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Showing papers by "Charles A. Dinarello published in 1997"


Journal ArticleDOI
TL;DR: Recent data suggest that interleukin 6 (IL-6) and IL-6-regulated APPs are anti-inflammatory and immuno-suppressive, and may negatively regulate the acute phase response.

646 citations



Journal Article
TL;DR: It is demonstrated that in turpentine-induced tissue necrosis, precursor IL-1 beta is processed by non-ICE proteases, but in complement-mediated inflammation, ICE participates in the processing of the IL- 1 beta precursor.
Abstract: IL-1 beta-converting enzyme (ICE) cleaves pro-IL-1 beta to the mature, released form. Although other proteases can process pro-IL-1 beta, ICE-deficient (ICE -/-) mice do not release mature IL-1 beta in response to endotoxin. The purpose of our study was to investigate the response of ICE -/- mice in two models of local inflammation, turpentine-induced tissue damage and zymosan-induced peritonitis. No differences were observed in the development of the systemic acute phase response after turpentine administration between wild-type and ICE -/- mice, but this response was completely impaired in IL-1 beta -/- mice. Accordingly, the levels of mature IL-1 beta produced in response to turpentine did not differ between wild-type and ICE -/- mice. In contrast, following zymosan-induced peritonitis, the levels of mature IL-1 beta were significantly lower in ICE -/- mice. This was associated with a 50% decrease in cellular infiltrate in ICE -/- mice compared with that in wild-type controls. The reduced production of zymosan-induced mature IL-1 beta in ICE -/- mice was also observed from cultured peritoneal or spleen cells. Our results demonstrate that in turpentine-induced tissue necrosis, precursor IL-1 beta is processed by non-ICE proteases, but in complement-mediated inflammation, ICE participates in the processing of the IL-1 beta precursor.

247 citations


Journal ArticleDOI
TL;DR: It is demonstrated that hemorrhage initially increases pulmonary cytokine expression through alpha- but not beta-adrenergic stimulation, and suggested that such alpha- adrenergic-mediated effects occur through activation of the transcriptional regulatory factor NF-kappaB.
Abstract: The expression of proinflammatory and immunoregulatory cytokines rapidly increases in the lungs after hemorrhage, and such alterations contribute to the frequent development of acute inflammatory lung injury in this setting. Blood loss also produces elevations in catecholamine concentrations in the pulmonary and systemic circulation. In the present experiments, we used alpha- and beta-adrenergic receptor blockade to examine in vivo interactions between hemorrhage-induced adrenergic stimulation and pulmonary cytokine expression. Treatment of mice with the alpha-adrenergic receptor antagonist phentolamine prevented not only the elevation in mRNA levels of IL-1beta, TNF-alpha, and TGF-beta1, the increase in IL-1beta protein, but also the activation of nuclear factor (NF)-KB and cyclic AMP response element binding protein, which occurred in lung cells of untreated animals during the first hour after hemorrhage. In contrast, treatment before hemorrhage with the beta-adrenergic receptor antagonist propranolol was associated with increases in mRNA levels for IL-1beta, TNF-alpha, and TGF-beta1, which were greater than those present in untreated hemorrhaged mice, and did not prevent hemorrhage-associated increases in lung IL-1beta protein. Treatment with propranolol prevented hemorrhage-induced phosphorylation of cyclic AMP response element binding protein, but increased hemorrhage-associated activation of NF-KB. These results demonstrate that hemorrhage initially increases pulmonary cytokine expression through alpha- but not beta-adrenergic stimulation, and suggest that such alpha-adrenergic-mediated effects occur through activation of the transcriptional regulatory factor NF-kappaB.

