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Joyce A Deleo - One of the best experts on this subject based on the ideXlab platform.
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intrathecal Interleukin 1 Receptor antagonist in combination with soluble tumor necrosis factor Receptor exhibits an anti allodynic action in a rat model of neuropathic pain
Neuroscience, 2001Co-Authors: S Sweitzer, D Martin, Joyce A DeleoAbstract:The expression of Interleukin-1beta and tumor necrosis factor has previously been shown to be up-regulated in the spinal cord of several rat mononeuropathy models. This present study was undertaken to determine whether blocking the action of central Interleukin-1beta and tumor necrosis factor attenuates mechanical allodynia in a gender-specific manner in a rodent L5 spinal nerve transection model of neuropathic pain, and whether this inhibition occurs via down-regulation of the central cytokine cascade or blockade of glial activation. Interleukin-1 Receptor antagonist or soluble tumor necrosis factor Receptor was administered intrathecally via lumbar puncture to male Holtzman rats in a preventative pain strategy, in which therapy was initiated 1h prior to surgery. Administration of soluble tumor necrosis factor Receptor attenuated mechanical allodynia, while Interleukin-1 Receptor antagonist alone was unable to decrease allodynia. Interleukin-1 Receptor antagonist in combination with soluble tumor necrosis factor Receptor, administered to both male and female rats in a preventative pain strategy, significantly reduced mechanical allodynia in a dose-dependent manner (P<0.01). The magnitude of attenuation in allodynia was similar in both males and females. Immunohistochemistry on L5 spinal cord revealed similar astrocytic and microglial activation regardless of treatment. At days 3 and 7 post-transection, animals receiving daily Interleukin-1 Receptor antagonist in combination with soluble tumor necrosis factor Receptor exhibited significantly less Interleukin-6, but not Interleukin-1beta, in the L5 spinal cord compared to vehicle-treated animals. In an existing pain paradigm, in which treatment was initiated on day 7 post-transection, Interleukin-1 Receptor antagonist in combination with soluble tumor necrosis factor Receptor attenuated mechanical allodynia (P<0.05) in male rats. These findings further support a role for central Interleukin-1beta and tumor necrosis factor in the development and maintenance of neuropathic pain through induction of a proinflammatory cytokine cascade.
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intrathecal Interleukin 1 Receptor antagonist in combination with soluble tumor necrosis factor Receptor exhibits an anti allodynic action in a rat model of neuropathic pain
Neuroscience, 2001Co-Authors: S Sweitzer, D Martin, Joyce A DeleoAbstract:The expression of Interleukin-1β and tumor necrosis factor has previously been shown to be up-regulated in the spinal cord of several rat mononeuropathy models. This present study was undertaken to determine whether blocking the action of central Interleukin-1β and tumor necrosis factor attenuates mechanical allodynia in a gender-specific manner in a rodent L5 spinal nerve transection model of neuropathic pain, and whether this inhibition occurs via down-regulation of the central cytokine cascade or blockade of glial activation. Interleukin-1 Receptor antagonist or soluble tumor necrosis factor Receptor was administered intrathecally via lumbar puncture to male Holtzman rats in a preventative pain strategy, in which therapy was initiated 1 h prior to surgery. Administration of soluble tumor necrosis factor Receptor attenuated mechanical allodynia, while Interleukin-1 Receptor antagonist alone was unable to decrease allodynia. Interleukin-1 Receptor antagonist in combination with soluble tumor necrosis factor Receptor, administered to both male and female rats in a preventative pain strategy, significantly reduced mechanical allodynia in a dose-dependent manner (P<0.01). The magnitude of attenuation in allodynia was similar in both males and females. Immunohistochemistry on L5 spinal cord revealed similar astrocytic and microglial activation regardless of treatment. At days 3 and 7 post-transection, animals receiving daily Interleukin-1 Receptor antagonist in combination with soluble tumor necrosis factor Receptor exhibited significantly less Interleukin-6, but not Interleukin-1β, in the L5 spinal cord compared to vehicle-treated animals. In an existing pain paradigm, in which treatment was initiated on day 7 post-transection, Interleukin-1 Receptor antagonist in combination with soluble tumor necrosis factor Receptor attenuated mechanical allodynia (P<0.05) in male rats. These findings further support a role for central Interleukin-1β and tumor necrosis factor in the development and maintenance of neuropathic pain through induction of a proinflammatory cytokine cascade.
