Circulating interleukin-1 receptor antagonist concentrations are increased in adult patients with thermal injury.

OBJECTIVE: To investigate the balance between circulating concentrations of interleukin (IL)-1 and its natural inhibitor interleukin-1 receptor antagonist (IL-1Ra) in human inflammation. DESIGN: Prospective case-control study. SETTING: University hospital burn care unit. PATIENTS: Fifteen patients with second- or third-degree thermal injuries of 7% to 78% of total body surface and 15 healthy age- and sex-matched control subjects. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Median plasma IL-1Ra, but not IL-1 beta or tumor necrosis factor-alpha (TNF-alpha) concentrations were markedly increased on the day of admission in patients with thermal injuries compared with controls (1615 [range 426 to 23,800] vs. 494 [range 196 to 1093] pg/mL; p < .001). In survivors, the median IL-1Ra concentration normalized 12 to 21 days after admission. The concentration of IL-1Ra on the day of admission was weakly positively correlated to the extent and degree of thermal injury (r2 = .46; p < .05). IL-1Ra on days 1 to 3 was highest in three nonsurvivors with inhalation injuries compared with survivors (2166 [range 1362 to 36,624] vs. 1344 [range 665 to 13,085] pg/mL; p < .05). IL-1Ra increased significantly after debridement and skin transplantation (preoperatively 742 [range 488 to 1506] vs. postoperatively 1431 [range 1286 to 2107] pg/mL; p < .01). In nonsurvivors, median IL-1Ra was 3.6-fold higher than IL-1 beta on days 1 to 2 and 36-fold higher than IL-1 beta in three patients with bacteremia. IL-1Ra was studied for its relationship to previously reported parameters of the acute-phase response determined in the same samples from these patients. The increased concentrations of IL-1Ra coincided with a decrease in serum albumin concentration and increases in rectal temperature. However, IL-1Ra did not correlate with rectal temperature, plasma concentrations of endotoxin, IL-1 beta, or TNF-alpha either at admission or in follow-up samples. CONCLUSIONS: Thermal injury causes an increase of circulating IL-1Ra, especially in patients with inhalation injuries. With the current plasma assays for IL-1 beta, IL-1Ra may be a more sensitive marker of human inflammation than IL-1 beta or TNF-alpha.

Interleukin-1 beta (IL-1) does not reduce the diabetes incidence in diabetes-prone BB rats.

The cytokine interleukin 1 beta (IL-1) has been implicated as a pathogenetic factor in the initial events leading to insulin-dependent diabetes mellitus. Previous studies investigating the impact of IL-1 on diabetes incidence in spontaneously diabetic rodent models have been conflicting. IL-1 induces anorexia and previous studies are hampered by the lack of pair-fed controls to the IL-1 treated animals. We report that daily injections of 4.0 micrograms/kg/day of recombinant human IL-1 (rhIL-1) for 13 weeks from 25-30 days of age did not alter the incidence of diabetes in the diabetes-prone (DP) BB rats (75%) when compared to pair-fed, vehicle treated controls (55%, p = 0.18), or to unhandled DP BB rats (80%, p = 0.71). However, IL-1 induced significantly higher blood glucose concentrations in the prediabetic period (p < 0.00005) and at diabetes onset (p < 0.00005) in the DP BB rats and caused episodes of blood glucose concentrations > 11 mmol/l in the prediabetic period in 11/20 DP BB rats compared to 4/27 diabetes-resistant (DR) BB rats and 4/28 Wistar Furth (WF) rats (both p < 0.004), compared to DP BB). Further, rhIL-1 induced fever in 11 weeks in the DP BB rats compared to 3 weeks in the DR BB and 6 weeks in the WF rats. Using high performance size exclusion chromatography specific anti-rhIL-1-antibodies were demonstrated in DR BB and WF, but not in DP BB rats. These antibodies neutralized the inhibitory effect of rhIL-1 on insulin secretion from isolated islets of Langerhans in vitro. The reduced pyrogenic and endocrine effect of rhIL-1 in the DR BB and WF rats compared to the DP BB rats could be explained by the impaired ability of the DP BB rats to produce anti-rhIL-1-antibodies. In conclusion, administration of rhIL-1 modulated the prediabetic period, and produced higher blood glucose concentrations at diagnosis, but did not change the diabetes incidence in DP BB rats. The results are not in conflict with the hypothesis that IL-1 is a pathogenetic factor in IDDM, caused by high local concentrations of rat IL-1 in the islets during early insulitis. The results also show the necessity of pair-feeding of the control group to the rhIL-1 group when interpreting data from experiments investigating rhIL-1 effects on diabetes development in animal models.

