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Receptor binding and biological activity properties of human interleukin-1 beta can be dissociated by mutating a single amino acid, arginine 127, to glycine (IL-1 beta R----G) [Gehrke et al. (1990) J. Biol. Chem. 265, 5922-5925]. The mechanism underlying the reduced biological activity has been examined by replacing arginine 127 with several other amino acids, followed by determination of biological activity using a T-helper cell proliferation assay. Mutant IL-1 beta proteins containing lysine, glutamic acid, tryptophan, or alanine in place of arginine 127 maintain biological activity. These data strongly suggest that IL-1 beta biological activity is not directly dependent upon the specific properties of charge, hydrophobicity/hydrophilicity, or side-chain group presented by the residue at position 127. Molecular modeling analyses indicate that the structural integrity of the antiparallel beta-strand 1/12 pair is disturbed in the glycine 127 mutant protein. Collapse of beta-strand 1 into a hydrated space between strands 1, 2, and 4 could structurally alter a cleft in IL-1 beta that contains a cluster of highly conserved amino acids, including a key aspartic acid residue [Ju et al. (1991) Proc. Natl. Acad. Sci. U.S.A. 88, 2658-2662]. Mutagenesis data and the differential activities of the IL-1 beta R----G and IL-1 receptor antagonist proteins in stimulating early and late gene expression [Conca et al. (1991) J. Biol. Chem. 266, 16265-16268] suggest that multiple receptor-ligand contacts, exclusive of those required for receptor binding, are required for the stimulation of full IL-1 biological activity.
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PMID:Multiple amino acid substitutions suggest a structural basis for the separation of biological activity and receptor binding in a mutant interleukin-1 beta protein. 138 53

Circulating phospholipase A2 (PLA2) has been recognized as a mediator of cardiovascular collapse in septic shock. Proximal mediators of endotoxemia, including tumor necrosis factor and interleukin 1, induce PLA2 synthesis and release, but the factors regulating PLA2 elimination are unknown. Similarly, the kinetics of PLA2 clearance during recovery from septic shock have not been examined. An autoregressive mathematical model was developed to describe the rate of PLA2 clearance during the recovery phase of septic shock. This model (which estimates that the current day's PLA2 level is 77% of the previous day's level), accounted for 89% of the variability seen in the data. The estimated circulating half-life of soluble PLA2 in septic shock in man was 32 hours. Since elevation in serum PLA2 activity is closely associated with bacteremia or endotoxemia, a significant deviation from predicted PLA2 values may denote impending relapse.
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PMID:A predictive model for the clearance of soluble phospholipase A2 during septic shock. 194 May 88

Both recombinant tumor necrosis factor (rTNF) and recombinant interleukin 1 (rIL-1) are able to mediate vascular collapse and death in a previously described murine model, using galactosamine to enhance the toxicity of these cytokines. Unexpectedly, both acid-treated tumor necrosis factor (TNF) and a site-specifically mutagenized form of interleukin 1 (IL-1) (His-30----Arg-30), which fails to bind to the IL-1 receptor, retain full in vivo toxicity in this model of TNF- and IL-1-mediated shock. Previous studies have shown that rTNF and rIL-1 exhibit two functionally distinct binding regions. Both cytokines bind to their respective cell surface receptors and they also express lectin like binding specificity (Muchmore and Decker, J. Biol. Chem., 261: 13404-13407, 1986; Muchmore and Decker, J. Immunol., 138: 2541-2546, 1987) for defined oligosaccharides. The specificity of these two types of interactions is quite different. Cell surface receptors for IL-1 and TNF demonstrate essentially no cross-reactivity, whereas, in the case of carbohydrate binding, competition studies reveal an almost identical carbohydrate specificity for the structure Man5(6)GlcNAc2-Asn. Man5(6)GlcNAc2-Asn binding is either unaffected or actually enhanced by either acid treatment of rTNF or mutation at His-30 for rIL-1. Both deoxymannojirimycin and swainsonine, inhibitors of glycoprotein processing, raise intracellular levels of Man5-9GlcNAc2 and enhance the in vitro biological activity of both rTNF and rIL-1. Conversely, castanosperimine, a glucosidase I inhibitor which blocks the synthesis of mature high mannose structures, inhibits the biological activity of IL-1. These observations support the hypothesis that some effects of IL-1 and TNF may involve interaction with high mannose-substituted glycoproteins.
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PMID:Evidence that high mannose glycopeptides are able to functionally interact with recombinant tumor necrosis factor and recombinant interleukin 1. 240 Sep 92