Gordon W Duff - One of the best experts on this subject based on the ideXlab platform.
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arterial inflammation in mice lacking the Interleukin 1 Receptor antagonist gene
Journal of Experimental Medicine, 2000Co-Authors: Martin J H Nicklin, David E Hughes, Jenny L Barton, Jan Ure, Gordon W DuffAbstract: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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Interleukin 1 Receptor antagonist gene polymorphism association with lichen sclerosus
Human Genetics, 1994Co-Authors: Frances E Clay, Joanna K Tarlow, Alexandra I. F. Blakemore, Michael J. Cork, C I Harrington, Fiona M Lewis, Gordon W DuffAbstract:Cytokines play key roles in immune responses, inflammation and fibrosis. The balance between levels of cytokines, their Receptors and specific inhibitors controls inflammatory reactions in tissues. The pathogenesis of lichen sclerosus is unknown but probably involves cytokine mediators such as Interleukin 1 (IL-1) and Interleukin 1 Receptor antagonist (IL-1ra). The IL-1ra is a competitive inhibitor of IL-1α and IL-1β, and therefore is a powerful endogenous anti-inflammatory molecule. The gene encoding IL-1ra (designated IL-1RN) has a variable number tandem repeat polymorphism in intron 2. There are five alleles of the gene corresponding to 2, 3, 4, 5 and 6 repeats of an 86-bp sequence. We have determined allele frequencies in a control population and a group of 78 patients with lichen sclerosus. The frequency of one of the alleles is related to increasing disease severity. Thus, IL-1RN may be a candidate gene or severity factor for lichen sclerosus or may possibly be a linked marker to another, as yet undefined, gene.
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Interleukin 1 Receptor antagonist gene polymorphism as a disease severity factor in systemic lupus erythematosus
Arthritis & Rheumatism, 1994Co-Authors: Alexandra I. F. Blakemore, Joanna K Tarlow, Michael J. Cork, Caroline Gordon, Paul Emery, Gordon W DuffAbstract:Objective. We have previously described associations between an allele of the Interleukin–1 Receptor antagonist gene (IL1RN) and several inflammatory diseases. In this study we tested the IL1RN gene as a possible marker in patients with systemic lupus erythematosus (SLE). Methods. Eighty–one SLE patients and 261 ethnically matched control subjects were genotyped by polymerase chain reaction. Results. We found an increase in both frequency and carriage rate of IL1RN*2 in the SLE group. This association strengthened with extensive disease and particularly with the presence of photosensitivity and discoid skin lesions. Conclusion. We describe a novel association between IL1RN*2 and SLE. Carriage of the allele seems to influence severity rather than susceptibility to SLE. We postulate that the association of this polymorphism with disease severity is a widespread feature of common inflammatory and autoimmune diseases.
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novel genetic association between ulcerative colitis and the anti inflammatory cytokine Interleukin 1 Receptor antagonist
Gastroenterology, 1994Co-Authors: John C Mansfield, Hazel Holden, Joanna K Tarlow, Francesco S Di Giovine, Tarra L Mcdowell, Anthony G Wilson, Derek C Holdsworth, Gordon W DuffAbstract:Abstract Background/Aims: Ulcerative colitis and Crohn's disease have well-recognized familial tendencies, but the genetic basis of this clinical observation remains unknown. The cytokine Interleukin-1 Receptor antagonist is a potent anti-inflammatory protein that can prevent immune-mediated bowel inflammation in animals. We have previously characterized a polymorphism within the gene for this cytokine and others in the genes for the proinflammatory cytokines Interleukin 1α, Interleukin 1β, and tumor necrosis factor α. The aim of this study was to determine whether inflammatory bowel disease was associated with particular alleles of these polymorphic cytokine genes. Methods: The allelic frequencies of these polymorphic cytokine genes were determined in patients with ulcerative colitis (n = 113), Crohn's disease (n = 78), and healthy controls (n = 261). Results: Allele 2 of Interleukin-1 Receptor antagonist was significantly over-represented in the ulcerative colitis patients: 35% versus 24% in controls ( P = 0.007). Carriage of at least one copy of this allele gave an odds ratio of 2.0 for ulcerative colitis compared with controls. This association with allele 2 of Interleukin 1 Receptor antagonist was greatest in patients with total colitis and was not seen in Crohn's disease. There were no associations between UC and any of the other cytokine genes examined. Conclusions: This observation provides evidence that Interleukin-1 Receptor antagonist may have a role in determining the genetic susceptibility to and pathogenesis of ulcerative colitis.
