Effects of Arg-vasopressin and corticosterone on IL-1b-induced modifications of pituitary ACTH-producing cells

Interleukin 1b (IL-1b) stimulates the hypothalamic-pituitary-adrenal axis, however the autoparacrineeffects of IL-1b‚ on pituitary ACTHproducingcells and the relations among IL-1band Arg-vasopressin or corticosterone have notyet been analyzed. To address these effects,pituitary monolayer cultures were treated withIL-1b, Arg-vasopressin and corticosterone, eitheralone or in combined treatment, and animmunocytochemical, morphometric and densitometricstudy of ACTH-positive cells was carriedout. IL-1b significantly increased the percentageand cellular and nuclear size ofACTH-positive cells, and similar effects werefound following treatment with Arg-vasopressin.Combined treatment with IL-1b andArg-vasopressin increased these parametersmore than in separate treatments. Corticosteronedecreased these parameters and blockedthe effects of IL-1b and Arg-vasopressin in thecombined treatments. In sum, our results suggestthat IL-1b is an auto-paracrine regulator ofpituitary ACTH-producing cells, that it reinforcesthe stimulatory effects of Arg-vasopressinand that corticosterone is an inhibitory regulatorof the auto-paracrine effects of IL-1b and Argvasopressin (AU)

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5-HT2A-mu opioid receptor mechanisms in the hypothalamus mediate interleukin-1beta fever in rats.

Direct administration of interleukin-1beta (IL-1beta) into the lateral cerebral ventricle of rat brain, in addition to inducing febrile responses, upregulated the immunoreactivity of tryptophan hydroxylase in the preoptic anterior hypothalamus. The fever induced by IL-1beta was significantly attenuated by pretreatment with intracerebroventricular injection of 5-HT2A receptor antagonists including cyproheptadine, ketanserin, or mianserin. In addition, the IL-1beta-induced fever was mimicked by intracerebroventricular administration of a 5-HT2A receptor agonist, 1-(2,5-dimethoxy-4-iodophenyl)-2-amionpropane (DOI). The DOI-induced (present results) or IL-1beta-induced (previous results) fever was further attenuated by pretreatment with an intracerebroventricular dose of mu-opioid receptor antagonists (e.g., buprenorphine or cyclic d-phe-cys-Try-d-Arg-Thr-pen-Thr-NH2) or 5-HT receptor antagonists (e.g., ketanserin or cyproheptadine). These findings suggest that a 5-HT2A-mu opioid receptor mechanism in the hypothalamus may mediate the IL-1beta fever.

Neuropeptides (SP and CGRP) augment pro-inflammatory cytokine production in HSV-infected macrophages.

Neuropeptides are able to modulate cytokine production by macrophages in response to various stimulators. In this study, the effects of neuropeptides substance P (SP) and calcitonin gene-related peptide (CGRP) on production of pro-inflammatory cytokines TNF and IL-1 beta by macrophages were considered. Mouse peritoneal macrophages were infected with herpes simplex virus type-1 (HSV-1), or remained unstimulated, and cytokine assays were performed after 12 h. IL-1 beta and TNF secretion by unstimulated macrophages have been significantly increased in the presence of SP and CGRP. Each neuropeptide, alone or in coordination with the other, caused significant increase in IL-1 beta and TNF production by HSV-infected mouse peritoneal macrophages. It was concluded that the macrophage-mediated inflammatory response to HSV-1 is enhanced in the presence of these neuropeptides.

Selective increase in TNF alpha permeation across the blood-spinal cord barrier after SCI.