189 citations


Journal ArticleDOI
TL;DR: AA in rats is a useful model of inflammatory cachexia that mimics the human pathophysiology in important ways, and is consistent with cytokine-driven cachexia in chronic inflammatory arthritis.
Abstract: Objective. To determine whether adjuvant arthritis (AA) leads to changes in body composition and cytokine production similar to those seen in patients with rheumatoid arthritis. Methods. AA was induced in Lewis rats using Freund's complete adjuvant. Body cell mass was measured by determining the concentration of total exchangeable potassium using 42K gavage. Splenocyte production of interleukin-1 (IL-1) and tumor necrosis factor α (TNFα) was measured by bioassay. Weight and food intake were also measured. Results. Animals that developed AA lost 6% of their body weight by the onset of clinically evident arthritis (day 14; P < 0.01) and lost 20% by the end of the inflammatory phase of AA (day 28; P < 0.0001). Body cell mass fell 24.7 ± 8.6% (mean ± SEM) in animals with AA, but did not change significantly in controls (increase of 6.3 ± 7.9%) (P < 0.03). Pair-fed animals lost one-fourth of the weight lost by the animals with AA (P < 0.01), indicating that anorexia alone does not explain inflammatory cachexia. Weight loss was correlated with TNFα production by spleen mononuclear cells (r = 0.68, P < 0.007), and a weaker correlation was seen with IL-1 production (r = 0.45, P < 0.04). Conclusion. AA in rats is a useful model of inflammatory cachexia that mimics the human pathophysiology in important ways, and is consistent with cytokine-driven cachexia in chronic inflammatory arthritis.

162 citations


Journal Article
TL;DR: It is demonstrated that in addition to short term endothelial activation, thrombin also functions as a long acting proinflammatory agent by inducing endothelial synthesis of the mediators required for neutrophils activation and extravazation during inflammation.
Abstract: In addition to its role in coagulation, thrombin is involved in the inflammatory process by inducing vessel neutrophilic infiltration Thrombin induces endothelial P-selectin expression and platelet activating factor release, which participate to induce early neutrophil adhesion and activation We employed HUVEC and now show that thrombin induces the production of the chemokine IL-8 in a time- and dose-dependent fashion Similarly, thrombin induced E-selectin expression on HUVEC Both IL-8 secretion and E-selectin expression were preceded by an increase in steady state levels of the respective mRNAs Thrombin action on HUVEC was inhibited by the specific thrombin inhibitor, hirudin In addition, these effects of thrombin on HUVEC were mimicked by the 14-amino acid thrombin receptor agonist peptide, which triggers the native thrombin receptor in a similar fashion to thrombin itself Although IL-1 and TNF-alpha also induce IL-8 and E-selectin, the thrombin effects in these experiments were not mediated by those cytokines, since neither IL-1 receptor antagonist nor anti-TNF-alpha Ab inhibited the effects of thrombin Furthermore, IL-1alpha, IL-1beta, and TNF-alpha were not detected in the supernatants of thrombin-activated HUVEC Although intracellular IL-1alpha was found in thrombin-activated HUVEC, antisense IL-1alpha had no inhibitory effect on IL-8 secretion These results demonstrate that in addition to short term endothelial activation, thrombin also functions as a long acting proinflammatory agent by inducing endothelial synthesis of the mediators required for neutrophils activation and extravazation during inflammation

149 citations


Journal ArticleDOI
TL;DR: In PBMC stimulated by hyperosmotic stress, the addition of femtomolar concentrations of bacterial lipopolysaccharide, IL-1, or 1% normal human serum resulted in a synergistic synthesis (at least twice that expected) of IL- 1 alpha,IL-1 beta, TNF-alpha, and IL-8.

135 citations


Journal ArticleDOI
01 Aug 1997-Blood
TL;DR: During the early stage of meningococcal infections IL-1Ra modulatesIL-1 activity, whereas during recovery IL-2sRII may be more important, which suggests different modulation of IL- 1beta activity in the subarachnoid space and the plasma compartment.

