Showing papers by "Charles A. Dinarello published in 1994"

The interleukin-1 family: 10 years of discovery.

Abstract: Ten years ago the cloning of two interleukin-1 molecules (IL-1 alpha and IL-1 beta) resolved the question of whether a single polypeptide could evoke a wide variety of biological effects During the past decade, the biology of IL-1 has greatly expanded our understanding of how the host responds to external challenges, such as injury and infection, as well as its role in several diseases We learned of the remarkable potency of IL-1 in the femtomolar range and of its ability to induce a response by triggering only one or two receptors per cell Unexpectedly, the IL-1 family of genes, receptors and associated molecules have been linked to those of Drosophila, nematodes, and microorganisms and IL-1 signal transduction is similar to that observed after cellular stress The cloning of IL-1 opened other avenues of fundamental biological interest For example, in addition to the two agonist molecules IL-1 alpha and IL-1 beta, a third member of the IL-1 gene family is a specific, high affinity receptor antagonist

Rheumatoid cachexia: cytokine-driven hypermetabolism accompanying reduced body cell mass in chronic inflammation.

Abstract: The cytokines IL-1 beta and TNF-alpha cause cachexia and hypermetabolism in animal models, but their role in human inflammation remains controversial. The relationship between in vitro cytokine production and metabolism was examined in 23 adults with RA and 23 healthy control subjects matched on age, sex, race, and weight. Body composition was measured by multicompartmental analysis of body cell mass, water, fat, and bone mass. Resting energy expenditure (REE) was measured by indirect calorimetry. Cytokine production by PBMC was measured by radioimmunoassay. Usual energy intake, physical activity, disability scores, medication use, and other confounders were also measured. Body cell mass was 13% lower (P < 0.00001), REE was 12% higher (P < 0.008), and physical activity was much lower (P < 0.001) in subjects with RA. Production of TNF-alpha was higher in RA than controls, both before and after stimulation with endotoxin (P < 0.05), while production of IL-1 beta was higher with endotoxin stimulation (P < 0.01). In multivariate analysis, cytokine production was directly associated with REE (P < 0.001) in patients but not in controls. While energy and protein intake were similar in the two groups and exceeded the Recommended Dietary Allowances, energy intake in subjects with RA was inversely associated with IL-1 beta production (P < 0.005). In this study we conclude that: loss of body cell mass is common in RA; cytokine production in RA is associated with altered energy metabolism and intake, despite a theoretically adequate diet; and TNF-alpha and IL-1 beta modulate energy metabolism and body composition in RA.

The biological properties of interleukin-1.

Abstract: Interleukin-1 (IL-1) is primarily an inflammatory cytokine Biologically, IL-1 is more closely related to tumor necrosis factor (TNF) than any other cytokine or interleukin, although the structure and receptors for IL-1 and TNF are clearly distinct IL-1 is active in the low pM and fM range and IL-1 receptors (IL-1R) are expressed in most cells, although less than 100 receptors per cell is not an uncommon finding Based on short-term blockade of IL-1 receptors in humans and animals and IL-1 beta knock-out mice, there is no evidence that IL-1 beta plays a role in development, or normal homeostasis such as metabolism, hematopoiesis, renal and hepatic function or regulation of blood pressure On the other hand, IL-1 alpha is found constitutively produced by various epithelial cells, keratinocytes of the skin and in the brain In these locations, IL-1 may contribute to cell growth and repair functions During inflammation, injury, immunological challenge or infection, IL-1 is produced and because of its multiple biological properties, IL-1 must contribute to disease Most studies on IL-1 are derived from experiments in which humans or animals are injected with IL-1 or IL-1 is added to cells in vitro The biological properties of IL-1 suggest that its effects often mimic host responses to infection, inflammation, injury or immunologic challenge Using specific IL-1 blockade, it is clear IL-1 is playing a critical role in some disease processes This review will focus on IL-1 as a cytokine of primary and strategic importance to the initiation and progression of inflammatory and infectious diseases

Interleukin-1 Receptor Blockade Reduces the Number and Size of Murine B16 Melanoma Hepatic Metastases

Abstract: Hepatic metastasis in melanoma is affected by processes of tumor cell adhesion to sinusoidal cells, avoidance of cytotoxic cells, and local growth-promoting activity. A role for interleukin-1 (IL-1) in these events was evaluated in vitro and in vivo by specifically blocking IL-1 receptors using the naturally occurring IL-1 receptor antagonist (IL-1Ra). At 10- and 100-fold molar excess, IL-1Ra reduced the IL-1-mediated adhesion of B16 melanoma cells to cultured hepatic sinusoidal endothelial cells by 60 and 100%, respectively. Conditioned media derived from murine hepatic sinusoidal endothelial cells contain growth-promoting activity for B16 cells, and IL-1 increased its production 2.5-fold (P

