This investigation examined the influence of hormone replacement therapy on plasma leptin concentrations in postmenopausal women and sought to determine if a relationship existed between plasma leptin, the thermoregulatory cytokine interleukin-1 (IL-1), and basal body temperature. Twenty-two women (54-71 years of age) were studied: eight were not taking hormone replacement, seven took oral estrogen only, and seven took oral estrogen plus progestin. Morning oral temperature, plasma leptin concentration, and mononuclear cell secretion of IL-1beta, IL-1 receptor antagonist (IL-1Ra), and soluble IL-1 receptor type II (sIL-1RII) were measured. Plasma leptin concentrations were not affected by hormone replacement therapy, but were inversely related to years since menopause (R = -0.48, P = 0.02) and were proportional to IL-1 activity (the balance of IL-1beta/IL-1Ra secretion, R = 0.69, P = 0.001). Moreover, morning oral temperature was positively related to plasma leptin (P = 0.03), after stratifying by progestin intake. These results support the concept that basal body temperature is regulated by a network of endocrine and immune mediators that are significantly influenced by age.

Hormone replacement therapy (HRT) reduces the risk for osteoporosis but transiently increases cardiovascular risk for some postmenopausal women. This study investigated the hypothesis that these risks are associated with HRT-induced changes in mononuclear cell secretion of interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-alpha), and associated soluble receptors. Compared to the untreated condition (n=8), estrogen therapy (n=7) and estrogen+progestin therapy (n=7) both caused 2-fold elevations in TNF-alpha secretion. IL-6 secretion was increased (48%, P=0.04) only by estrogen+progestin therapy. Although soluble receptor secretion was not different among groups, soluble TNF receptor type I and IL-6 receptor secretion were inversely related to plasma follicle stimulating hormone (P<0.05). Both therapies reduced plasma osteocalcin (a marker for osteoporosis) by approximately 50% (P<0.002). Plasma C-reactive protein (CRP, a marker for cardiovascular risk) was 3-fold higher in women receiving only estrogen, compared to untreated women (P=0.01), and twice as high as those receiving estrogen+ progestin (P=0.045). Simple linear relationships were not observed between cytokine secretion and these markers, but a significant HRT/TNF-alpha interaction with osteocalcin (P=0.022) and an HRT/IL-6 interaction with CRP (P =0.016) indicated more complex relationships between hormone replacement, cytokine activity, and health risks associated with menopause.

Daun, Jane M., and Joseph G. Cannon. Macrophage migration inhibitory factor antagonizes hydrocortisone-induced increases in cytosolic IkBa. Am J Physiol Regulatory Integrative Comp Physiol 279: R1043–R1049, 2000.—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-kB/IkB 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 IkBa levels and the subsequent increase in nuclear NF-kB DNA binding. In the presence of both LPS and hydrocortisone, 1 ng/ml of MIF antagonized the effects of hydrocortisone, resulting in decreased cytosolic IkBa levels (P , 0.05) and increased nuclear NF-kB DNA binding (P , 0.05). In the absence of hydrocortisone, MIF had no effect on LPSinduced decreases in IkBa. In the absence of LPS, MIF inhibited hydrocortisone-induced increases in IkBa (P 5 0.03). Thus the mechanism by which MIF antagonizes the effect of hydrocortisone on the NF-kB/IkB signal transduction pathway is through inhibiting the ability of hydrocortisone to increase cytosolic IkBa.

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.

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.

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.

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.

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.

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-1alpha) in rats. We report that injection of IL-1alpha 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-1alpha. We conclude CCK may mediate, at least in part, IL-1alpha-induced anorexia.

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.

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.

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.

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.

McCarthy, Donna O. RN, PhD; Ouimet, Mary E. RN, MSN; Daun, Jane M. BS Author Information