Aspirin-induced increases in soluble IL-1 receptor type II concentrations in vitro and in vivo.

This study examined the influence of low-dose aspirin on interleukin (IL)-1alpha , IL-1 receptor antagonist (IL-1ra), and soluble receptor type II (sIL-1RII) secretion in vivo and in vitro. Blood mononuclear cells were isolated from healthy young men who ingested 81 mg of aspirin on alternate days for 2 weeks and from unmedicated controls. Aspirin had minor effects on ex vivo secretion of IL-1beta and no influence on IL-1ra. In contrast, unstimulated ex vivo secretion of sIL-1RII was over twice as high by cells from aspirin-treated subjects (1115+/-123 vs. 460+/-77 pg/mL, P = 0.02). Lipopolysaccharide-stimulated sIL-1RII secretion was influenced similarly. Plasma sIL-1RII concentrations were 23% higher in aspirin-treated subjects (10.2+/-0.6 vs. 8.4+/-0.3 ng/mL, P = 0.03). In addition, cells from unmedicated subjects cultured in vitro with aspirin (10 microg/mL) secreted significantly greater amounts of sIL-1RII. Thus, low-dose aspirin therapy may prevent inflammation by increasing soluble receptor secretion, thereby preventing IL-1 from binding target cells.

Examination of chlorpromazine and other amphipathic drugs on the activity of lipopolysaccharide antagonists, E5564 and E5531.

The synthetic antagonists of lipopolysaccharide (LPS), E5531 and E5564, are analogs of the lipid A portion of LPS that not only lack agonistic activity but also inhibit the biological effects of LPS both in vitro and in vivo. The effects of LPS and these synthetic antagonists have been localized to the recently described Toll-like receptor 4 (TLR4). A recent report indicated that the naturally occurring LPS antagonist Rhodobacter sphaeroides LPS loses its antagonist properties and gains pro-inflammatory qualities in the presence of chlorpromazine and other amphipathic drugs. To determine whether these reported actions occur with our chemically defined LPS antagonists, we examined the effects of chlorpromazine, fluphenazine, trifluoperazine, and lidocaine on the antagonism elicited by RsLPS and E5531 in U373 cells, which produce IL-6 in response to LPS. We also tested the effects of these amphipathic molecules on the LPS-neutralizing activity of RsLPS and E5564 on LPS-induced TNF-alpha release in human whole blood. The results indicate that neither chlorpromazine, fluphenazine, trifluoperazine nor lidocaine alter the activity of E5531 or E5564 in an in vitro cell system or human whole blood. Furthermore, chlorpromazine did not affect the antagonistic activity of RsLPS or E5564 on IL-6 generation by peripheral blood mononuclear cells. Thus, based on these data, our purified synthetic LPS-antagonists do not appear to lose their antagonistic properties and/or become agonists in the presence of amphipathic agents or drugs.

Interleukin-1/Toll receptor family members: receptor structure and signal transduction pathways.

Interleukin-1 (IL-1) is a central mediator of the inflammatory response. It plays a role in both systemic and local immune responses to invading microbes. There are two receptors (IL-1RI and IL-1RII) that mediate the cellular responses. These receptors belong to a family of receptors based on homologous receptor structure within the intracellular signaling domain. Other family members include the Drosophila protein Toll, the recently discovered mammalian Toll-like receptors (TLR), and the IL-18 receptor. Engagement of these receptors by their diverse ligands results in activation of very similar signal transduction cascades through use of common signaling intermediates. These signal transduction cascades lead to the activation of cellular responses that are known to regulate the innate immune response. Therefore, elucidating the function and redundancy of this receptor family is essential to the understanding of the innate immune response. This review examines each member of this receptor family and emphasizes similarities and potential differences in both receptor structure and signal transduction pathways to further the understanding of this complex receptor family.

The role of cholecystokinin in interleukin-1-induced anorexia.