We generated a novel mouse model of spinal cord injury (SCI) by hemisection of the right L1 lumbar spinal cord, measured the permeability of the blood-spinal cord barrier (BSCB), and tested the hypothesis that tumor necrosis factor alpha (TNF alpha) penetrates the injured BSCB by an enhanced transport system. SCI produced stereotypical sensorimotor deficits resembling the classically described Brown-Seqúard syndrome. Disruption of the BSCB was reflected by increased spinal cord uptake of radiolabeled albumin from blood; this was transient (immediately after SCI) and confined to the lumbar spinal cord. By contrast, specific increase in the entry of TNF alpha was detected in brain, cervical, thoracic, and lumbar spinal cord at 1 week after SCI, in addition to its immediate and transient increase consistent with barrier disruption. Lack of a second peak of increase in the entry of IL1 beta further supported the specificity of the TNF alpha response. Moreover, enhanced uptake of radiolabeled TNF alpha was suppressed by excess non-radiolabeled TNF alpha, indicating competition of entry via the known transport system for TNF alpha. Therefore, upregulation of the transport system after SCI probably mediates the increased permeation of TNF alpha across the BSCB. Enhanced entry of TNF alpha at 1 week after SCI was concurrent with sensorimotor and gait improvement of the mouse. We conclude that SCI by lumbar hemisection activates the transport system for TNF alpha at the BBB and suggest that selective permeation of TNF alpha may facilitate functional recovery.

Procalcitonin and proinflammatory cytokine clearance during continuous venovenous haemofiltration in septic patients.

Procalcitonin (PCT), interleukin-6 (IL-6), tumour necrosis factor a (TNFalpha), and interleukin-1beta (IL-1beta) are important clinical prognostic markers in ICU septic patients. The goal of the study was to determine whether continuous venovenous haemofiltration (CWH), using an AN69 haemofilte, leads to elimination of PCT, TNFalpha, IL-6 and IL-1beta in 13 septic patients with multi-organ failure. At the start of haemofiltration (0), 6 and 12 hours the mean afferent plasma concentration +/- SD of PCT (10.1 +/- 9.1, 7 +/- 6, 5.9 +/- 5.7 ng/ml), IL-6 (804.6 +/- 847.6, 611.7 +/- 528.4, 575.2 +/- 539.2 pg/ml), and that of TNFalpha (4.5 +/- 2.6, 4 +/- 3.1, 3.8 +/- 2.9 pg/ml) significantly declined during CVVH. The efferent plasma concentrations were significantly lower than the corresponding afferent concentrations. PCT; IL-6 and TNFalpha were detectable in the ultrafiltrate of all patients. IL-1beta was only detectable in the plasma of eight patients and the ultrafiltrate of five patients. The plasma clearance of PCT, IL-6 and TNFalpha significantly decreased after 12 hours as a result of a decline in the adsorptive elimination of the mediators due to progressive membrane saturation. We demonstrated that if PCT, IL-6 and TNFalpha are used as clinical prognostic markers in septic patients who are treated with CWIH using an AN69 membrane, one should be aware that their plasma level could be modified by the therapy. In addition CWH could represent an appropriate tool to remove a broad spectrum of proinflammatory mediators, if such removal is required in septic patients.

Interleukin-1 beta, but not IL-1 alpha, mediates nerve growth factor secretion from rat astrocytes via type I IL-1 receptor.

In astrocytes, nerve growth factor (NGF) synthesis and secretion is stimulated by the cytokine interleukin-1 beta (IL-1 beta). In the present study, the role of IL-1 receptor binding sites in the regulation of NGF release was evaluated by determining the pharmacological properties of astroglially localized IL-1 receptors, and, by comparing the effects of both the agonists (IL-1 alpha and IL-1 beta) and the antagonist (IL-1ra)-members of the IL-1 family on NGF secretion from rat neonatal cortical astrocytes in primary culture. Using receptor-binding studies, binding of [(125)I] IL-1 beta to cultured astrocytes was saturable and of high affinity. Mean values for the K(D) and B(max) were calculated to be 60.7+/-7.4 pM and 2.5+/-0.1 fmol mg(-1) protein, respectively. The binding was rapid and readily reversible. IL-1 receptor agonists IL-1 alpha (K(i) of 341.1 pM) and IL-1 beta (K(i) 59.9 pM), as well as the antagonist IL-1ra (K(i) 257.6 pM), displaced specific [(125)I] IL-1 beta binding from cultured astrocytes in a monophasic manner. Anti-IL-1RI antibody completely blocked specific [(125)I] IL-1 beta binding while anti-IL-1RII antibody had no inhibitory effect. Exposure of cultured astrocytes to IL-1 alpha and IL-1 beta revealed the functional difference between the agonists in influencing NGF release. In contrast to IL-1 beta (10 U/ml), which caused a 3-fold increase in NGF secretion compared to control cells, IL-1 alpha by itself had no stimulatory action on NGF release. The simultaneous application of IL-1 alpha and IL-1 beta elicited no additive response. IL-1ra had no effect on basal NGF release but dose-dependently inhibited the stimulatory response induced by IL-1 beta. We concluded that IL-1 beta-induced NGF secretion from cultured rat cortical astrocytes is mediated by functional type I IL-1 receptors, whereas IL-1 alpha and IL-1ra, in spite of their affinity for IL-1RI, have no effect on NGF secretion from these cells. Type II IL-1R is not present on rat neonatal cortical astrocytes.