This study describes the alterations induced by Interleukin-1 alpha and -beta (IL-1 alpha and IL-1 beta) on fibroblast-synthesized extracellular matrix. Fibroblasts were grown between pieces of dentin or in collagen-coated Terasaki wells for 3 or 6-9 weeks to create 3-dimensional cell-containing matrices constituted primarily of proteoglycans and collagens, respectively. Following incubation with IL-1 alpha or IL-1 beta (10(-9) M) at 37 degrees C for 24 or 72 hr, samples were prepared for light and electron microscopy. Both IL-1 alpha and IL-1 beta induced collapse of the extracellular matrix by 72 hr, as manifested by a decrease of the cross-sectional area and an increased density of the matrices. Three-week matrices were reduced 26% and 45% by using IL-1 alpha and IL-1 beta, respectively. Comparable values obtained by using 6-week matrices were 14% and 30%. Cells within the matrix, normally stellate in shape with numerous extended processes, attained a more rounded or spindle shape with few and reduced processes and showed apparent alterations at cell matrix attachment sites and rearrangement of the cytoskeleton. Elongated cells at the top of the matrix appeared more compressed. The alterations were more pronounced in cultures incubated with IL-beta than with IL-1 alpha. Immunocytochemistry of extracellular matrix components revealed a decrease in staining intensity of chondroitin and dermatan sulfate in the 3-week matrix following IL-1 beta incubation. There was also a decrease in collagen type 1 staining of 9-week matrices treated with IL-1 alpha or IL-1 beta. These studies show that IL-1 has an effect on fibroblast-synthesized extracellular matrix and indicate that the effects of IL-1 alpha and IL-1 beta may differ. The resulting collapse of the matrix appears at least in part to be due to changes in proteoglycans and collagens.
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PMID:Effects of interleukin-1 on fibroblast extracellular matrix, using a 3-dimensional culture system. 278 80

Since the more frequent use of highly permeable membranes and bicarbonate dialysate, hypersensitivity reactions are more often described during hemodialysis and raise the question of the entry of pyrogens from dialysate towards blood due to high permeability of membranes and to possible backfiltration. During dialysis sessions with such membranes, authors observed a severe collapse in a patient on bicarbonate fluid and a repeated Quincke's edema in another on acetate fluid. After exclusion of other causes of such hypersensitivity accidents, they discuss the role of bacterial contamination of dialysis fluid. They analyse the phenomenons of bidirectional high permeability and of backfiltration linked to these new membranes. They recall the different causes of dialysate contamination and give some means of avoiding these inconveniences which expose on one hand to acute severe reactions and on the other are prejudicial in the long term for the patients because of interleukin 1 production.
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PMID:[Hypersensitivity reactions during hemodialysis. Role of high permeability, retrofiltration and bacterial contamination of the dialysate]. 313 22