Repetitive in vivo treatment with human recombinant interleukin-1 beta modifies beta-cell function in normal rats.

It is unknown whether interleukin-1 exerts a bimodal effect on Beta-cell function in vivo, and whether interleukin-1 has a diabetogenic action in normal animals. We therefore studied: (a) acute effects 2 h after an intraperitoneal bolus injection of 4 micrograms of recombinant human interleukin-1 beta per kg body weight on blood glucose, plasma levels of insulin, glucagon and corticosterone in Wistar Kyoto rats, either untreated or pre-treated with 4 micrograms/kg of interleukin-1 daily for 3 or 5 days; (b) the cumulative effects of repetitive intraperitoneal injections of 4 micrograms/kg interleukin-1 on blood glucose, glucose tolerance, plasma levels of insulin, glucagon and corticosterone, pancreatic insulin content and pancreatic ultrastructure; and (c) blood glucose and plasma concentrations of insulin, glucagon and corticosterone 10 h after the last of five intraperitoneal injections of interleukin-1, at which time point the inhibitory effect of short-term interleukin-1 exposure on insulin secretion reaches its nadir in vitro. A single injection of 4 micrograms/kg of interleukin-1 caused a slight, but significant lowering of blood glucose 2 h after interleukin-1 injection with no significant changes in plasma insulin and in spite of increases in plasma glucagon and corticosterone. A lowering of blood glucose 2 h after interleukin-1 administration was reproduced with 40, but not 0.4 micrograms/kg of interleukin-1, and was also seen in interleukin-1 pre-treated rats. Two hours after the fifth injection of interleukin-1, intraperitoneal glucose tolerance was impaired with elevated plasma insulin and corticosterone levels and increased pancreatic insulin content, indicating a state of insulin resistance.(ABSTRACT TRUNCATED AT 250 WORDS)

The pharmacokinetics, distribution and degradation of human recombinant interleukin 1 beta in normal rats.

Based upon in vivo rat experiments it was recently suggested that interleukin 1 in the circulation may be implicated in the initial events of beta-cell destruction leading to insulin-dependent diabetes mellitus (IDDM) in humans. The aim of the present study was to estimate half-lives of distribution (T1/2 alpha) and elimination phases (T1/2 beta) of human recombinant interleukin 1 beta (rIL-1 beta), and its tissue distribution and cellular localization by means of mono-labelled, biologically active 125I-rIL-1 beta. After intravenous (i.v.) injection, 125I-rIL-1 beta was eliminated from the circulation with a T1/2 alpha of 2.9 min and a T1/2 beta of 41.1 min. The central and peripheral volume of distribution was 20.7 and 19.1 ml/rat, respectively, and the metabolic clearance rate was 16.9 ml/min/kg. The kidney and liver showed the highest accumulation of tracer, and autoradiography demonstrated that 125I-rIL-1 beta was localized to the proximal tubules in the kidney and to the hepatocytes in the liver. Furthermore, grains were localized to the islets of Langerhans in the pancreas. Tracer-bound proteins corresponding to intact 125I-rIL-1 beta were found in the circulation after i.v., intraperitoneal (i.p.) and subcutaneous (s.c.) injections, as demonstrated by high performance size exclusion chromatography, trichloracetic acid precipitation and SDS-PAGE until 5 h after tracer injection. Pre-treatment with 'cold' rIL-1 beta enhanced degradation of a subsequent injection of tracer. The route of administration was of importance for the biological effects of rIL-1 beta, as demonstrated by a reduced food intake, increased rectal temperature and blood glucose after s.c. injection of rIL-1 beta compared with i.p. The present demonstration of intact rIL-1 beta in the circulation and the islets of Langerhans supports the hypothesis that systemic IL-1 beta may be involved in the initial beta-cell destruction leading to IDDM in humans.