1,25-dihydroxyvitamin D3 differentially regulates IL-1alpha-stimulated IL-8 and MCP-1 mRNA expression and chemokine secretion by human primary proximal tubular epithelial cells.

Beside its role in calcium homeostasis, 1,25-D3 modulates multiple immunological functions in cells of the immune system. In tubular epithelial cells, it increases the expression of HLA-DR and ICAM-1 molecules. Since production of chemokines, such as IL-8 and MCP-1, by tubular epithelial cells is crucial for the inflammatory response in acute transplant rejection and interstitial nephritis, we tested whether 1,25-D3 influences the production of IL-8 and MCP-1 by primary human tubular epithelial cells (TEC). For chemokine detection we used enzyme-linked immunosorbent assays. We differentiated between chemokine secretion directed to the apical and basolateral environment by using cell culture inserts as a model for the tubular basement membrane. mRNA of IL-8 and MCP-1 after stimulation of TEC with IL-1alpha and/or 1,25-D3 was isolated and compared by competitive RT-PCR. We found that basolateral production of IL-8 was higher than luminal secretion. 1,25-D3 (10(-8) M) alone and in combination with IL-1alpha suppressed IL-8 production after 48 h. Basolateral compared to luminal MCP-1 secretion was higher after stimulation either with IL-1alpha alone or combined with 1,25-D3. After 72 h, 1,25-D3 enhanced the IL-1alpha-stimulated MCP-1 secretion. Increased IL-8 mRNA expression after stimulation with IL-1alpha was suppressed by coincubation with 1,25-D3, while MCP-1 mRNA synthesis was enhanced by 1,25-D3 alone and in combination with IL-1 alpha. We conclude that 1,25-D3 differently modulates the expression of CXC-chemokine IL-8 and CC-chemokine MCP-1 by human TEC. The differential effects of 1,25-D3 on renal tubular cytokine secretion have to be considered in therapeutic dials on this hormone, e.g. in renal transplant rejection.

Disruption of the blood-aqueous barrier following retinal laser photocoagulation and cryopexy in pigmented rabbits.

Disruption of the blood-aqueous barrier (BAB) induced by retinal photocoagulation and cryopexy in pigmented rabbits was evaluated by laser flare photometry. A significant increase in flare values after retinal photocoagulation was measured from the 1st postoperative day, with values returning to baseline levels by day 7. Cryopexy induced consistently high flare values for 14 days. Intravitreal injection of interleukin (IL) 1, IL-6 and prostaglandin (PG) E(2) induced a significant increase in flare values. Following these treatments, introduction of a PG synthetase inhibitor can partially ameliorate BAB disruption. IL-1, IL-6 and PGE(2) may be involved in BAB disruption following retinal photocoagulation and cryopexy.

Diffusion and action of intracerebroventricularly injected interleukin-1 in the CNS.