Luke A J Oneill - One of the best experts on this subject based on the ideXlab platform.
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the Interleukin 1 Receptor toll like Receptor superfamily 10 years of progress
Immunological Reviews, 2008Co-Authors: Luke A J OneillAbstract:Summary: The Interleukin-1 Receptor (IL-1R)/Toll-like Receptor (TLR) superfamily was first defined in 1998 as a family of proteins that contain the Toll-IL-1 Receptor domain. At that time, there were a number of orphan Receptors in the IL-1R branch, and the TLRs had yet to be shown to be key innate immune Receptors that sense microbial products. We now know a great deal more about this superfamily, with the description of novel IL-1 family members such as IL-1F6 signaling via IL-1Rrp2 and IL33 signaling via ST2. Remarkable progress has been made in our understanding of the functions of the TLRs, leading to a renaissance of interest in innate immunity. The importance of IL-1 is also being rediscovered, with the observation that Nalp3 is a key regulator of caspase-1, the enzyme that processes pro-IL-1β into the mature cytokine. This area has therefore proved very fruitful in terms of improving our knowledge of the molecular basis for innate immunity and inflammation, and we can anticipate further discoveries in the coming years.
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st2 is an inhibitor of Interleukin 1 Receptor and toll like Receptor 4 signaling and maintains endotoxin tolerance
Nature Immunology, 2004Co-Authors: Elizabeth Brint, Haiying Liu, Aisling Dunne, Andrew N J Mckenzie, Luke A J Oneill, Foo Y LiewAbstract:The Toll-Interleukin 1 Receptor (TIR) superfamily, defined by the presence of an intracellular TIR domain, initiates innate immunity through activation of the transcription factor NF-kappa B, leading to the production of proinflammatory cytokines. ST2 is a member of the TIR family that does not activate NF-kappa B and has been suggested as an important effector molecule of T helper type 2 (T(H)2) responses. We show here that the membrane-bound form of ST2 negatively regulated type I Interleukin 1 Receptor (IL-1RI) and Toll-like Receptor 4 (TLR4) but not TLR3 signaling by sequestrating the adaptors MyD88 and Mal. In contrast to wild-type mice, ST2-deficient mice failed to develop endotoxin tolerance. Thus, these results provide a molecular explanation for the function of ST2 in T(H)2 responses, as inhibition of TLRs promotes a T(H)2 response, and also identify ST2 as a key regulator of endotoxin tolerance.
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structural complementarity of toll Interleukin 1 Receptor domains in toll like Receptors and the adaptors mal and myd88
Journal of Biological Chemistry, 2003Co-Authors: Aisling Dunne, Mikael Ejdeback, Phumzile L Ludidi, Luke A J OneillAbstract:The Toll/Interleukin 1 Receptor (TIR) domain is a region found in the cytoplasmic tails of members of the Toll-like Receptor/Interleukin-1 Receptor superfamily. The domain is essential for signaling and is also found in the adaptor proteins Mal (MyD88 adaptor-like) and MyD88, which function to couple activation of the Receptor to downstream signaling components. Experimental structures of two Toll/Interleukin 1 Receptor domains reveal a alpha-beta-fold similar to that of the bacterial chemotaxis protein CheY, and other evidence suggests that the adaptors can make heterotypic interactions with both the Receptors and themselves. Here we show that the purified TIR domains of Mal and MyD88 can form stable heterodimers and also that Mal homodimers and oligomers are dissociated in the presence of ATP. To identify structural features that may contribute to the formation of signaling complexes, we produced models of the TIR domains from human Toll-like Receptor 4 (TLR4), Mal, and MyD88. We found that although the overall fold is conserved the electrostatic surface potentials are quite distinct. Docking studies of the models suggest that Mal and MyD88 bind to different regions in TLRs 2 and 4, a finding consistent with a cooperative role of the two adaptors in signaling. Mal and MyD88 are predicted to interact at a third non-overlapping site, suggesting that the Receptor and adaptors may form heterotetrameric complexes. The theoretical model of the interactions is supported by experimental data from glutathione S-transferase pull-downs and co-immunoprecipitations. Neither theoretical nor experimental data suggest a direct role for the conserved proline in the BB-loop in the association of TLR4, Mal, and MyD88. Finally we show a sequence relationship between the Drosophila protein Tube and Mal that may indicate a functional equivalence of these two adaptors in the Drosophila and vertebrate Toll pathways.
