretion from the hypothalamus may be responsible for the lower serum concentrations of reproductive hormones, pituitary and testicular function of fasted rats have not been considered in detail. We studied the luteinizing hormone (LH) dynamics (storage, secretion, circulation and excretion) in the male rat to determine if fasting alters the responsiveness of the testes or the pituitary to hormonal stimulation. Our results indicate that after a 4-d fast: 1) serum LH and testosterone (T) concentrations are reduced (P less than or equal to 0.001); 2) hypothalamic LHRH, pituitary LH and follicle-stimulating hormone (FSH) concentrations are unaffected, but testicular T content is reduced (P less than or equal to 0.001); 3) urine output of LH and FSH are reduced (P less than or equal to 0.001); 4) in vitro and in vivo LH responses of the pituitary to LHRH are not affected; and 5) hCG-stimulated in vitro T production by the testis is not affected. These results are consistent with the hypothesis that fasting inhibits LHRH secretion.