Interleukin-1beta acts on the CNS to induce fever, neuroendocrine activation and behavioural depression. We have previously demonstrated that interleukin-1beta is synthesized in glial cells and macrophages of circumventricular organs and choroid plexus after intraperitoneal administration of bacterial lipopolysaccharide. Whether, and how, interleukin-1beta produced in glial cells affects neuronal functioning is unknown. Diffusion throughout the extracellular space is an important pathway by which factors produced by glial cells act on distant cells, a phenomenon coined "volume transmission". The present study assessed diffusion of recombinant rat interleukin-1beta, recombinant human interleukin-1 receptor antagonist and 10mol. wt dexran in the rat CNS after intracerebroventricular administration to model interleukin-1beta release from choroid plexus. Immunocytochemistry with specific antibodies directed against interleukin-1beta and interleukin-1 receptor antagonist revealed that these molecules rapidly penetrated into periventricular tissue and spread along white matter fibre bundles and blood vessels in the caudoputamen, hypothalamus and amygdala. The transcription factor nuclear factor kappa B and the immediate-early gene product Fos were detected immunocytochemically to reveal interleukin-1beta action. Intracerebroventricular infusion of interleukin-1beta induced nuclear factor kappa B translocation in choroid plexus, ependymal cells, basolateral amygdala, cerebral vasculature and meninges. Fos immunoreactivity was found in the supraoptic and paraventricular hypothalamus and central amygdala. We propose that intracerebroventricular injected interleukin-1beta can enter the brain parenchyma and act as a "volume transmission" signal in, for example, the basolateral amygdala where it might activate a neuronal projection to the central amygdala.

Differential transport of rat and human interleukin-1alpha across the blood-brain barrier and blood-testis barrier in rats.

Human interleukin-1alpha is transported across the murine blood-brain barrier (BBB) and blood-testis barrier (BTB) by a saturable transport system. Differences in the biological activity and binding of human IL-1 in mouse and rat brain raise the possibility of species differences in the transport of IL-1 across the BBB and BTB. We measured the transport of recombinant human 125I-IL-1alpha (I-huIL-1alpha) and rat 125I-IL-1alpha (I-ratIL-1alpha) across the rat BBB and BTB after intravenous injection using a sensitive in vivo technique and film autoradiography. I-ratIL-1alpha was found to cross the rat BBB and rat BTB at rates comparable to those reported previously for murine IL-1alpha in mice. Passage across the BBB was inhibited by the addition of unlabeled rat IL-1alpha, demonstrating saturable transport. In contrast, I-huIL-1alpha entered the brain of the rat much more slowly, and its entry was not inhibited by the addition of unlabeled human IL-1alpha. These results show that the rat interleukin-1 transporter, unlike the murine transporter, does not transport human IL-1alpha. This difference highlights the importance of species specificity in IL-1alpha transport and may partly explain the different physiological responses to exogenous human IL-1alpha among rodent species.

Hemodiafiltration with online regeneration of the ultrafiltrate.

The concept of regeneration of dialysis fluids and of ultrafiltrate in particular has been recently revisited. Hemodiafiltration with online regeneration of the ultrafiltrate allows the concomitant infusion of sodium, calcium, and bicarbonate. Here, we studied the adsorptive characteristics of an integrated two-step sorbent system relative to different solutes present in the ultrafiltrate: sodium, calcium, phosphate, bicarbonate, uric acid, creatinine, and beta2-microglobulin. In vitro studies were performed in order to differentiate the relative roles for each sorbent (mineral-activated charcoal or hydrophobic resin) in adsorbing a given solute. Ex vivo studies were performed in order to evaluate the presence of cytokines (interleukin-1 beta and tumor necrosis factor-alpha), of cytokine (interleukin-1 beta and tumor necrosis factor-alpha)-inducing activities, and of the cytokine release in response to exogenous bacterial lipopolysaccharide by normal whole blood incubated with ultrafiltrate samples obtained at 15, 120, and 240 minutes after the start of treatment. The results of the present studies show the presence of immunomodulatory substances in the ultrafiltrate and the significant (P < 0.01) increase in the lipopolysaccharide-induced release of both interleukin-1 beta and tumor necrosis factor-alpha. The biological relevance of the ultrafiltrate and the possible relevance of the online, endogenous reinfusion are discussed.