Human C5a anaphylatoxin is a potent bioactive molecule that possesses both spasmogenic and leukocyte-related properties. As such, it normally serves as a local mediator of the acute inflammatory response. Additionally, C5a, through its actions of mononuclear phagocytes, may act to bridge the gap in the acute-chronic inflammatory continuum. While these properties are critical to normal host defense mechanisms, it is now apparent that this anaphylatoxin and/or its des-Arg74 derivative, may exert significant systemic effects that are manifest as cardiopulmonary abnormalities and intravascular activation of granulocytes. Knowledge of these properties is critically important for understanding the clinical sequelae exhibited by patients undergoing extracorporeal circulation since we now know that both hemodialysis and cardiopulmonary bypass [28-30] procedures promote intravascular complement activation and C5a formation. Viewed in this context, it seems reasonable to postulate that many of the immediate and delayed responses to extracorporeal circulation might be mediated by C5a formed in the extracorporeal circuit (table IV). For example, it is now recognized that a few particularly susceptible patients display adverse reactions during the initial phases of hemodialysis. The symptoms of this so-called 'first-use syndrome' may range from severe urticaria and angioedema to life-threatening bronchospasm, hypotension, and cardiopulmonary collapse. Some investigators have presented data which suggest that complement-derived products may be causative of these symptoms in some patients [31]. While this hypothesis remains to be confirmed, present evidence clearly demonstrates that C5a alone may produce many of the observed phenomena. In addition to the acute effects produced by C5a, both our own basic studies and the clinical investigations presented by others at this conference suggest that the long-term effects of repeated C5a exposure in the dialyzed patient may be considerable. Thus, there has been a great deal of interest in the role of complement-derived mediators as initiators of leukocyte degranulation and toxic oxygen radical production and an exploration of the significance of these events in the eventual development of chronic pulmonary fibrosis in the dialyzed patient. Similarly, the effects of repeated exposure to IL-1 that has been postulated to occur as a result of C5a triggering of monocytes during dialysis is currently an active area of investigation.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The properties of human C5a anaphylatoxin. The significance of C5a formation during hemodialysis. 332 50

Experiments were designed to examine whether calcitonin gene-related peptide (CGRP), a potent adenosine 3',5'-cyclic monophosphate (cAMP)-dependent vasodilator, affects the production of NO evoked by interleukin-1 beta) (IL-1 beta) in cultured rat aortic smooth muscle cells (SMC). CGRP, in a concentration-dependent manner, enhanced the release of nitrite (a stable oxidation product of NO) and the formation of L-citrulline from L-arginine caused by IL-1 beta. Two cAMP-dependent vasodilators, forskolin and isoproterenol, and the activator of the cAMP-dependent protein kinase, Sp-cAMPS, also enhanced the release of nitrite and the formation of L-citrulline evoked by IL-1 beta. The enhancing effect of isoproterenol required the presence of the vasodilator during the induction of NO synthase (NOS). IL-1 beta-treated vascular SMC inhibited the aggregation of indomethacin-treated platelets. Inhibition of platelet aggregation was more marked with SMC exposed to a combination of IL-1 beta and either CGRP or isoproterenol than with cells exposed to IL-1 beta alone. This inhibition was prevented by methylene blue and oxyhemoglobin. IL-1 beta induced the expression of inducible NOS mRNA in vascular SMC, which was enhanced by coincubation of IL-1 beta with either CGRP, isoproterenol, or forskolin. These observations indicate that CGRP via a cAMP-dependent mechanism potentiates the IL-1-beta-induced production of NO by enhancing the expression of inducible NOS. Therefore CGRP may contribute to the substantial production of NO in the vasculature during septic shock, which accounts, at least in part, for the collapse of the vascular system.
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PMID:CGRP enhances induction of NO synthase in vascular smooth muscle cells via a cAMP-dependent mechanism. 752 98