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bruton s tyrosine kinase is a toll Interleukin 1 Receptor domain binding protein that participates in nuclear factor κb activation by toll like Receptor 4
Journal of Biological Chemistry, 2003Co-Authors: Caroline A Jefferies, Elizabeth Brint, Aisling Dunne, Sarah L Doyle, Cornelia Brunner, Claudia Wietek, Eva Walch, Thomas Wirth, Luke A J OneillAbstract:Abstract In this study we have identified members of the Toll-like Receptor (TLR) family (namely, TLRs 4, 6, 8, and 9) as proteins to which the intracellular protein tyrosine kinase, Bruton's tyrosine kinase (Btk), binds. Detailed analysis of the interaction between Btk and TLR8 demonstrates that the presence of both Box 2 and 3 motifs in the Toll/Interleukin-1 Receptor domain was required for the interaction. Furthermore, co-immunoprecipitation experiments revealed that Btk can also interact with key proteins involved in TLR4 signal transduction, namely, MyD88, Mal (MyD88 adapter-like protein), and Interleukin-1 Receptor-associated kinase-1, but not TRAF-6. The ability of Btk to interact with TLR4 and Mal suggests a role for Btk in lipopolysaccharide (LPS) signal transduction. Stimulation of the human monocytic cell line THP-1 with LPS resulted in an increase in the level of tyrosine phosphorylation of Btk (indicative of activation). The autokinase activity of Btk was also stimulated after LPS stimulation. In addition, a dominant negative form of Btk inhibited TLR4-mediated activation of a nuclear factor κB (NFκB)-dependent reporter gene in HEK293 cells as well as LPS-induced activation of NFκB in the astrocytoma cell line U373 and the monocytic cell line RAW264.7. Further investigation revealed that the Btk-specific inhibitor, LFM-A13, inhibited the activation of NFκB by LPS in THP-1 cells. Our findings implicate Btk as a Toll/Interleukin-1 Receptor domain-binding protein that is important for NFκB activation by TLR4.
S Sweitzer - One of the best experts on this subject based on the ideXlab platform.
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intrathecal Interleukin 1 Receptor antagonist in combination with soluble tumor necrosis factor Receptor exhibits an anti allodynic action in a rat model of neuropathic pain
Neuroscience, 2001Co-Authors: S Sweitzer, D Martin, Joyce A DeleoAbstract:The expression of Interleukin-1beta and tumor necrosis factor has previously been shown to be up-regulated in the spinal cord of several rat mononeuropathy models. This present study was undertaken to determine whether blocking the action of central Interleukin-1beta and tumor necrosis factor attenuates mechanical allodynia in a gender-specific manner in a rodent L5 spinal nerve transection model of neuropathic pain, and whether this inhibition occurs via down-regulation of the central cytokine cascade or blockade of glial activation. Interleukin-1 Receptor antagonist or soluble tumor necrosis factor Receptor was administered intrathecally via lumbar puncture to male Holtzman rats in a preventative pain strategy, in which therapy was initiated 1h prior to surgery. Administration of soluble tumor necrosis factor Receptor attenuated mechanical allodynia, while Interleukin-1 Receptor antagonist alone was unable to decrease allodynia. Interleukin-1 Receptor antagonist in combination with soluble tumor necrosis factor Receptor, administered to both male and female rats in a preventative pain strategy, significantly reduced mechanical allodynia in a dose-dependent manner (P<0.01). The magnitude of attenuation in allodynia was similar in both males and females. Immunohistochemistry on L5 spinal cord revealed similar astrocytic and microglial activation regardless of treatment. At days 3 and 7 post-transection, animals receiving daily Interleukin-1 Receptor antagonist in combination with soluble tumor necrosis factor Receptor exhibited significantly less Interleukin-6, but not Interleukin-1beta, in the L5 spinal cord compared to vehicle-treated animals. In an existing pain paradigm, in which treatment was initiated on day 7 post-transection, Interleukin-1 Receptor antagonist in combination with soluble tumor necrosis factor Receptor attenuated mechanical allodynia (P<0.05) in male rats. These findings further support a role for central Interleukin-1beta and tumor necrosis factor in the development and maintenance of neuropathic pain through induction of a proinflammatory cytokine cascade.