Efecto de la interleucina 1ß sobre la expresión de la molécula de adhesión ICAM-1 soluble tras una agresión endotóxica experimental / Effect of interleukin 1- on expression of the adhesion molecule ICMs-1 following experimental endotoxic shock

Introducción. Durante el síndrome de respuesta inflamatoria sistémica, la célula endotelial expresa en su membrana moléculas de adhesión, favoreciendo la acción lesiva local de los leucocitos polimorfonucleares de neutrófilos. En este trabajo estudiamos el efecto que ejerce la administración de interleucina 1ß murina sobre la expresión de la molécula de adhesión intercelular (ICAM-1) soluble tras una agresión endotóxica. Material y métodos. Se han dividido 72 ratones de la cepa CBA/H en tres grupos de 24: grupo 1 (simulado); grupo 2 (control, el shock endotóxico se provocó mediante la inyección de lipopolisacárido de membrana bacteriana de Escherichia coli serotipo 055:B5 a dosis de 125 mg/kg); grupo 3 (tratado con interleucina 1ß murina a dosis de 80 ng/ratón 24 h antes del lipopolisacárido de membrana). Se han determinado, mediante la técnica de ELISA, las concentraciones séricas de ICAM-1 soluble a las 1, 2, 4 y 24 h de inyectar el lipopolisacárido. Resultados. El tratamiento con interleucina 1ß provocó un significativo descenso de las concentraciones séricas de ICAM-1 soluble a las 4 y 24 h tras la agresión endotóxica respecto al grupo control. Conclusiones. La administración de interleucina 1ß disminuye las concentraciones séricas de ICAM-1 soluble, que aparecen elevadas tras una agresión endotóxica experimental (AU)

Glycosylated human interleukin-1alpha, neoglyco IL-1alpha, coupled with N-acetylneuraminic acid exhibits selective activities in vivo and altered tissue distribution.

In order to study the effect of glycosylation on its biological activities and to develop IL-1 with less deleterious effects, N-acetylneuraminic acid (NeuAc) with C9 spacer was chemically coupled to human recombinant IL-1alpha. NeuAc-coupled IL-1alpha (NeuAc-IL-1alpha) exhibited reduced activities in vitro and receptor-binding affinities by about ten times compared to IL-1alpha. In this study, we examined a variety of IL-1 activities in vivo. NeuAc-IL-1alpha exhibited a marked reduction in the activity to up-regulate serum IL-6, moderate reduction in the activities to up-regulate serum amyloid A and NOx. However, it exhibited comparable activities as IL-1alpha to down-regulate serum glucose and to improve the recovery of peripheral white blood cells from myelosuppression in 5-fluorouracil-treated mice. In addition, tissue level of NeuAc-IL-1alpha was high compared to IL-1alpha. These results indicate that coupling with NeuAc enabled us to develop neo-IL-1 with selective activities in vivo and enhanced tissue level.

Intrarenal handling of recombinant human interleukin-1alpha in rats: mechanism for proximal tubular protein reabsorption.

The intrarenal distribution of recombinant human interleukin (IL)-la was studied in Sprague-Dawley male rats by immunohistochemical staining. The effects of the concurrent administration of various proteins or synthetic polypeptides on the urinary excretion of IL-1alpha were also studied to clarify the mechanism(s) for the reabsorption of IL-la in the renal tubules. Microscopic immunohistochemistry showed that IL-1alpha distributed to early proximal convoluted tubules but not to glomeruli, Henle's loops, distal tubules, or collecting ducts. Electron microscopic immunohistochemistry showed that IL-la was taken up into the endocytic vesicle located close to the apical membrane of the proximal tubular epithelial cells, then accumulated in lysosomes. Urinary excretion of intravenous IL-la at 500 microg/kg was extremely low, accounting for only 0.014% of the dose administered. The coadministration of intravenous human serum albumin did not affect the urinary excretion of IL-1alpha, whereas trypsinogen, myoglobin, and trypsin inhibitor dose-dependently produced an increase in the excretion of IL-la, the potency of which was greatest in that order. Poly-L-lysine, but not poly-L-glutamic acid dose-dependently increased the urinary excretion of IL-1alpha. These results indicate that most of the glomerular filtrated IL-1alpha could be easily reabsorbed into the proximal tubular cells via endocytosis, and the reabsorption was inhibited by coadministered low molecular weight proteins, particularly basic proteins. This result suggests that scavengers with a negative charge and broad binding ability for glomerular filtered proteins exist on the surface of the apical membrane of proximal tubular cells and play an important role in the reabsorption of filtered proteins.

