Showing papers by "Charles A. Dinarello published in 1988"

Detection of circulating tumor necrosis factor after endotoxin administration.

Abstract: Cytokines, products of stimulated macrophages, are thought to mediate many host responses to bacterial infection, but increased circulating cytokine concentrations have not been detected consistently in infected patients. We measured plasma concentrations of circulating tumor necrosis factor alpha (cachectin), interleukin-1β, and gamma interferon, together with physiologic and hormonal responses, in 13 healthy men after intravenous administration of Escherichia coli endotoxin (4 ng per kilogram of body weight) and during a control period of saline administration. Eight additional subjects received ibuprofen before receiving endotoxin or saline. Plasma levels of tumor necrosis factor were generally less than 35 pg per milliliter throughout the control period, but increased 90 to 180 minutes after endotoxin administration to mean peak concentrations of 240±70 pg per milliliter, as compared with 35±5 pg per milliliter after saline administration. Host responses were temporally associated with the in...

Biology of interleukin 1.

Abstract: Interleukin 1 (IL 1) is a polypeptide that is produced after infection, injury, or antigenic challenge. Although the macrophage is a primary source of IL 1, epidermal, epithelial, lymphoid, and vascular tissues synthesize IL 1. When IL 1 gains access to the circulation, it acts like a hormone and induces a broad spectrum of systemic changes in neurological, metabolic, hematologic, and endocrinologic systems. Some of the IL 1 that is synthesized remains associated with the plasma membrane and induces changes in local tissues without producing systemic responses. IL 1 affects mesenchymal tissue remodeling where it contributes to both destructive and repair processes. IL 1 activates lymphocytes and plays an important role in the initiation of the immune response. Receptors for IL 1 have been identified, but receptors are scarce and their affinities often do not match the potency of the biological response. The most consistent property of IL 1 is up-regulation of cellular metabolism and increased expression of several genes coding for biologically active molecules. IL 1 is a highly inflammatory molecule and stimulates the production of arachidonic acid metabolites. IL 1 also acts synergistically with other cytokines, particularly tumor necrosis factor. The multitude of biological responses to IL 1 is an example of the rapid adaptive changes that take place to increase the host's defensive mechanisms.

Interleukin 1 induces a shock-like state in rabbits. Synergism with tumor necrosis factor and the effect of cyclooxygenase inhibition.

Abstract: In addition to activating T and B lymphocytes, interleukin 1 (IL-1) induces several hematologic and metabolic changes typical of host responses to infection and injury. We now report a new biological property, namely, the induction of hypotension. Rabbits given a single intravenous injection of recombinant human IL-1-beta (5 micrograms/kg) rapidly developed decreased systemic arterial pressure, which reached the lowest levels after 50-60 min and slowly returned to pre-IL-1 values after 3 h. Associated with the hypotension, systemic vascular resistance and central venous pressure fell, while cardiac output and heart rate increased. These responses were prevented by ibuprofen given 15 min before the IL-1. A bolus injection of IL-1 followed by a 2-h infusion sustained the hypotension and was associated with leukopenia and thrombocytopenia. Ibuprofen given at the mid-point of the infusion reversed the changes in all hemodynamic parameters, but had no effect on the leukopenia or thrombocytopenia. Tumor necrosis factor (TNF) also induced a shock-like state in rabbits. When the dose of IL-1 or TNF was reduced to 1 microgram/kg, no hemodynamic changes were observed; however, the combination of these low doses of both cytokines resulted in a profound shock-like state including histological evidence of severe pulmonary edema and hemorrhage. Pretreatment with ibuprofen prevented the hemodynamic, leukocyte, and platelet changes induced by the low-dose cytokine combination, and ameliorated the pulmonary tissue damage. These results demonstrate that IL-1, like TNF, possesses the ability to induce hemodynamic and hematological changes typical of septic shock, and that the combination of IL-1 and TNF is more potent than either agent alone. These effects seem to require cyclooxygenase products, and suggest that intravenous cyclooxygenase inhibitors may be of therapeutic value in patients with IL-1/TNF-mediated shock.