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intrathecal Interleukin 1 Receptor antagonist in combination with soluble tumor necrosis factor Receptor exhibits an anti allodynic action in a rat model of neuropathic pain
Neuroscience, 2001Co-Authors: S Sweitzer, D Martin, Joyce A DeleoAbstract:The expression of Interleukin-1β and tumor necrosis factor has previously been shown to be up-regulated in the spinal cord of several rat mononeuropathy models. This present study was undertaken to determine whether blocking the action of central Interleukin-1β and tumor necrosis factor attenuates mechanical allodynia in a gender-specific manner in a rodent L5 spinal nerve transection model of neuropathic pain, and whether this inhibition occurs via down-regulation of the central cytokine cascade or blockade of glial activation. Interleukin-1 Receptor antagonist or soluble tumor necrosis factor Receptor was administered intrathecally via lumbar puncture to male Holtzman rats in a preventative pain strategy, in which therapy was initiated 1 h prior to surgery. Administration of soluble tumor necrosis factor Receptor attenuated mechanical allodynia, while Interleukin-1 Receptor antagonist alone was unable to decrease allodynia. Interleukin-1 Receptor antagonist in combination with soluble tumor necrosis factor Receptor, administered to both male and female rats in a preventative pain strategy, significantly reduced mechanical allodynia in a dose-dependent manner (P<0.01). The magnitude of attenuation in allodynia was similar in both males and females. Immunohistochemistry on L5 spinal cord revealed similar astrocytic and microglial activation regardless of treatment. At days 3 and 7 post-transection, animals receiving daily Interleukin-1 Receptor antagonist in combination with soluble tumor necrosis factor Receptor exhibited significantly less Interleukin-6, but not Interleukin-1β, in the L5 spinal cord compared to vehicle-treated animals. In an existing pain paradigm, in which treatment was initiated on day 7 post-transection, Interleukin-1 Receptor antagonist in combination with soluble tumor necrosis factor Receptor attenuated mechanical allodynia (P<0.05) in male rats. These findings further support a role for central Interleukin-1β and tumor necrosis factor in the development and maintenance of neuropathic pain through induction of a proinflammatory cytokine cascade.
Marc Y Donath - One of the best experts on this subject based on the ideXlab platform.
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sustained effects of Interleukin 1 Receptor antagonist treatment in type 2 diabetes
Diabetes Care, 2009Co-Authors: Claus M Larsen, Mirjam V Faulenbach, Jan A Ehses, Allan Vaag, Marc Y Donath, Thomas MandruppoulsenAbstract:OBJECTIVE Interleukin (IL)-1 impairs insulin secretion and induces β-cell apoptosis. Pancreatic β-cell IL-1 expression is increased and Interleukin-1 Receptor antagonist (IL-1Ra) expression reduced in patients with type 2 diabetes. Treatment with recombinant IL-1Ra improves glycemia and β-cell function and reduces inflammatory markers in patients with type 2 diabetes. Here we investigated the durability of these responses. RESEARCH DESIGN AND METHODS Among 70 ambulatory patients who had type 2 diabetes, A1C >7.5%, and BMI >27 kg/m 2 and were randomly assigned to receive 13 weeks of anakinra, a recombinant human IL-1Ra, or placebo, 67 completed treatment and were included in this double-blind 39-week follow-up study. Primary outcome was change in β-cell function after anakinra withdrawal. Analysis was done by intention to treat. RESULTS Thirty-nine weeks after anakinra withdrawal, the proinsulin-to-insulin (PI/I) ratio but not stimulated C-peptide remained improved (by −0.07 [95% CI −0.14 to −0.02], P = 0.011) compared with values in placebo-treated patients. Interestingly, a subgroup characterized by genetically determined low baseline IL-1Ra serum levels maintained the improved stimulated C-peptide obtained by 13 weeks of IL-1Ra treatment. Reductions in C-reactive protein (−3.2 mg/l [−6.2 to −1.1], P = 0.014) and in IL-6 (−1.4 ng/l [−2.6 to −0.3], P = 0.036) were maintained until the end of study. CONCLUSIONS IL-1 blockade with anakinra induces improvement of the PI/I ratio and markers of systemic inflammation lasting 39 weeks after treatment withdrawal.