Increased Levels of Interleukin-1 Are Detected in Nasal Secretions of Volunteers during Experimental Rhinovirus Colds

Abstract: The potential involvement of interleukin-1 (IL-1) in the pathogenesis of experimental rhinovirus colds was examined. Nasal lavages were recovered before and for 5 days after rhinovirus infection from 44 subjects, 22 of whom were randomized to receive prophylaxis with glucocorticoids, while the rest received placebo. Immunoreactive IL-1 beta was significantly increased in subjects who were infected and symptomatic compared with noninfected volunteers or subjects who were infected but asymptomatic. Concentrations of immunoreactive IL-1 beta correlated with levels of kinins and albumin in lavage fluids. Studies of IL-1 bioactivity established that most activity in lavages from infected subjects was IL-1 beta. Glucocorticoid prophylaxis did not inhibit IL-1 production, nor did it significantly affect the symptomatic response to infection or, in a subset of patients, neutrophil infiltration. These data are consistent with the hypothesis that IL-1 could contribute to the pathogenesis of rhinovirus infections.

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

Abstract: 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.

Monokine antagonism is reduced in patients with IDDM

Abstract: Interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF-alpha) have been implicated as immune effector molecules in the pathogenesis of insulin-dependent diabetes mellitus (IDDM). Recently, an increased frequency of the A1/A1 genotype of an IL-1 receptor antagonist (IL-1Ra) gene polymorphism was observed in patients with IDDM. Therefore, we investigated plasma IL-1Ra and soluble TNF p55 receptor (TNFsRp55) levels in 18 men with recent-onset IDDM, 10 men with long-standing IDDM, and 35 age-matched healthy men. No differences in plasma IL-1Ra were found among the three groups. However, when the plasma IL-1Ra levels in the subjects with IDDM and the control subjects were analyzed according to IL-1Ra genotypes, we found a 30% lower level of plasma IL-1Ra in subjects with IDDM carrying the A1/A1 genotype compared with the levels in those carrying the A1/A2 genotype (372 +/- 40 vs. 530 +/- 54 ng/l, respectively, P = 0.025). In contrast, no significant association was seen between plasma IL-1Ra and IL-1Ra genotype in the control subjects. The TNFsRp55 level in heparinized plasma was 17% lower in patients with IDDM than in control subjects (3.93 +/- 0.22 vs. 4.72 +/- 0.24 micrograms/l, respectively, P = 0.038). These findings could not be explained by metabolic derangement in the IDDM patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Genetic susceptibility markers in Danish patients with type 1 (insulin-dependent) diabetes : evidence for polygenecity in man

Abstract: Fifty-five Danish families with two offspring concordant for type 1 diabetes-identified through a nationwide population-based survey, and 57 “true sporadic” cases-matched with familial cases for age at onset, but with no IDDM-affected first-degree relatives and long disease duration, and 110 control subjects were typed for putative genetic susceptibility markers for type 1 diabetes identified from a pathogenetic model. The markers included MHC class I, II and III loci, the manganese superoxide dismutase (MnSOD) locus (chr. 6q), interleukin-1β (IL1B), the IL-1 receptor antagonist (IL1RN), and the IL-1 type 1 receptor (IL1RI) loci (each chr. 2q). No significant differences between familial and sporadic cases were found within the MHC region (including the following loci: HLA-DQ,-DR, heat shock protein (HSP) 70, tumour necrosis factor (TNF), HLA-B and-A). In both groups of patients 11% were negative for both DQA1*0301-DQB 1*0302 and DQA1*0501-DQB1*0201 genotypes, and 7% of the type 1 diabetics had genotypes ...

Altered interleukin-1 and tumor necrosis factor production and secretion during pyrogenic tolerance to LPS in rabbits.

Abstract: Rabbits were injected intravenously with 10 micrograms/kg of endotoxin [lipopolysaccharide (LPS)] on days 0, 1, and 7, and rectal temperatures were monitored. The febrile responses were compared with circulating levels of interleukin-1 beta (IL-1 beta) and tumor necrosis factor (TNF) and in vitro synthesis of these cytokines by peripheral blood mononuclear cells (PBMC) isolated just before the injection of LPS. Fever after the first LPS injection was biphasic on day 0, attenuated and monophasic after the second LPS injection on day 1, and augmented after third injection of LPS on day 7. On day 1, circulating TNF and IL-1 beta levels were significantly (P < 0.05) decreased compared with those on days 0 and 7. Similarly, TNF and IL-1 beta synthesis by LPS-stimulated PBMC were significantly reduced on day 1. On day 7, cellular synthesis and secretion of IL-1 beta were significantly increased compared with that on day 0. A significant positive correlation was observed between fever index and total in vitro IL-1 beta synthesis by LPS-stimulated PBMC (r = 0.866, P = 0.001). These data demonstrate that pyrogenic tolerance in the rabbit after a single LPS injection is associated with decreased circulating IL-1 beta and TNF levels as well as decreased production of these cytokines in vitro. In addition, the pyrogenic hyperresponsiveness to LPS after 7 days is associated with increased synthesis and secretion of IL-1 beta from PBMC in vitro.