Interleukin-1 immunoreactive innervation of the human hypothalamus

Abstract: Interleukin-1 (IL-1) is a cytokine that mediates the acute phase reaction. Many of the actions of IL-1 involve direct effects on the central nervous system. However, IL-1 has not previously been identified as an intrinsic component within the brain, except in glial cells. An antiserum directed against human IL-1 beta was used to stain the human brain immunohistochemically for IL-1 beta-like immunoreactive neural elements. IL-1 beta-immunoreactive fibers were found innervating the key endocrine and autonomic cell groups that control the central components of the acute phase reaction. These results indicate that IL-1 may be an intrinsic neuromodulator in central nervous system pathways that mediate various metabolic functions of the acute phase reaction, including the body temperature changes that produce the febrile response.

New Concepts on the Pathogenesis of Fever

Abstract: For more than 50 years, experimental studies on fever have focused on a substance from leukocytes called leukocytic or endogenous pyrogen. Various investigators concluded that changes associated with infection--such as numbers of circulating leukocytes; levels of trace metals, amino acids, and hepatic proteins; and altered lymphocyte function--were also caused by endogenous leukocyte mediators. There was reasonable evidence that fever and these other changes were brought about through the action of a single endogenous pyrogen, now known as interleukin 1 (IL-1). Two forms of IL-1 have been cloned (IL-1 beta and IL-1 alpha), and studies of recombinant IL-1 preparations have confirmed that fever and the broad spectrum of host responses to infection and injury are indeed mediated by this substance. However, IL-1 is not the only leukocyte product that induces fever: tumor necrosis factor (cachectin) and interferon produce fever in humans and animals. Accordingly, the concept of a single endogenous pyrogen now requires modification. Nature has conferred the ability to produce fever on no fewer than three structurally distinct molecules. Investigators trying to determine what triggers the hypothalamus to initiate fever in a particular disease must now consider these three endogenous pyrogens, either alone or together, as mediators of fever.

A low dose of recombinant interleukin 1 protects granulocytopenic mice from lethal gram-negative infection

Abstract: Natural and synthetic immunomodulators that increase nonspecific resistance to infection induce interleukin 1 (IL-1) production. Therefore, we investigated the effect of the administration of IL-1 on the survival of lethally infected granulocytopenic mice. Mice with cyclophosphamide-induced granulocytopenia were injected with approximately 10(7) Pseudomonas aeruginosa in the thigh muscle at time 0; gentamicin was administered 6 hr and 23 hr later. When recombinant human IL-1 beta (one of the two forms of IL-1) was given as a single i.p. injection 24 hr before the infection, survival was increased. Using 80 ng of IL-1 beta per mouse, survival compared to control animals was 98% vs. 71% at 24 hr, 98% vs. 60% at 30 hr, 86% vs. 36% at 36 hr, and 61% vs. 11% at 48 hr (P less than 0.001) after the infection. No effect of IL-1 was observed when it was given 0.5 hr before or 6 hr after the infection. Animals not treated with gentamicin also benefited from the IL-1. Administration of the cyclooxygenase inhibitor ibuprofen did not affect the activity of IL-1. Numbers of bacteria cultured from the blood, thigh muscle, liver, spleen, and kidney were similar in IL-1-treated and control animals. Superoxide production by peritoneal macrophages was also similar in the two groups. These studies demonstrate that IL-1 pretreatment protects granulocytopenic mice against lethal pseudomonas infection and suggest that this protection occurs through a noncellular mechanism.

C5a stimulates secretion of tumor necrosis factor from human mononuclear cells in vitro : Comparison with secretion of interleukin-1 beta and interleukin-1 alpha

Abstract: We have demonstrated that purified C5a is a potent stimulus to human PBMC secretion of TNF-alpha, IL-1 beta, and IL-1 alpha, which proceeds in a dose-dependent fashion. At a given concentration of C5a, TNF-alpha and IL-1 beta secretion did not differ significantly; both were secreted in significantly greater quantity than IL-1 alpha. Clinical conditions such as Gram-positive and Gram-negative bacterial infections, trauma, and immune complex diseases activate complement. Through the mediation of TNF and IL-1 secreted in response to C5a, these diverse disorders can share common features of fever, coagulopathy, acute phase protein production, and disordered metabolism.