Anorexia is a common response to infection which is thought to be mediated, at least in part, by interleukin (IL-1), an immunoregulatory peptide secreted by activated monocytes. Cholecystokinin (CCK) is a neuropeptide that suppresses food intake and gastric emptying when injected into healthy animals. There is increasing evidence of bidirectional interactions between neuropeptides, immune cell function, and secretion of immunoregulatory cytokines. Therefore, the present study was undertaken to determine if administration of L364,718 (L364), a CCK receptor antagonist, might block the anorexigenic effects of recombinant human IL-1 alpha (IL-1 alpha) in rats. We report that injection of IL-1 alpha significantly increased plasma CCK 1 h after injection, and decreased food intake and emptying of gastric contents. Pretreatment with 1 mg/kg L364 partially blocked the decrease in food intake and gastric stasis induced by IL-1 alpha. We conclude CCK may mediate, at least in part, IL-1 alpha-induced anorexia.

The role of prostaglandins in interleukin-1 induced gastroparesis.

Interleukin-1 is a small molecular weight peptide that is thought to mediate much of the acute phase response to infection, including fever and anorexia and gastric stasis. In the present study, we examined the effects of recombinant human IL-1 alpha (rhIL-1a) on food intake and gastric emptying, and the role of prostaglandins (PG) in IL-1 induced gastroparesis. We report that pretreatment with ibuprofen significantly improved food intake and gastric emptying in IL-1 injected rats, but did not return them to control levels. We conclude that PGs mediate, at least in part, IL-1 induced gastroparesis. The role of gastroparesis in IL-1 induced anorexia remains to be determined.

Macrophage migration inhibitory factor antagonizes hydrocortisone-induced increases in cytosolic IkappaBalpha.

Macrophage migration inhibitory factor (MIF) is an inflammatory cytokine secreted by several cell types, including mononuclear and pituitary cells. It has also been shown to counteract cortisol-induced inhibition of inflammatory cytokine secretion. The purpose of this study was to determine whether MIF antagonized the effect of hydrocortisone on the NF-kappaB/IkappaB signal transduction pathway in lipopolysaccharide (LPS)-stimulated human peripheral blood mononuclear cells. Physiological doses of hydrocortisone (50-200 ng/ml) diminished both the LPS-stimulated decrease in cytosolic IkappaBalpha levels and the subsequent increase in nuclear NF-kappaB DNA binding. In the presence of both LPS and hydrocortisone, 1 ng/ml of MIF antagonized the effects of hydrocortisone, resulting in decreased cytosolic IkappaBalpha levels (P < 0.05) and increased nuclear NF-kappaB DNA binding (P < 0.05). In the absence of hydrocortisone, MIF had no effect on LPS-induced decreases in IkappaBalpha. In the absence of LPS, MIF inhibited hydrocortisone-induced increases in IkappaBalpha (P = 0.03). Thus the mechanism by which MIF antagonizes the effect of hydrocortisone on the NF-kB/IkappaB signal transduction pathway is through inhibiting the ability of hydrocortisone to increase cytosolic IkappaBalpha.

The effect of diet consistency on food intake of anorectic tumor-bearing rats.

Delayed gastric emptying has been shown to occur in cancer patients complaining of anorexia and early satiety. Given that liquids are emptied from the stomach faster than solid food, the present study was undertaken to determine if diet consistency would affect food intake of hypophagic rats implanted with the Walker 256 carcinosarcoma. By Day 15 of tumor-growth, caloric intake of tumor-bearing animals was 20% less than controls. The caloric intake of tumor-bearing animals fed a liquid diet was not significantly different from animals fed a solid diet. Furthermore, a delay in gastric emptying was not seen in this animal model of tumor-induced anorexia.

The role of gastric stasis in tumor-induced anorexia in rats.

BACKGROUND: The current study was undertaken to determine if changes in gastric emptying contribute to tumor-induced anorexia. METHODS: Rats were implanted with the Walker 256 carcinoma, and food intake was measured daily. On days 0, 8, and 15, the rats were fasted overnight, gavage fed a bolus of liquid food, and residual gastric contents were measured 3 hours later. RESULTS: Tumor growth was associated with a progressive decline in voluntary food intake. When the rats were gavage fed 2.5 or 7 ml of liquid food, the percent of gastric contents cleared in 3 hours was unchanged with tumor growth. CONCLUSIONS: Changes in gastric emptying did not contribute to decreased food intake with growth of the Walker 256 in rats.

The effects of cyclooxygenase inhibitors on tumor-induced anorexia in rats.