Dietary supplementation with omega-3-polyunsaturated fatty acids decreases mononuclear cell proliferation and interleukin-1 beta content but not monokine secretion in healthy and insulin-dependent diabetic individuals.

The effects of dietary supplementation with omega-3-polyunsaturated fatty acids (omega-3-PUFA) on the proliferative response of PBMC and on the secretion of monokines and arachidonic acid metabolites from PBMC and monocytes (Mo) from healthy subjects and patients with recent-onset insulin-dependent diabetes mellitus (IDDM) were examined. Three groups of eight to nine healthy individuals were randomized to either 2.0 g/day or 4.0 g/day of omega-3-PUFA devoid of vitamins A and D, or an isocaloric amount of placebo. Furthermore, eight patients with recent-onset IDDM received 4.0 g/day of omega-3-PUFA. IL-1 beta production and TNF-alpha secretion was determined before and after 7 weeks of treatment, and 10 weeks after withdrawal of treatment. Significant increases in platelet and PBMC membrane eicosapentaenoic acid was found in omega-3-PUFA-treated individuals. omega-3-PUFA treatment significantly reduced the content of IL-1 beta in lysates of PBMC, but did not affect PBMC or Mo secretion of IL-1 beta, TNF-alpha or prostaglandin E2 (PGE2) or PBMC leukotriene B4 (LTB4) secretion in healthy subjects or in IDDM patients. A significant inhibition of the PHA-stimulated, but not the spontaneous or PPD-stimulated, proliferative response of PBMC was observed in healthy and diabetic subjects treated with omega-3-PUFA. No correlation was found between PHA-stimulated PBMC proliferation and PBMC secretion of TNF-alpha and IL-1 beta. There were no significant differences in the spontaneous or the PPD- or PHA-stimulated proliferative responses of PBMC between diabetic and healthy individuals at entry. We conclude that although dietary supplementation with 4.0 g/day of omega-3-PUFA inhibits the proliferation of PBMC and reduces IL-1 beta immunoreactivity in PBMC and Mo, it does not alter monokine, PGE2 or LTB4, secretion in healthy or IDDM subjects.

Functional and morphological effects of interleukin-1 beta on the perfused rat pancreas.

We recently reported a potentiating effect of recombinant human interleukin-1 beta on glucose-stimulated insulin release from the isolated perfused pancreas. With the aim of determining whether the stimulatory effect of recombinant interleukin-1 beta on the B cell in the intact gland was modulated by varying the concentration, time of exposure to recombinant interleukin-1 beta or B-cell activity, and to elucidate a possible mechanism of action, we measured in the perfused rat pancreas the release of insulin, glucagon and/or prostaglandin E2 according to the following three different protocols: (1) perfusion with 20 ng/ml of recombinant interleukin-1 beta for 92 min at 5 and 20 mmol/l D-glucose (2) perfusion with varying concentrations of recombinant interleukin-1 beta ranging from 0.1 x 10(-3) ng/ml to 100 ng/ml at 5 and 20 mmol/l D-glucose (3) perfusion with 20 ng/ml of recombinant interleukin-1 beta at 5, 11 or 20 mmol/l D-glucose. Furthermore, in a separate set of experiments we examined the influence of the cytokine on the morphology of the endocrine pancreas. Interleukin-1 beta stimulated insulin secretion at 11 and 20 mmol/l D-glucose and potentiated first as well as second phase insulin release in a dose-dependent fashion, with decreasing effect at higher concentrations. Glucagon secretion was also stimulated by recombinant interleukin-1 beta, irrespective of increasing glucose (5, 11, 20 mmol/l) and insulin concentrations. The potentiating effect of recombinant interleukin-1 beta on insulin secretion was evident even after discontinued perfusion with the cytokine, suggesting a priming effect on B-cell function.(ABSTRACT TRUNCATED AT 250 WORDS)

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

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.