Induction of circulating tumor necrosis factor (TNFα) as the mechanism for the febrile response to interleukin-2 (IL-2) in cancer patients

Abstract: Fever is frequently observed in cancer patients treated with high-dose recombinant human interleukin-2 (rIL-2). The preincubation of rIL-2 with polymyxin B, an antibiotic that inhibits the biologic effects of endotoxins, did not diminish the pyrogenicity of IL-2 in New Zealand rabbits, indicating that IL-2-induced fever is not due to contaminating endotoxins. In contrast to interleukin-1 (IL-1), tumor necrosis factor (TNF), and interferon α, which cause fever through their effects on arachidonic acid metabolism in the hypothalamus, IL-2 was unable to induce prostaglandin E2 synthesis in hypothalamic cells or fibroblastsin vitro, suggesting that IL-2 is not intrinsically pyrogenic. To determine if IL-2-induced fever is mediated indirectly through the generation of pyrogenic cytokines, culture supernatants from IL-2-stimulated human peripheral blood mononuclear cells were screened for the presence of pyrogens by direct injection into rabbits and by measuring the amounts of IL-1α, IL-1β, and TNFα by specific radioimmunoassays (RIA). All three cytokines were readily detected by RIA in these supernatants, which in turn caused fever when injected into rabbits. Furthermore, in six of six cancer patients treated with rIL-2, elevated levels of TNFα were detected in the plasma by RIA 2 hr after IL-2 administration. Plasma TNF levels increased from pretreatment values of 14±7 to 765±150 pg/ml 2 hr after an IL-2 injection. These results strongly implicate IL-2-induced pyrogenic cytokines, in particular TNFα, as a major cause of the fever and possibly other aspects of the acute-phase response associated with IL-2 therapy.

Inhibition of Cyclo-oxygenase Attenuates the Metabolic Response to Endotoxin in Humans

Abstract: • Acute infection initiates fever, acute-phase changes, and catabolic responses in the host, resulting in weight loss, hypermetabolism, and accelerated proteolysis. To test the hypothesis that cyclo-oxygenase inhibition might attenuate these responses, we administered Escherichia coli endotoxin intravenously to seven normal volunteers and to seven additional subjects pretreated with a cyclo-oxygenase inhibitor (ibuprofen). Control studies were also performed following administration of saline and ibuprofen alone. Vital signs, metabolic rate, and concentrations of pituitary and stress hormones, as well as those of other substrates, were serially measured. Endotoxin administration produced a response similar to an acute illness, with flulike symptoms, fever, tachycardia, increased metabolic rate, and stimulation of stress hormone release. These changes were markedly attenuated by cyclo-oxygenase inhibition. The leukocytosis, hypoferremia, and elevation of the C-reactive protein level induced by endotoxin were unaffected by cyclo-oxygenase inhibition. These data indicate that activation of the cyclooxygenase pathway is necessary to produce many of the metabolic changes observed during critical illness. ( Arch Surg 1988;123:162-170)

Concentrations of immunoreactive human tumor necrosis factor alpha produced by human mononuclear cells in vitro