91 citations


Journal ArticleDOI
TL;DR: It is demonstrated that IL-1 beta plays a significant, although not exclusive, role in the physiological and cytokine responses to zymosan-mediated inflammation.
Abstract: Interleukin (IL)-1 beta-deficient (IL-1 beta -/-) mice exhibited decreased zymosan-induced lethality and reduced production of IL-6 compared with wild-type controls (IL-1 beta +/+). In addition, IL-1 beta -/- mice had a diminished cellular infiltrate (33%) in the peritoneal cavity after zymosan. However, anorexia and hypoglycemia were not affected by the lack of IL-1 beta. The induction of corticosterone was only slightly reduced (14%) in IL-1 beta -/- mice. Peritoneal lavage fluid levels for IL-1 alpha, but not for tumor necrosis factor (TNF)-alpha, were also decreased. To evaluate the role of residual IL-1 alpha production in IL-1 beta -/- mice, we used IL-1-receptor antagonist (IL-1ra). In IL-1 beta +/+ mice, IL-1ra inhibited production of IL-6 after zymosan, without affecting TNF-alpha synthesis. There was no further inhibitory effect of IL-1ra on IL-6 production in IL-1 beta -/- mice, suggesting no role for IL-1 alpha in zymosan-induced IL-6. Our results demonstrate that IL-1 beta plays a significant, although not exclusive, role in the physiological and cytokine responses to zymosan-mediated inflammation.

57 citations


Journal ArticleDOI
TL;DR: Despite evidence of in vitro neutralization of TNF functional activity and partial inhibition of other secondary biologic effects of IL-2, rhuTNFR:Fc does not reduce the clinical toxicity associated with high-dose IL- 2 therapy.
Abstract: PURPOSEA randomized, double-blind, placebo-controlled trial was performed to compare the toxicity and biologic effects of treatment with high-dose intravenous (IV) bolus interleukin-2 (IL-2) plus the recombinant human soluble p75 tumor necrosis factor (TNF) receptor immunoglobulin G (IgG) chimera (rhuTNFR:Fc) with high-dose IL-2 alone in patients with advanced melanoma and renal cell carcinoma.PATIENTS AND METHODSTwenty patients with advanced melanoma or renal cell carcinoma were randomized to receive IL-2 (Chiron, Emeryville, CA) 600,000 IU/kg every 8 hours on days 1 to 5 and 15 to 19 (maximum, 28 doses) combined with placebo or the rhuTNFR:Fc fusion protein (Immunex, Seattle, WA) 10 mg/m2 on days 1 and 15 and 5 mg/m2 on days 3, 5, 17, and 19. The impact of rhuTNFR:Fc on IL-2 toxicity and biologic effects was evaluated.RESULTSNo clinically significant difference in toxicity was observed in the two treatment arms. The adjusted median number of IL-2 doses administered during cycle 1 was 24.5 (range, seven ...

53 citations


Book ChapterDOI
01 Jan 1997
TL;DR: The study shows that autonomous growth of AML cells is inhibited by antisense oligonucleotide to IL-1β converting enzyme and by IL- 1RA, and suggests that pro-IL-1 β processing is an essential step in the regulation ofAML cell growth.
Abstract: Publisher Summary This chapter presents a study on pro-1L-1β processing in the autocrine regulation of acute myeloid leukaemic (AML) cell growth. For this study, leukaemia cells of 19 randomly selected AML patients were obtained at diagnosis from bone marrow (BM) and peripheral blood (PB) samples. Low-density leukaemia cells were prepared by using the Ficoll–Hypaque density gradient, and they were grown continuously in the presence of recombinant human IL-1RA, or phosphorothioate-derived 16-mer antisense oligonucleotide for human IL-1β converting enzyme CCT-TGT-CGG-CCA-TGG-C. The effects of the agents on AML cell growth were assessed by using two complementary systems: colony formation (CFU-AML) and AML cell proliferation. Both BM-derived and PB-derived AML cells displayed autonomous growth. Spontaneous cell proliferation varied, as well as CFU-AML colony formation, and did not correlate with the type of AML according to the FAB criteria. The study shows that autonomous growth of AML cellsis inhibited by antisense oligonucleotide to IL-1β converting enzyme and by IL-1RA. IL-1 blockade affected AML cell proliferation as well as AML cell progenitors. Since the inhibitory effect of antisense ICE oligonucleotide was more efficient when compared to the effect of IL-1RA, the results suggest that pro-IL-1β processing is an essential step in the regulation of AML cell growth.