Addenbrookes Center for Clinical Investigation
Addenbrookes Center for Clinical Investigation
Patel M.N.,University of Cambridge |
Bernard W.G.,University of Cambridge |
Bernard W.G.,Addenbrookes Center for Clinical Investigation |
Milev N.B.,University of Cambridge |
And 29 more authors.
Proceedings of the National Academy of Sciences of the United States of America | Year: 2015
Obesity increases the risk of developing life-threatening metabolic diseases including cardiovascular disease, fatty liver disease, diabetes, and cancer. Efforts to curb the global obesity epidemic and its impact have proven unsuccessful in part by a limited understanding of these chronic progressive diseases. It is clear that low-grade chronic inflammation, or metaflammation, underlies the pathogenesis of obesity-associated type 2 diabetes and atherosclerosis. However, the mechanisms that maintain chronicity and prevent inflammatory resolution are poorly understood. Here, we show that inhibitor of κB kinase epsilon (IKBKE) is a novel regulator that limits chronic inflammation during metabolic disease and atherosclerosis. The pathogenic relevance of IKBKE was indicated by the colocalization with macrophages in human and murine tissues and in atherosclerotic plaques. Genetic ablation of IKBKE resulted in enhanced and prolonged priming of the NLRP3 inflammasome in cultured macrophages, in hypertrophic adipose tissue, and in livers of hypercholesterolemic mice. This altered profile associated with enhanced acute phase response, deregulated cholesterol metabolism, and steatoheptatitis. Restoring IKBKE only in hematopoietic cells was sufficient to reverse elevated inflammasome priming and these metabolic features. In advanced atherosclerotic plaques, loss of IKBKE and hematopoietic cell restoration altered plaque composition. These studies reveal a new role for hematopoietic IKBKE: To limit inflammasome priming and metaflammation.
Mistry P.,Glaxosmithkline |
Reid J.,Glaxosmithkline |
Pouliquen I.,Glaxosmithkline |
McHugh S.,Addenbrookes Center for Clinical Investigation |
And 6 more authors.
International Journal of Clinical Pharmacology and Therapeutics | Year: 2014
Objective: To investigate the safety, tolerability, pharmacokinetics, and pharmacodynamics of GSK1070806, a novel IgG1 mAb that neutralizes human interleukin (IL)-18. Methods: In this first-time-in-human (FTIH) study, cohorts of healthy and obese subjects were randomly allocated to receive single doses of GSK1070806 (0.008 - 10 mg/kg) or placebo. Blood was sampled ≤ 274 days post-dosing, and safety monitored. Results: GSK1070806 was generally well tolerated. The most common AEs were nasopharyngitis and headache, arising as frequently in the placebo as in the active drug groups; most AEs were mild to moderate and unrelated to dose level. There were no allergic, delayed-type hypersensitivity, or infusion-related reactions and the incidence of immunogenicity was low. GSK1070806 plasma pharmacokinetic profiles were comparable in healthy and obese subjects; there was no major deviation from dose proportionality for AUC∞ and Cmax although a trend for dose-dependent increase in t1/2 was observed. Serum drug-bound IL-18 levels increased post-dosing and were sustained for a long time-period following GSK1070806 administration. Ex-vivo whole blood assay demonstrated prolonged pharmacological activity of GSK1070806 as determined by its primary immunological mechanism of action, inhibition of IL-18-induced IFN-γ production. Conclusion: GSK1070806 warrants clinical investigation in patients. ©2014 Dustri-Verlag Dr. K. Feistle.
Harzheim D.,Babraham Institute |
Harzheim D.,Caesar Research Center |
Talasila A.,Babraham Institute |
Movassagh M.,Addenbrookes Center for Clinical Investigation |
And 5 more authors.
Channels | Year: 2010
Cardiac hypertrophy is associated with profound remodeling of Ca 2+ signaling pathways. During the early, compensated stages of hypertrophy, Ca2+ fluxes may be enhanced to facilitate greater contraction, whereas as the hypertrophic heart decompensates, Ca2+ homeostatic mechanisms are dysregulated leading to decreased contractility, arrhythmia and death. Although ryanodine receptor Ca2+ release channels (RyR) on the sarcoplasmic reticulum (SR) intracellular Ca2+ store are primarily responsible for the Ca2+ flux that induces myocyte contraction, a role for Ca2+ release via the inositol 1,4,5-trisphosphate receptor (InsP3R) in cardiac physiology has also emerged. Specifically, InsP3-induced Ca2+ signals generated following myocyte stimulation with an InsP3-generating agonist (e.g., endothelin, ET-1), lead to modulation of Ca2+ signals associated with excitation-contraction coupling (ECC) and the induction of spontaneous Ca2+ release events that cause cellular arrhythmia. Using myocytes from spontaneously hypertensive rats (SHR), we recently reported that expression of the type 2 InsP3R (InsP3R2) is significantly increased during hypertrophy. Notably, this increased expression was restricted to the junctional SR in close proximity to RyRs. There, enhanced Ca 2+ release via InsP3Rs serves to sensitize neighboring RyRs causing an augmentation of Ca2+ fluxes during ECC as well as an increase in non-triggered Ca2+ release events. Although the sensitization of RyRs may be a beneficial consequence of elevated InsP 3R expression during hypertrophy, the spontaneous Ca2+ release events are potentially of pathological significance giving rise to cardiac arrhythmia. InsP3R2 expression was also increased in hypertrophic hearts from patients with ischemic dilated cardiomyopathy and aortically-banded mice demonstrating that increased InsP3R expression may be a general phenomenon that underlies Ca2+ changes during hypertrophy. © 2010 Landes Bioscience.