Are events after endotoxemia related to circulating phospholipase A2

Abstract: 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.

Does the route of feeding modify the inflammatory response

Abstract: OBJECTIVE: The authors compared the responses to endotoxin in enterally and parenterally fed human volunteers. BACKGROUND: Recent investigations have reported that the response to endotoxin in humans is greater in individuals who receive parenteral nutrition rather than enteral feeding. It was proposed that this difference was related to gut barrier dysfunction during intravenous nutrition. To evaluate this hypothesis, the authors analyzed the responses of human subjects to an intravenously administered bolus of endotoxin after enteral or parenteral nutrition. METHODS: Fifteen randomly selected healthy volunteers were studied during two separate investigations; ten studies were performed in ten subjects who received enteral nutrition, and nine studies were carried out in five additional subjects who received parenteral nutrition. After 2 days of enteral feedings or 7 days of parenteral feedings, endotoxin was administered by intravenous injection; temperature, symptom score, and duration then were measured serially. Blood samples were obtained for leukocyte and platelet count, and plasma concentrations of corticotrophin, cortisol, epinephrine, norepinephrine, tumor necrosis factor, and interleukin-6. Mononuclear cell response to phytohemagglutinin was determined at 0, 4, and 24 hours. RESULTS: In the parenteral group, a diminished response was observed in platelet count and plasma interleukin-6 levels compared with volunteers who received enteral nutrition. The duration of symptoms tended to be reduced in the parenterally fed group, although this did not achieve significance. Other responses were not significantly different between the two groups. CONCLUSION: The responses to endotoxin in human subjects who received parenteral nutrition were similar compared with subjects who received enteral nutrition, although platelet count and plasma interleukin-6 concentration were diminished.

Blocking interleukin-1 receptors.

Abstract: During inflammation, injury, immunological challenge or infection, interleukin-1 appears to mediate, in part, the pathogenesis, of disease. Most studies on interleukin-1 are derived from experiments in which bacterial products, such as endotoxins from Gram-negative bacteria or exotoxins from Gram-positive organisms, are used to stimulate macrophagic cells. In general, several cytokines are induced by microbes to their products. Although cytokines are thought to play a role in the outcome of disease, only a few have been directly implicated as mediators of the pathogenic mechanisms of the host. Studies on specific inhibition of interleukin-1 activity have employed interleukin-1 receptor antagonist, interleukin-1 receptors blocking antibodies or soluble interleukin-1 receptors. Experiments in vitro, in animal models of disease and in human subjects have shed considerable light on a critical role for interleukin-1 in the pathogenesis of disease. This review focuses on interleukin-1 as a cytokine of strategic importance to the outcome of disease, particularly inflammatory and infectious diseases.

Interleukin-1 in disease.

Abstract: As outlined in this review, the inflammatory cytokine interleukin-1 (IL-1) mediates a number of pathological processes associated with disease. To prove a role for IL-1, a variety of modalities have been used to block the production and/or activity of IL-1. These include agents which inhibit or reduce 1) IL-1 transcription and/or synthesis, 2) the processing of pro-IL-1β into its mature forms, 3) the secretion of IL-β, 4) the activity of IL-1 using neutralizing anti-IL-1 antibodies or 5) soluble (extracellular) IL-1 receptors, 6) the ability of IL-1 to bind to its receptors using receptor blockade, 7) the availability of surface receptors using agents which down-regulate receptor expression or (8) agents which affect IL-1-mediated signal transduction. Some of these modalities have already entered clinical trials. Clearly, the therapeutic advantage of reducing the activity of IL-1 resides in preventing its deleterious biological effects without interfering with host defense and homeostasis. For example, blocking IL-1-induced prostaglandins is one target in treating inflammatory diseases. Drugs inhibiting cyclooxygenase have well-known toxicities because they block the normal physiologic synthesis of prostaglandins in many tissues such as platelets and gastric lining cells. Blocking IL-1, in contrast, reduces only that portion of prostaglandin synthesis due to elevated IL-1, sparing the synthesis of prostaglandins necessary for physiologic homeostasis. A similar case can be made for endogenous nitric oxide. Thus, there is a unique pharmacological advantage to blocking IL-1 in disease.

