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.

Changes in energy expenditure and fat metabolism in rats infused with interleukin-1.

Abstract: Metabolic alterations related to resting energy expenditure (REE) and fat metabolism have been noted during sepsis, and often depend on the causative agent and the stage and severity of the illness. We studied the effect of IL-1, the protein mediator of the 'acute phase' response during infection, on REE, respiratory quotient (RQ), and fat metabolism in male rats (210 g), who were infused over an 8-h period with (1-14C)-palmitate (PALM), (2-3H)-glycerol (GLY) and either saline or interleukin-1 (IL-1). At 7-8 h post infusion, the IL-1 group showed a significant increase in REE but no change in RQ. The IL-1 group also exhibited a significant decrease in serum free fatty acid (FFA) and an increase in FFA clearance. Free fatty acid flux, %PALM oxidation, serum (GLY), glycerol clearance, and glycerol flux (a measure of lipolytic rate) were not significantly different between the two groups. We conclude that IL-1 can mimic the increase in REE seen during infection; the increase in REE is not due to a selective increase in fat oxidation only, although the unchanged RQ and increased REE suggest that there is a proportional increase in net FFA oxidation.

Direct effects of a monoclonal B cell differentiation factor and of purified interleukin 1 on B cell differentiation.

Abstract: We have previously described the presence of factors in mixed lymphocyte culture supernatants that induce activated but not resting human B cells to secrete Ig. In the present study, we describe the effects of a B cell differentiation factor in the supernatant (SN) of a T-T hybridoma (clone 7D5). We find that it induces Ig secretion by human B cells in the absence of T cells or monocytes. It acts only on activated B cells, because small (resting) B cells isolated by centrifugal counterflow elutriation do not respond to it, whereas the same cells do develop into Ig-secreting cells if activated in culture with Staphylococcus aureus Cowan I before exposure to SN 7D5. By using class-specific reagents in enzyme-linked immunosorbent assays, we found SN 7D5 to result in the secretion of significant amounts of IgM, IgG, and IgA. We also studied the effects of highly purified interleukin 1 on this differentiation process. Interleukin 1 by itself failed to induce Ig secretion by activated B cells, and its presence was not required for the induction of Ig secretion by SN 7D5. However, interleukin 1 consistently synergized with SN 7D5 in inducing Ig secretion by purified B cells.

Lysine deacetylase inhibition prevents diabetes by chromatin-independent immunoregulation and β-cell protection.

Abstract: Type 1 diabetes is due to destruction of pancreatic β-cells. Lysine deacetylase inhibitors (KDACi) protect β-cells from inflammatory destruction in vitro and are promising immunomodulators. Here we demonstrate that the clinically well-tolerated KDACi vorinostat and givinostat revert diabetes in the nonobese diabetic (NOD) mouse model of type 1 diabetes and counteract inflammatory target cell damage by a mechanism of action consistent with transcription factor—rather than global chromatin—hyperacetylation. Weaning NOD mice received low doses of vorinostat and givinostat in their drinking water until 100–120 d of age. Diabetes incidence was reduced by 38% and 45%, respectively, there was a 15% increase in the percentage of islets without infiltration, and pancreatic insulin content increased by 200%. Vorinostat treatment increased the frequency of functional regulatory T-cell subsets and their transcription factors Gata3 and FoxP3 in parallel to a decrease in inflammatory dendritic cell subsets and their cytokines IL-6, IL-12, and TNF-α. KDACi also inhibited LPS-induced Cox-2 expression in peritoneal macrophages from C57BL/6 and NOD mice. In insulin-producing β-cells, givinostat did not upregulate expression of the anti-inflammatory genes Socs1-3 or sirtuin-1 but reduced levels of IL-1β + IFN-γ–induced proinflammatory Il1a, Il1b, Tnfα, Fas, Cxcl2, and reduced cytokine-induced ERK phosphorylation. Further, NF-κB genomic iNos promoter binding was reduced by 50%, and NF-κB-dependent mRNA expression was blocked. These effects were associated with NF-κB subunit p65 hyperacetylation. Taken together, these data provide a rationale for clinical trials of safety and efficacy of KDACi in patients with autoimmune disease such as type 1 diabetes.

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.