Abstract: The concentrations of tumor necrosis factor (TNF) produced by human peripheral blood mononuclear cells (MNC) were measured using a radioimmunoassay (AlA) for human TNF. This was developed using a rabbit antiserum against human recombinant TNF (Hu rTNF), and Hu rTNF labeled with Na’25l by a modification of the chloramine T method. This AlA does not detect human lymphotoxin, interleukin-1 alpha or beta, interleukin 2, interleukln 6, interferon alpha or gamma, granulocyte-macrophage-colony stimulating factor, and C5a des arg. A good correlation (r = 0.89) was found between the RIA and the cytolytic bioassay for TNF. The sensitivity of the AlA is between 3 and 78 pg/mi (median 11 pg/mI). The mean concentration of TNF in 24-h culture supernatants of human MNC exposed to different concentrations of lipopolysaccharide (LPS) was found to increase in dosedependent fashion and then level off between 50 and 100 ng/ml. The concentrations of IL-i beta and alpha detected by specific RIA5 in these supematants were between 0.2 and 19 ng/ml and 0.04 and 1 ng/ml, respectively. The amount ot TNF produced by human MNC in vitro was determined in a cohort of 50 normal volunteers. Without exogenous stimuli, TNF concentrations were almost always below the detection limit; with 0.5 ng/ ml LPS, the median concentration of TNF was 2 ng/mi, and with PHA the median was 3.8 ng/mi. In cultures performed in the presence of indomethacin significantly (p <0.005) more TNF was produced. Using this AlA, we could detect TNF in the circulation of mice injected with Hu rTNF. When plasma samples of patients with febrlle illnesses were added directly to the AlA, TNF was not detectable, with the exception of patients with malaria. These studies demonstrate the range and sensitivity of LPS-induced and mitogeninduced production of immunoreactive TNF by human MNC in vitro without interference of similar cytokines in bloassays.

Interleukin-1 beta in human plasma: optimization of blood collection, plasma extraction, and radioimmunoassay methods.

Abstract: Current immunoassays for interleukin-1 beta (IL-1 beta) are effective for analyzing fluids derived from cultured cells. However, IL-1 beta determinations in human plasma or serum samples are technically complicated by higher protein and lipid concentrations, physicochemical differences which exist between samples from healthy subjects and those experiencing acute phase responses, and by the fact that IL-1 beta can be produced and degraded in the blood collection tube after the sample is drawn. A simple chloroform extraction process has been developed which eliminates several of the interfering factors from plasma samples and increases the amount of IL-1 beta detected by radioimmunoassay and lymphocyte activation assay. In the radioimmunoassay, rabbit sera was found to influence the accuracy and variability of plasma measurements. Improvements in radioimmunoassay reagents and methods are reported which reduce this influence. Finally, different concentrations of IL-1 beta were measured depending on whether serum or plasma was tested. We propose that plasma samples collected with EDTA and aprotinin provide a better determination of free circulating IL-1 beta in vivo than serum samples, which may contain IL-1 beta secreted from blood leukocytes during the clotting process.

Interleukin-1 enhances pain reflexes. Mediation through increased prostaglandin E2 levels.

Abstract: Interleukin-1 (IL-1) has been shown to induce inflammatory reactions in part through increased prostaglandin production. Prostaglandins of the E- and I-type sensitize nociceptors in peripheral tissues. We have therefore investigated the effect of IL-1 perfusion in the isolated rabbit ear, a model which allows the assessment of peripheral pain. Natural IL-1 from human monocytes, IL-1 from glioblastoma cells as well as recombinant IL-1 alpha or beta, increased the pain reflex induced by acetylcholine in a concentration dependent manner. The PGE2 levels were measured in the perfusate and were found to be enhanced more than 10-fold after the infusion of IL-1 alpha or IL-1 beta. This effect was paralleled by the enhanced pain reflexes and persisted for at least one hour after cessation of the IL-1 perfusion. Both the increased pain reflexes as well as the enhanced PGE2 levels were abolished by addition of the cyclooxygenase inhibitor diclofenac-Na (Voltaren) to the perfusion fluid. These results show that besides the numerous known physiological functions of IL-1, it may also play a role in peripheral pain sensations.