Tumor necrosis factor-alpha and interleukin-1beta synergistically depress human myocardial function.

OBJECTIVE: Proinflammatory cytokines such as tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta have been implicated in the pathogenesis of myocardial dysfunction in ischemia-reperfusion injury, sepsis, chronic heart failure, viral myocarditis, and cardiac allograft rejection. Although circulating TNF-alpha and IL-1beta are both often elevated in septic shock, it remains unknown whether TNF-alpha or IL-1beta are the factors induced during sepsis that directly depress human myocardial function, and if so, whether the combination synergistically depresses myocardial function. Furthermore, the mechanism(s) by which these cytokines induce human myocardial depression remain unknown. We hypothesized the following: a) TNF-alpha and IL-1beta directly depress human myocardial function; b) together, TNF-alpha and IL-1beta act synergistically to depress human myocardial function; and c) inhibition of ceramidase or nitric oxide synthase attenuates myocardial depression induced by TNF-alpha or IL-1beta by limiting proximal cytokine signaling or production of myocardial nitric oxide (NO). DESIGN: Prospective, randomized, controlled study. SETTING: Experimental laboratory in a university hospital. SUBJECTS: Freshly obtained human myocardial trabeculae. INTERVENTIONS: Human atrial trabeculae were obtained at the time of cardiac surgery, suspended in organ baths, and field simulated at 1 Hz, and the developed force was recorded. After a 90-min equilibration, TNF-alpha (1.25, 12.5, 125, or 250 pg/mL for 20 mins), IL-1beta (6.25, 12.5, 50, or 200 pg/mL for 20 mins), or TNF-alpha (1.25 pg/mL) plus IL-1beta (6.25 pg/mL) were added to the bath, and function was measured for the subsequent 100 mins after the 20-min exposure. To assess the roles of the sphingomyelin and NO pathways in TNF-alpha and IL-1beta cross-signaling, the ceramidase inhibitor N-oleoyl ethanolamine (1 microM) or the NO synthase inhibitor N(G)-monomethyl-L-arginine (10 microM) was added before TNF-alpha (125 pg/mL) or IL-1beta (50 pg/mL). MEASUREMENTS AND MAIN RESULTS: TNF-alpha and IL-1beta each depressed human myocardial function in a dose-dependent fashion (maximally depressing to 16.2 + 1.9% baseline developed force for TNF-alpha and 25.7 + 6.3% baseline developed force for IL-1beta), affecting systolic relatively more than diastolic performance (each p < .05). However, when combined, TNF-alpha and IL-1beta at concentrations that did not individually result in depression (p > .05 vs. control) resulted in contractile depression (p < .05 vs. control). Inhibition of myocardial sphingosine or NO release abolished the myocardial depressive effects of either TNF-alpha or IL-1beta. CONCLUSIONS: TNF-alpha and IL-1beta separately and synergistically depress human myocardial function. Sphingosine likely participates in the TNF-alpha and IL-1beta signal leading to human myocardial functional depression. Therapeutic strategies to reduce production or signaling of either TNF-alpha or IL-1beta may limit myocardial dysfunction in sepsis.

Peripheral effects of centrally administered interleukin-1beta in mice in relation to its clearance from the brain into the blood and tissue distribution.