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Interleukin 1 Receptor antagonist in type 2 diabetes mellitus
The New England Journal of Medicine, 2007Co-Authors: Claus M Larsen, Mirjam V Faulenbach, Aage Volund, Jan A Ehses, Allan Vaag, Thomas Mandruppoulsen, Burkhardt Seifert, Marc Y DonathAbstract:BACKGROUND: The expression of Interleukin-1-Receptor antagonist is reduced in pancreatic islets of patients with type 2 diabetes mellitus, and high glucose concentrations induce the production of Interleukin-1beta in human pancreatic beta cells, leading to impaired insulin secretion, decreased cell proliferation, and apoptosis. METHODS: In this double-blind, parallel-group trial involving 70 patients with type 2 diabetes, we randomly assigned 34 patients to receive 100 mg of anakinra (a recombinant human Interleukin-1-Receptor antagonist) subcutaneously once daily for 13 weeks and 36 patients to receive placebo. At baseline and at 13 weeks, all patients underwent an oral glucose-tolerance test, followed by an intravenous bolus of 0.3 g of glucose per kilogram of body weight, 0.5 mg of glucagon, and 5 g of arginine. In addition, 35 patients underwent a hyperinsulinemic-euglycemic clamp study. The primary end point was a change in the level of glycated hemoglobin, and secondary end points were changes in beta-cell function, insulin sensitivity, and inflammatory markers. RESULTS: At 13 weeks, in the anakinra group, the glycated hemoglobin level was 0.46 percentage point lower than in the placebo group (P=0.03); C-peptide secretion was enhanced (P=0.05), and there were reductions in the ratio of proinsulin to insulin (P=0.005) and in levels of Interleukin-6 (P<0.001) and C-reactive protein (P=0.002). Insulin resistance, insulin-regulated gene expression in skeletal muscle, serum adipokine levels, and the body-mass index were similar in the two study groups. Symptomatic hypoglycemia was not observed, and there were no apparent drug-related serious adverse events. CONCLUSIONS: The blockade of Interleukin-1 with anakinra improved glycemia and beta-cell secretory function and reduced markers of systemic inflammation. (ClinicalTrials.gov number, NCT00303394 [ClinicalTrials.gov].).
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Interleukin 1 Receptor antagonist in type 2 diabetes mellitus
The New England Journal of Medicine, 2007Co-Authors: Claus M Larsen, Mirjam V Faulenbach, Aage Volund, Jan A Ehses, Allan Vaag, Thomas Mandruppoulsen, Burkhardt Seifert, Marc Y DonathAbstract:Background The expression of Interleukin-1–Receptor antagonist is reduced in pancreatic islets of patients with type 2 diabetes mellitus, and high glucose concentrations induce the production of Interleukin-1β in human pancreatic beta cells, leading to impaired insulin secretion, decreased cell proliferation, and apoptosis. Methods In this double-blind, parallel-group trial involving 70 patients with type 2 diabetes, we randomly assigned 34 patients to receive 100 mg of anakinra (a recombinant human Interleukin-1–Receptor antagonist) subcutaneously once daily for 13 weeks and 36 patients to receive placebo. At baseline and at 13 weeks, all patients underwent an oral glucose-tolerance test, followed by an intravenous bolus of 0.3 g of glucose per kilogram of body weight, 0.5 mg of glucagon, and 5 g of arginine. In addition, 35 patients underwent a hyperinsulinemic–euglycemic clamp study. The primary end point was a change in the level of glycated hemoglobin, and secondary end points were changes in beta-cell function, insulin sensitivity, and inflammatory markers. Results At 13 weeks, in the anakinra group, the glycated hemoglobin level was 0.46 percentage point lower than in the placebo group (P = 0.03); C-peptide secretion was enhanced (P = 0.05), and there were reductions in the ratio of proinsulin to insulin (P = 0.005) and in levels of Interleukin-6 (P<0.001) and C-reactive protein (P = 0.002). Insulin resistance, insulin-regulated gene expression in skeletal muscle, serum adipokine levels, and the body-mass index were similar in the two study groups. Symptomatic hypoglycemia was not observed, and there were no apparent drugrelated serious adverse events. Conclusions The blockade of Interleukin-1 with anakinra improved glycemia and beta-cell secretory function and reduced markers of systemic inflammation. (ClinicalTrials.gov number, NCT00303394.)