Induction by Toxic-Shock-Syndrome Toxin-1 of a Circulating Tumor Necrosis Factor-Like Substance in Rabbits and of Immunoreactive Tumor Necrosis Factor and Interleukin-1 from Human Mononuclear Cells

Abstract: A shock-like syndrome was induced in rabbits by administering toxic-shock-syndrome toxin-1 (TSST-1); tumor necrosis factor (TNF)-like activity was detected in sera of rabbits 3.5 h after injection, as measured by cytotoxic effects on the tumorigenic L929 murine fibroblast cell line. Appearance of this activity in sera coincided with onset of significant shock-related hemodynamic changes. TSST-1 stimulated release of TNF-like material from rabbit mononuclear cells in culture. Human mononuclear cells also secreted a cytotoxic substance shown to be TNF by radioimmunoassay. Maximal TNF secretion was higher in human mononuclear cells stimulated with TSST-1 than in those stimulated with bacterial lipopolysaccharide. Lipopolysaccharide, however, was a more potent inducer of interleukin-1 alpha and interleukin-1 beta from the same cells than was TSST-1. Because TNF and interleukin-1 act synergistically during induction of a shock-like state, these results suggest that part of the TSST-1-induced shock is due to production of interleukin-1 and TNF.

Protection of neutropenic mice from lethal Candida albicans infection by recombinant interleukin 1.

Abstract: Natural and synthetic immunomodulators that increase nonspecific resistance to infection are also known to induce interleukin 1 (IL 1) production. Previous studies have demonstrated a protective effect of recombinant human IL 1 beta against death from infection caused by Pseudomonas aeruginosa. In the present study we investigated the effect of IL 1 beta or IL 1 alpha on the survival of neutropenic mice with a lethal Candida albicans infection. Mice with cyclophosphamide-induced neutropenia were injected with 3 X 10(5) C. albicans i.v. When 80 ng IL 1 beta was given as a single i.p. injection 24 h before the infection, survival compared to that in control animals was as follows: 100% vs. 97% at 24 h, 83% vs. 70% at 48 h and 70% vs. 23% at 72 h after the infection (p less than 0.01). The effect of IL 1 was also apparent when it was given 1/2 h before or 6 h after the infection. The results obtained with 80 ng IL 1 alpha given at 24 h before infection were similar to that obtained with IL 1 beta. The numbers of Candida cultured from the blood, liver, spleen, and kidney were not significantly different in IL 1 beta-treated and control animals. Passive transfer of serum obtained from mice pretreated with IL 1 to recipient mice did not provide protection against a subsequent lethal candidal infection. In conclusion, the present study demonstrates that IL 1 beta and IL 1 alpha prolong survival in neutropenic mice with a lethal C. albicans infection.

Plasma Interleukin-1 Activity during Hemodialysis: The Influence of Dialysis Membranes

Abstract: Plasma interleukin-1 (IL-1) activity was measured in 7 stable ESRD patients on regular hemodialysis for no less than 5 months. Predialysis levels were significantly raised compared to 8 normal control subjects. During hemodialysis with four different membranes, plasma IL-1 activity rose with Cuprophan and Hemophan and was unchanged or reduced with Gambrane and Polysulfon. In spite of these differences, body temperature rose in all forms of hemodialysis. Factors responsible for the predialysis elevation included the absence of renal function and/or the repeated stimulus of human blood monocytes by hemodialysis. In view of the uniform increase of body temperature during hemodialysis, the differences in changes of plasma IL-1 activity observed with the various membranes may not be caused by a variable stimulation of monocytes but rather by the presence or absence of the membrane's ability to remove and/or absorb IL-1. Thus, the consequences of monocyte hemodialysis stimulation may be obtained locally, even in the presence of unchanged or reduced plasma IL-1 activity.

IL-2 receptor(p55)/Tac-inducing factor. Purification and characterization of adult T cell leukemia-derived factor.