BACKGROUND: Interleukin-1 (IL-1) and tumor necrosis factor (TNF) are potent induces of prostaglandin (PG) synthesis and injection of PGE, IL-1, or TNF decreases food intake in healthy animals, whereas the anorexigenic effects of injected IL-1 and TNF are blocked by inhibitors of PG synthesis. It has been hypothesized that host secretion of IL-1 and TNF contribute to tumor-induced anorexia. This study was undertaken to determine whether administration of PG inhibitors alters food intake in anorectic rats implanted with Walker 256 carcinoma. METHODS: Groups of six tumor-bearing rats were implanted with slow-release pellets containing ibuprofen, indomethacin, or acetylsalicylic acid. Food intake, tumor growth, and body temperature were monitored for 14 days and compared with control tumor-bearing animals implanted with placebo pellets. RESULTS: Tumor growth was associated with anorexia, fever, weight loss, and increased leukocyte secretion of IL-1 and TNF. Indomethacin and ibuprofen retarded tumor growth 30-40% and lowered body temperature compared with controls, but had no effect on food intake or body weight of tumor-bearing animals. CONCLUSIONS: Prostaglandins do not mediate tumor-induced anorexia.

Meperidine attenuates the febrile response to endotoxin and interleukin-1 alpha in rats.

Intravenous meperidine is commonly used to treat rigors and chills in febrile patients, though its mechanism of action is unknown. Therefore a laboratory model of pyrogen-induced fever was used to evaluate the effects of meperidine on the febrile response of rats injected with bacterial endotoxin or IL-1 alpha. Fever was measured using a computerized biotelemetry system for the continuous monitoring of body temperature. Injection of meperidine blocked the onset of fever in rats injected with endotoxin and attenuated the febrile response in rats injected with IL-1 beta. Furthermore, incubation of human mononuclear leukocytes (MNL) in the presence of meperidine significantly reduced endotoxin-induced secretion of IL-1 beta in vitro. These data suggest that meperidine decreases rigors and chills by decreasing the "set point" for fever, perhaps by reducing MNL secretion of IL-1 beta.

The effects of noise stress on leukocyte function in rats.

It has been reported that exposure to increased noise levels impairs wound healing in surgical patients and in rats. The purpose of the present study was to determine if exposure to noise stress would alter the biological function of neutrophils, macrophages, and lymphocytes, leukocytes that are involved in wound healing. Rats were exposed to 80 db of "rock" music for 24 hr, during which time the control animals were maintained in their usual environment. Leukocyte subpopulations were obtained and stimulated in vitro. Neutrophils and macrophages from noise-exposed animals secreted significantly less superoxide anion and interleukin-1 than cells from control animals. Lymphocyte function was not altered following noise stress. We conclude that short-term exposure of rats to noise stress alters some of the biological functions of leukocytes.

Glucocorticoid sensitivity of interleukin-1 agonist and antagonist secretion: the effects of age and gender.

Interleukin-1 (IL-1) is a primary mediator of inflammation that is regulated, in part, by the hypothalamic-pituitary-adrenal axis. The purpose of this study was to determine if gender- or age-related differences exist in the sensitivity of IL-1-producing cells to hydrocortisone. Peripheral blood mononuclear cells (PBMC) isolated from men and women (21-77 yr old) were incubated with hydrocortisone (0, 50, 100, 500, or 1,000 ng/ml) with or without lipopolysaccharide (LPS). Secretion of IL-1beta and IL-1 receptor antagonist was inhibited in a dose-dependent manner (P = 0.001) without age- or gender-related differences. Hydrocortisone decreased soluble IL-1 receptor type II (sIL-1RII) secretion by unstimulated cells (P = 0. 0001), but it increased secretion by LPS-stimulated cells (P = 0. 0001) in all groups. Unstimulated cell supernatants from men contained greater concentrations of sIL-1RII than the supernatants from women (P = 0.011). Compared with men, PBMCs from women were less responsive to hydrocortisone inhibition of sIL-1RII secretion, regardless of age (P = 0.001), and compared with the follicular phase, sIL-1RII secretion was lower in the luteal phase of the menstrual cycle (P < 0.05). These data indicate that basal secretion and glucocorticoid modulation of sIL-1RII secretion by cultured PBMCs are gender dependent. Moreover, glucocorticoid influences on sIL-1RII secretion depend on the presence or absence of gram-negative bacterial toxins.