Induction of circulating antagonists to IL-1 and TNF by IL-2 administration and their effects on IL-2 induced cytokine production in vitro.

Abstract: The objectives of this study were to determine whether intensive immunotherapy with IL-2 results in detectable levels of circulating IL-1 and TNF antagonists and whether the levels achieved in vivo are sufficient to affect the generation of secondary proinflammatory cytokines such as IL-1 beta and TNF-alpha. We also sought to determine the extent to which endogenous TNF mediates the generation of an IL-1 antagonist by IL-2-activated PBMCs. In patients undergoing high dose IL-2 immunotherapy, plasma IL-1 receptor antagonist (IL-1ra) levels rose dramatically after the first IL-2 injection, reaching a plateau of 11.03 +/- 0.92 ng/ml within 4 h. TNF-soluble receptor p55 (TNFsRp55) was also detected in the plasma shortly after initiating treatment, and the levels progressively increased throughout the treatment course. PBMCs exposed to IL-2 expressed IL-1ra mRNA and secreted the IL-1ra protein, but neither PBMCs nor neutrophils shed TNFsRp55 in response to IL-2 or supernatants from IL-2-activated PBMCs. IL-1ra at concentrations achieved in the plasma during IL-2 immunotherapy (approximately 10 ng/ml) inhibited the in vitro production of IL-1 beta and TNF-alpha by IL-2-activated PBMCs by 65% and 30%, respectively. Although the monomeric receptor TNFsRp55 at concentrations achieved in the plasma had no effect on the in vitro production of IL-1ra, TNF-alpha, or IL-1 beta, the bivalent TNFsRp75-Fc chimera suppressed the generation of TNF and IL-1. IL-1ra synthesis was unaffected. These results suggest that the amount of IL-1ra generated in response to IL-2 is most likely sufficient to down-modulate the production of proinflammatory cytokines.

Interleukin-1 receptor antagonist: an index of dialysis-induced interleukin-1 production.

Abstract: Interleukin-1 receptor antagonist (IL-1Ra) is a specific inhibitor of interleukin-1 (IL-1). It is structurally similar to IL-1 and binds to IL-1 cell surface receptors, but does not transduce a signal. To examine the relationship between the production of IL-1Ra and IL-1, we incubated peripheral blood mononuclear cells (PBMC) with endotoxin (10 ng/ml) and after 24 h measured the total synthesis (intra- and extracellular) of IL-1Ra, IL-lα and IL-1β. PBMC from 25 patients with chronic renal failure were studied. The total synthesis of IL-1Ra closely correlated with that of IL-1β (R = 0.786, p 0.05). These results suggest that in dialysis patients, the endogenous production of IL-1Ra is a ‘footprint’ of IL-1β production and can probably be used as a marker of the level of production of IL-1.

Is there a role for interleukin-1 blockade in intravenous immunoglobulin therapy?

Abstract: Several mechanisms have been proposed to explain the effectiveness of i.v.Ig therapy in a variety of inflammatory and autoimmune diseases. This review focuses on the concept that reducing the production of interleukin-1 (IL-1) or blocking the activity of IL-1 results in a reduction in disease severity. More specifically, this overview examines the effect of intravenous Ig (i.v.Ig) on the production and activity of IL-1 and its naturally occurring receptor antagonist (IL-lRa). The discussion is limited to the biological effects of i.v.Ig prepared from a very large pool of human sera and not to those prepared from a smaller donor pool with high titers of specific antibodies, for example, high-titer i.v.Ig against cytomegalovirus or varicella. Several commercially available preparations of i.v.Ig contain neutralizing antibodies to IL-1 (Svenson et al. 1993). In vitro, i.v.Ig reduces the production of IL1 from stimulated monocytes (Shimozato et al. 1991) and enhances the production of IL-lRa (Poutsiaka et al. 1991). In humans, i.v.Ig increases the circulating levels of IL-lRa. However, it remains unclear whether the magnitude of these responses to i.v.Ig accounts for a sufficient reduction and/or blockade of IL-1 activity and to what extent they contribute to the mechanism(s) of i.v.Ig in the treatment of diseases. There are many biological and immunological activities of i.v.Ig which have been proposed to account for the benefit observed in a wide range of human diseases. These include the triggering of the Fc yRI and FcyRII on phagocytic and immunocompetent cells and the effects of various immunoglobulins present in the preparations. However, what is the connection between the administration of i.v.Ig and IL-1? Some experimental studies suggest that i.v.Ig suppresses the production of IL-1 in vitro (there is also suppression of tumor-necrosis factor