Abstract: Many human T cell lymphotropic virus-I (HTLV-I) transformed T cells from adult T cell leukemia (ATL) patients continuously produce a humoral factor called ATL-derived factor (ADF) which induces IL-2R/Tac expression on T and NK cells. Using gel filtration, procion red Sepharose, DEAE, and reverse phase chromatography, we have purified ADF protein to homogeneity from 15 liters of serum-free culture supernatant of an HTLV-I(+) T cell line ATL-2. Purified ADF protein had the m.w. of 14,000 by SDS-PAGE and gel filtration, and its isoelectric point is around 5.0. ADF did not react with heteroantibodies against IL-1 alpha and IL-1 beta, which have also IL-2R/Tac-inducing activity on suitable target cells. Partial N-terminal amino acid sequence of ADF is different from other cytokines such as, IFN, BSF-2, and various IL whose cDNA has been cloned. Western blot analysis using rabbit antibodies against N-terminal 10mer synthetic peptide of ADF showed that IL-1 alpha and ADF are different proteins. ADF had its IL-2R/Tac-inducing activity not only on human NK-like cell line YT, but also on HTLV-I(+) T cells, such as ED. In contrast, macrophage-derived IL-1 lacked IL-2R/Tac-inducing activity on ED cells despite their IL-2R/Tac induction on YT, indicating that ADF and IL-1 have their effect via different receptors.

Recombinant human tumor necrosis factors alpha and beta stimulate fibroblasts to produce hemopoietic growth factors in vitro.

Abstract: The influences of TNF alpha and TNF beta were evaluated for their stimulatory and inhibitory effects on in vitro colony formation by human bone marrow granulocyte-macrophage (CFU-GM), erythroid (BFU-E), and multipotential (CFU-GEMM) progenitor cells. Both TNF alpha and TNF beta induced fibroblasts to produce stimulators of CFU-GM, BFU-E, and CFU-GEMM in a dose-dependent fashion. Similar results were seen when equivalent concentrations of TNF alpha and TNF beta were used. Prior incubation of the TNF alpha and TNF beta with their respective antibodies inactivated the ability of the TNF preparations to induce the release of granulocyte-macrophage, erythroid, and multipotential colony-stimulating activity from fibroblasts. In addition, incubation of the TNF-induced fibroblast supernatant with antibody before colony assay resulted in enhanced colony formation, suggesting that the TNF carried over into the colony assay suppressed colony formation. Additional proof of this suppression by TNF was evident when TNF was added directly to the CFU-GM, BFU-E, and CFU-GEMM colony assays. IL-1 does not appear to function as an intermediary in growth factor production by fibroblasts stimulated with TNF because antibody to IL-1 displayed no effect. Furthermore, assay of TNF-induced fibroblast supernatant was negative for IL-1. These results suggest that TNF alpha and TNF beta exert both a positive and negative influence on in vitro hemopoietic colony formation.

A radioimmunoassay for human interleukin-1 alpha: measurement of IL-1 alpha produced in vitro by human blood mononuclear cells stimulated with endotoxin.

Abstract: A specific radioimmunoassay (RIA) for human interleukin-1 alpha (IL-1 alpha) which detects less than 25-50 pg/ml IL-1 alpha is described. Although human IL-1 alpha shares structural homology, receptors and multiple biological properties with IL-1 beta, this RIA does not detect human IL-1 beta or other human cytokines. We recovered nearly 100% of IL-1 alpha added to fresh human heparinized blood or freshly voided urine; in contrast, using a specific RIA for IL-1 beta, recovery of IL-1 beta added to fresh blood is approximately 50% reduced by nonspecific factors. In the present study, we employed this RIA to measure the amount of total (extracellular and cell-associated) immunoreactive IL-1 alpha produced by human blood mononuclear cells stimulated in vitro by different concentrations of endotoxin. Using ultrafiltered culture medium to reduce endotoxin content, there was no detectable (less than 50 pg/ml) IL-1 alpha produced after 24 hours. Endotoxin (0.5 ng/ml) induced a mean concentration of 900 pg/ml (range 180-1660 pg/ml). At higher concentrations of endotoxin (500 ng/ml), a mean of 6,990 pg/ml (range 415-11,900 pg/ml) was produced. These levels were comparable to the amount of IL-1 beta produced under similar culture conditions. The results indicate that IL-1 alpha can be measured independently of IL-1 beta in human body fluids and from human mononuclear cells.

