Charles A. Dinarello

Bio: Charles A. Dinarello is an academic researcher from University of Colorado Denver. The author has contributed to research in topics: Interleukin & Cytokine. The author has an hindex of 190, co-authored 1058 publications receiving 139668 citations. Previous affiliations of Charles A. Dinarello include University of Guadalajara & Pennsylvania State University.

Role of interleukin-18 in host defense against disseminated Candida albicans infection.

Abstract: In mice injected intravenously with Candida albicans, administration of anti-interleukin-18 (IL-18) antibodies increased the yeast load in the kidneys. There was no effect on the organ load with Candida when gamma interferon (IFN-γ)-deficient mice were treated with anti-IL-18 antibodies, suggesting that the protective effect of IL-18 is mediated through endogenous IFN-γ.

Novel targets for interleukin 18 binding protein.

Abstract: BACKGROUND—Interleukin 18 (IL18) is related to the IL1 family by structure, receptors, signalling molecules, and function. IL18 induces gene expression and synthesis of tumour necrosis factor (TNF), IL1, Fas ligand, several chemokines, and vascular adhesion molecules. Similar to IL1β, IL18 is synthesised as a biologically inactive precursor molecule lacking a signal peptide. The IL18 precursor requires cleavage into an active, mature molecule by the intracellular cysteine protease, IL1β converting enzyme (ICE, or caspase-1). Inhibitors of ICE activity limit the biological activity of IL18 in animals and may be useful in reducing the activity of IL18 in human disease. However, a constitutively secreted IL18 binding protein (IL18BP) exists which functions as a natural inhibitor of IL18 activity. IL18BP binds IL18 with a high affinity (Kd of 400 pM) and, at equimolar ratios, inhibits 50-70% of IL18; at twofold molar excess, IL18BP neutralises nearly all IL18 activity. METHOD—IL18 was investigated for its role in human myocardial function. An ischaemia/reperfusion (I/R) model of suprafused human atrial myocardium was used to assess myocardial contractile force. RESULTS—The addition of IL18BP to the perfusate during and after I/R resulted in improved post-I/R contractile function from 35% of control to 76% with IL18BP. Also, IL18BP treatment preserved intracellular tissue creatine kinase levels (by 420%). Because active IL18 requires cleavage of its precursor form by ICE, inhibition of ICE attenuated the depression in contractile force after I/R (from 35% of control compared with 75.8% in treated atrial muscle, p<0.01). CONCLUSION—Myocardial ischaemia is a target for IL18BP and use of IL18BP may thereby reduce ischaemia-induced myocardial dysfunction.

Interleukin-1 Receptor Blockade Rescues Myocarditis-Associated End-Stage Heart Failure

Abstract: Support measures currently represent the mainstay of treatment for fulminant myocarditis, while effective and safe anti-inflammatory therapies remain an unmet clinical need. However, clinical and experimental evidence indicates that inhibition of the pro-inflammatory cytokine interleukin 1 (IL-1) is effective against both myocardial inflammation and contractile dysfunction. We thus evaluated treatment with the IL-1 receptor antagonist anakinra in a case of heart failure secondary to fulminant myocarditis. A 65-year-old man with T cell lymphoma developed fulminant myocarditis presenting with severe biventricular failure and cardiogenic shock requiring admittance to the Intensive Care Unit and mechanical circulatory and respiratory support. Specifically, acute heart failure and cardiogenic shock were initially treated with non-invasive ventilation and mechanical circulatory support with an intra-aortic balloon pump (IABP). Nevertheless, cardiac function deteriorated further, and there were no signs of improvement. Treatment with anakinra, the recombinant form of the naturally occurring IL-1 receptor antagonist, was started at a standard subcutaneous dose of 100 mg/day. We observed a dramatic clinical improvement within 24 hrs of initiating anakinra. Prompt, progressive amelioration of cardiac function allowed weaning from mechanical circulatory and respiratory support within 72 hrs of anakinra administration. Recent studies point at inhibition of IL-1 activity as an attractive treatment option for both myocardial inflammation and contractile dysfunction. Furthermore, IL-1 receptor blockade with anakinra is characterized by an extremely rapid onset of action and remarkable safety, and may thus be suitable for the treatment of patients critically ill with myocarditis.

The pathogenesis of atherosclerosis: a perspective for the 1990s

Abstract: Atherosclerosis, the principal cause of heart attack, stroke and gangrene of the extremities, is responsible for 50% of all mortality in the USA, Europe and Japan. The lesions result from an excessive, inflammatory-fibroproliferative response to various forms of insult to the endothelium and smooth muscle of the artery wall. A large number of growth factors, cytokines and vasoregulatory molecules participate in this process. Our ability to control the expression of genes encoding these molecules and to target specific cell types provides opportunities to develop new diagnostic and therapeutic agents to induce the regression of the lesions and, possibly, to prevent their formation.

Cancer-related inflammation.

Abstract: The mediators and cellular effectors of inflammation are important constituents of the local environment of tumours. In some types of cancer, inflammatory conditions are present before a malignant change occurs. Conversely, in other types of cancer, an oncogenic change induces an inflammatory microenvironment that promotes the development of tumours. Regardless of its origin, 'smouldering' inflammation in the tumour microenvironment has many tumour-promoting effects. It aids in the proliferation and survival of malignant cells, promotes angiogenesis and metastasis, subverts adaptive immune responses, and alters responses to hormones and chemotherapeutic agents. The molecular pathways of this cancer-related inflammation are now being unravelled, resulting in the identification of new target molecules that could lead to improved diagnosis and treatment.

Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012.

Abstract: Objective:To provide an update to the “Surviving Sepsis Campaign Guidelines for Management of Severe Sepsis and Septic Shock,” last published in 2008.Design:A consensus committee of 68 international experts representing 30 international organizations was convened. Nominal groups were assembled at ke

Inflammation in atherosclerosis

Abstract: Abundant data link hypercholesterolaemia to atherogenesis. However, only recently have we appreciated that inflammatory mechanisms couple dyslipidaemia to atheroma formation. Leukocyte recruitment and expression of pro-inflammatory cytokines characterize early atherogenesis, and malfunction of inflammatory mediators mutes atheroma formation in mice. Moreover, inflammatory pathways promote thrombosis, a late and dreaded complication of atherosclerosis responsible for myocardial infarctions and most strokes. The new appreciation of the role of inflammation in atherosclerosis provides a mechanistic framework for understanding the clinical benefits of lipid-lowering therapies. Identifying the triggers for inflammation and unravelling the details of inflammatory pathways may eventually furnish new therapeutic targets.