Administration of interleukin IL-1 induces acute-phase response and inhibition of gastric secretion more efficiently when administered intracerebroventricularly (i.c.v.) than when the same dose of IL-1 is administered systemically. In this study we describe the pharmacokinetics of IL-1beta, administered centrally or systemically, in the serum or in peripheral tissues. IL-1beta administered i.c.v. resulted in higher peak IL-1beta concentrations, and lasted longer, than intravenous (i.v.) or intraperitoneal (i.p.) administration. Higher IL-1beta levels in the liver and heart were observed after i. c.v. administration (compared to the i.p. or i.v. route). Our data suggest that centrally injected IL-1 induces higher circulating and hepatic IL-1 levels and contributes to the fact that the i.c.v. route of administration is particularly effective in inducing a liver acute-phase response.

Effect of IL-1alpha on the release of norepinephrine in rat hypothalamus.

The increased release of norepinephrine (NE) in the brain as part of the 'acute phase response' has been postulated to result from a direct action of IL-1 on the hypothalamus. To test whether the effects of IL-1alpha were direct, we carried out in vivo experiments using microdialysis and measured NE release in the hypothalamus using high pressure liquid chromatography (HPLC). Two groups of male Sprague Dawley rats were either injected intraperitoneally with 1 ml of IL-1alpha (2 microg/ml) or had IL-1alpha 2 microl (100 ng/ml) infused directly into the medial hypothalamus. A significant increase in extracellular hypothalamic NE was observed in the animal group treated with IL-1alpha intraperitoneally and not in the controls or the group treated with IL-1alpha intracerebrally. One-way ANOVA showed a significant effect of drug and route of administration with the ip IL-1alpha treated group, differing from all other groups (vehicle ip, IL-1alpha ic, and vehicle ic). Therefore these findings suggest that some aspects of IL-1alpha actions on the HPA may be indirect requiring other intermediate steps or mediators outside the central nervous system.

Interleukin 1 (IL-1) type I receptors mediate activation of rat hypothalamus-pituitary-adrenal axis and interleukin 6 production as shown by receptor type selective deletion mutants of IL-1beta.

The cytokine interleukin 1 (IL-1) plays an important role in the activation of the hypothalamus-pituary-adrenal (HPA)-axis and interleukin 6 (IL-6) production during infection or inflammation. Which of the interleukin-1 receptor types mediates these effects is not known. To investigate this issue a pharmacological approach was chosen by using recently developed IL-1 receptor type selective ligands. Rats were given one of various doses of recombinant human IL-1beta (rhIL-1beta; 1 and 10 microg/kg) and of several IL-1beta mutants (DeltaSND, DeltaQGE and DeltaI; 1, 10 and 100 microg/kg), that differ in their affinities for the IL-1 type I receptor but have similar affinities for the IL-1 type II receptor. One hour after intravenous administration of rhIL-1beta or IL-1beta mutants, plasma levels of ACTH, corticosterone (cort) and IL-6 were measured. Doses of 1 and 10 microg/kg rhIL-1beta markedly elevated plasma levels of ACTH, cort and IL-6. However, 10-100-fold higher doses of IL-1beta mutants DeltaSND and DeltaQGE and at least 100-fold higher doses of DeltaI have to be administered to increase plasma levels of ACTH, cort and IL-6. The potency differences correlate with their respective affinity for the type I receptor but not with that of the IL-1 type II receptor. It is concluded that IL-1beta induced ACTH, cort and IL-6 production is mediated by interleukin 1 type I receptors.

Transfer of endogenous pyrogens across artificial membranes?

Synthetic high-flux dialyzer membranes used in continuous veno-venous hemofiltration are permeable to middle molecular size endogenous pyrogens, the pro-inflammatory cytokines IL-1 beta and TNF-alpha. The quantities removed by sieving are, however, negligible in vitro as well as in vivo. Adsorption of cytokines to the membrane polymer is the major mechanism of pyrogen removal. Adsorption seems to be semispecific for pro-inflammatory cytokines because levels of anti-inflammatory mediators were not changed or even increased during CVVH. Thus, CVVH may change cytokine profiles in septic patients supporting the predominance of anti-inflammatory over pro-inflammatory activity in plasma. It remains to be demonstrated whether modifications of extracorporeal blood purification systems (high-volume CVVH, plasma separation + adsorption) are able to amplify the change in cytokine profiles and whether this change influences outcome of septic patients.