Interleukin-1 affects the function of cultured human thyroid cells

Abstract: Cytokines are peptide hormones essential for cellular communication in the immune response. The purpose of this study was to investigate the influence of cytokines, especially recombinant interleukin 1 beta (rIL-1 beta), on human thyroid cells. Thyroglobulin (Tg) was measured by a double antibody radioimmunoassay, and cyclic AMP (cAMP) by a competitive protein binding assay. Supernatants from unstimulated and phytohaemagglutinin-stimulated blood mononuclear cells were added to human thyroid cells cultured in monolayers. A dose-dependent inhibition of the secretion of Tg and cAMP was demonstrated. Both subcultured and primary cultured cells incubated with rIL-1 beta at pharmacological levels (10(-1)-10(2) U/ml) exhibited an inhibition of Tg and cAMP secretion, while at physiological levels (10(-5)-10(-3) U/ml), the secretion of Tg was enhanced. The similar stimulation of cAMP was demonstrated in subcultures. These in vitro studies suggest that IL-1 beta may play a role in the pathogenesis of autoimmune thyroid diseases. Further, the stimulations at low concentrations indicate that IL-1 beta may regulate the function of the thyroid gland under physiological conditions.

Interleukin-1 – Its Multiple Biological Effects and Its Association with Hemodialysis

Abstract: It has been proposed that monocyte activation during hemodialysis involves the release of interleukin-1 (IL-1) and related cytokines. In this review, the biological properties of recombinant human IL-1 are discussed with particular emphasis on hemodialysis. Models of monocyte activation which likely occur during hemodialysis are presented. We conclude that pyrogens, solutes, complement components and the physical nature of the dialysis membrane itself contribute to monocyte activation and cytokine release.

Interleukin-1 potentiates glucose stimulated insulin release in the isolated perfused pancreas.

Abstract: The acute effects of recombinant human interleukin-1 beta (rIL-1) on basal and glucose-stimulated insulin release were investigated in the isolated perfused pancreas. At a concentration of 20 micrograms/l rIL-1 had no effect on basal insulin release, but increased the total amount of insulin released during first and second phase insulin release in response to 20 mmol/l D-glucose in the rat pancreas (P less than 0.05). In addition, 26 micrograms/l of rIL-1 potentiated insulin release in response to square wave infusions of stimulatory concentrations of glucose (11 mmol/l) in the porcine pancreas. We hypothesize that IL-1 in the systemic circulation may affect B cell function in vivo.

Recombinant Interleukin 1 and Tumor Necrosis Factor Acting in Synergy to Release Thromboxane, 6-KETO-PGF1α, and PGEI2, by Human Neutrophils

Abstract: The cyclooxgenase pathway promotes formation of an endoperoxide that is the precursor of prostaglandins (PG), throm boxanes (Tx) and prostacyclines (PGI2), all of which have important biologic activities. In this study, we examined the ability of human polymorphonuclears (PMN) to synthesize TRxA2, 6-KETO-PGF1α and PGE2 in response to human recombinant interleukin 1 (IL1) and tumor necrosis factor (TNF) alone and in combination. Blood was obtained from healthy donors and whole blood was centrifuged over Ficoll-Hypaque in 2% dextran for 30 min. PM Ns were resuspended in Gey's buffer, exposed to the IL1 and TNFF at 300 ng/ml and 0.5 ng/ml concentrations, and incubate for 30 min. at 106 Cell/ml. Results indicate that IL1 and TNF alone have little or no effect on human neutrophils synthesize TxA2, 6-KETO-PGF1α and PGE2 production. This effect was completely inhibited by two non-steroidal anti-inflammatory drugs (Le. indomethacin and proglumetacin).

IL-1βprotein precursor

Abstract: The subject invention concerns a nucleic acid comprising a nucleotide sequence encoding human interleukin-1 (IL-1), and fragments thereof, and the polypeptides and peptides obtained Specifically, the subject invention comprises the cloning of a cDNA synthesized by reverse transcription of poly(A)RNA isolated from adherent human monocytes-stimulated with bacterial endotoxin Human IL-1 is useful to induce the production of IL-2 by activated T-cells; it also acts on B-cells and NK-cells