The most well characterized function of pulmonary surfactant is its ability to reduce surface tension at the alveolar air-liquid interface, thereby preventing lung collapse. However, several lines of evidence suggest that surfactant may also have 'non-surfactant' functions: specific components of surfactant (proteins and phospholipids) may interact with different alveolar cells, inhaled particles and micro-organisms modulating pulmonary host defence systems. SP-A, the most abundant surfactant protein, binds to alveolar macrophages via a specific surface receptor with high affinity [128]. Such binding effects the release of reactive oxygen species from resident alveolar macrophages if SP-A is properly presented to the target cell. SP-A also stimulates chemotaxis of alveolar macrophages [142], and serves as an opsonin in the phagocytosis of herpes simplex virus [161] Candida tropicalis [138] and various bacteria [137]. In addition, SP-A enhances the uptake of particles by monocytes and culture-derived macrophages [140] and improves bacterial killing. SP-D, another hydrophobic surfactant-associated protein, might interact with alveolar macrophages as well, stimulating the release of oxygen radicals [148], while for the hydrophilic surfactant proteins SP-B and SP-C no macrophage interactions have been described so far. SP-A and SP-D are members of the so-called 'collectins', pattern recognition molecules involved in first line defence. While some surfactant proteins appear to stimulate certain macrophage defence functions, surfactant phospholipids seem to inhibit those of lymphocytes. Suppressed lymphocyte functions include lymphoproliferation in response to mitogens and alloantigens, B cell immunoglobulin production and natural killer cell cytotoxicity. Concerning surfactant's phospholipid composition phosphatidylglycerol is more suppressive than phosphatidylcholine on a molar basis [38]. Bovine surfactant has an immunosuppressive effect on the development of hypersensitivity pneumonitis in a guinea pig model [150]. Despite these interesting observations, several important questions concerning the interactions of surfactant components with pulmonary host defence systems remain unanswered. Sufficient host defence in the lungs works through various humoral-cellular systems in conjunction with the specific anatomy of the airways and the gas exchange surface--how does the surfactant system fit into this network? Surfactant and alveolar cells are both altered during lung injury--is there a relationship between alveolar cells from RDS patients and the endogenous surfactant isolated from such patients? How does exogenous surfactant as used for substitution therapy modulate the defence system of the host? Some of those artificial surfactants have been shown to inhibit the endotoxin-alveolar macrophages, PMNs and monocytes including IL-1, IL-6 and TNF [139,152].(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Host defence capacities of pulmonary surfactant: evidence for 'non-surfactant' functions of the surfactant system. 782 30

Branch points and flexures in the high pressure arterial system have long been recognized as sites of unusually high turbulence and consequent stress in humans are foci for atherosclerotic lesions. We show that mice that are homozygous for a null mutation in the gene encoding an endogenous antiinflammatory cytokine, interleukin 1 receptor antagonist (IL-1ra), develop lethal arterial inflammation involving branch points and flexures of the aorta and its primary and secondary branches. We observe massive transmural infiltration of neutrophils, macrophages, and CD4(+) T cells. Animals appear to die from vessel wall collapse, stenosis, and organ infarction or from hemorrhage from ruptured aneurysms. Heterozygotes do not die from arteritis within a year of birth but do develop small lesions, which suggests that a reduced level of IL-1ra is insufficient to fully control inflammation in arteries. Our results demonstrate a surprisingly specific role for IL-1ra in the control of spontaneous inflammation in constitutively stressed artery walls, suggesting that expression of IL-1 is likely to have a significant role in signaling artery wall damage.
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PMID:Arterial inflammation in mice lacking the interleukin 1 receptor antagonist gene. 1063 74

The liver is believed to play a major role in the initiation of multiorgan failure, the most lethal complication in the clinical course of sepsis. Microbes and their virulence factors enter the hepatic circulation where they first activate sinusoidal endothelial cells and Kupffer cells to produce proinflammatory mediators, including TNF-alpha, IL-1, IL-6, reactive oxygen metabolites, and eicosanoids. These mediators cause not only microbial killing, but also structural and functional liver damage concerning mainly the parenchymal cells. Leukocytes are targeted to the liver sinusoids by chemoattractants and, like platelets, tether to the sinusoidal endothelial cells, which are in a procoagulant state of inflammatory activation. Clogging of the sinusoids by these cells leads to a decrease of blood flow through the sinusoids, which is further aggravated by endothelin-1 effectuating the constriction of hepatic stellate cells in the sinusoids. In contrast, both nitric oxide (NO) and carbon monoxide (CO) act as antagonists of endothelin-1 by mediating relaxation of sinusoidal vessels. By maintaining an adequate sinusoidal perfusion, both NO and CO are hepatoprotective during the early, hyperdynamic phase of sepsis characterized by an increased cardiac output and moderate peripheral vasodilation. However, during the late, hypodynamic phase of sepsis, massive overproduction of NO by the inducible NO synthase leads to circulatory collapse, which inevitably includes breakdown of the liver circulation.
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PMID:The hepatic microvascular responses to sepsis. 1112 15


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