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.

Eukaryotic Translation Initiation Factor 5A Small Interference RNA-Liposome Complexes Reduce Inflammation and Increase Survival in Murine Models of Severe Sepsis and Acute Lung Injury

Abstract: Approximately 900,000 cases of sepsis occur annually in the United States, causing roughly 210,000 deaths and resulting in costs of almost 17 billion dollars [1]. Sepsis is characterized by an initial hyperinflammatory state, which is followed by a hypoinflammatory, immunosuppressive state during which apoptosis occurs [2]. Because of the dearth of therapeutics for sepsis, new strategies and tools are needed for sepsis management. Polyamines are important mediators of inflammation [3], and studies have indicated that polyamine biosynthesis is increased during sepsis [4, 5]. Although the functions of the up-regulated polyamines during sepsis and inflammation are not clear, we hypothesize that polyamine levels may increase during inflammation to help fuel hypusine biosynthesis, which is a polyamine-dependent reaction. Eukaryotic translation initiation factor 5A (eIF5A) is an abundant, constitutively expressed protein, and it is the only known protein to contain the unique amino acid hypusine. The hypusine residue is formed posttranslationally in a 2-step process that results in the mature, active form of eIF5A. The first step, catalyzed by deoxyhypusine synthase (DHS), involves the transfer of a butylamine group from the polyamine spermidine to a conserved lysine on eIF5A [6]. The second hydroxylation step, which is mediated by deoxyhypusine hydroxylase (DOHH), results in the formation of the mature hypusine-modified eIF5A [7]. Inhibitors of DHS and DOHH that block the hypusination reaction have been found to have anti-inflammatory properties [8, 9]. eIF5A is widely believed to have a function in regulated mRNA transport [10–12], protein translation [13, 14], and cell proliferation [15–21]. It also appears to be involved in the activation and/or proliferation of T lymphocytes [22] and seems to be required for the maturation and function of dendritic cells [23], thereby suggesting that eIF5A may be an important target in inflammatory diseases. eIF5A also has an important role in apoptosis [24–26], and small interference RNA (siRNA) targeting eIF5A can protect cells from apoptosis caused by tumor necrosis factor (TNF)–α [24] and genotoxic stress [26], thus making it a potential target for sepsis therapy. Many studies have identified apoptosis, particularly apoptosis of lymphocytes, as a risk factor for death due to sepsis [2, 27, 28]. Recent therapeutic strategies have used siRNA to knock down the genes that are involved in apoptosis and up-regulated during sepsis. For example, Fas ligand and caspases have been targeted in mice with sepsis, resulting in increased survival [29]. To determine whether a reduction in eIF5A expression may have anti-inflammatory effects, an siRNA targeting eIF5A was tested in murine models of severe sepsis and acute lung injury, and the effects on proinflammatory cytokine production and animal survival were monitored.

Interleukin-1 affects the function of cultured human thyroid cells

Abstract: Cytokines are peptide hormones essential for cellular communication in the immune response. The purpose of this study was to investigate the influence of cytokines, especially recombinant interleukin 1 beta (rIL-1 beta), on human thyroid cells. Thyroglobulin (Tg) was measured by a double antibody radioimmunoassay, and cyclic AMP (cAMP) by a competitive protein binding assay. Supernatants from unstimulated and phytohaemagglutinin-stimulated blood mononuclear cells were added to human thyroid cells cultured in monolayers. A dose-dependent inhibition of the secretion of Tg and cAMP was demonstrated. Both subcultured and primary cultured cells incubated with rIL-1 beta at pharmacological levels (10(-1)-10(2) U/ml) exhibited an inhibition of Tg and cAMP secretion, while at physiological levels (10(-5)-10(-3) U/ml), the secretion of Tg was enhanced. The similar stimulation of cAMP was demonstrated in subcultures. These in vitro studies suggest that IL-1 beta may play a role in the pathogenesis of autoimmune thyroid diseases. Further, the stimulations at low concentrations indicate that IL-1 beta may regulate the function of the thyroid gland under physiological conditions.

Peptides modulating conformational changes in secreted chaperones: from in silico design to preclinical proof of concept

Abstract: Blocking conformational changes in biologically active proteins holds therapeutic promise Inspired by the susceptibility of viral entry to inhibition by synthetic peptides that block the formation of helix–helix interactions in viral envelope proteins, we developed a computational approach for predicting interacting helices Using this approach, which combines correlated mutations analysis and Fourier transform, we designed peptides that target gp96 and clusterin, 2 secreted chaperones known to shift between inactive and active conformations In human blood mononuclear cells, the gp96-derived peptide inhibited the production of TNFα, IL-1β, IL-6, and IL-8 induced by endotoxin by >80% When injected into mice, the peptide reduced circulating levels of endotoxin-induced TNFα, IL-6, and IFNγ by >50% The clusterin-derived peptide arrested proliferation of several neoplastic cell lines, and significantly enhanced the cytostatic activity of taxol in vitro and in a xenograft model of lung cancer Also, the predicted mode of action of the active peptides was experimentally verified Both peptides bound to their parent proteins, and their biological activity was abolished in the presence of the peptides corresponding to the counterpart helices These data demonstrate a previously uncharacterized method for rational design of protein antagonists

Cytokines and microbicidal molecules regulated by IL-32 in THP-1-derived human macrophages infected with New World Leishmania species.

Abstract: Background Interleukin-32 (IL-32) is expressed in lesions of patients with American Tegumentary Leishmaniasis (ATL), but its precise role in the disease remains unknown. Methodology/Principal findings In the present study, silencing and overexpression of IL-32 was performed in THP-1-derived macrophages infected with Leishmania (Viannia) braziliensis or L. (Leishmania) amazonensis to investigate the role of IL-32 in infection. We report that Leishmania species induces IL-32γ, and show that intracellular IL-32γ protein production is dependent on endogenous TNFα. Silencing or overexpression of IL-32 demonstrated that this cytokine is closely related to TNFα and IL-8. Remarkably, the infection index was augmented in the absence of IL-32 and decreased in cells overexpressing this cytokine. Mechanistically, these effects can be explained by nitric oxide cathelicidin and β-defensin 2 production regulated by IL-32. Conclusions Thus, endogenous IL-32 is a crucial cytokine involved in the host defense against Leishmania parasites.

Interleukin-18 and the treatment of rheumatoid arthritis.

Abstract: Interleukin (IL)-18 is a new member of the IL-1 family of proinflammatory cytokines. Based on preclinical studies in animals, IL-18 likely plays a role in rheumatoid arthritis, and strategies to block IL-18 activity are underway in clinical trials. In one of these trials,a naturally occurring IL-18 binding protein (IL-18 BP) binds IL-18 with a high affinity and reduces disease severity in models of inflammatory diseases. IL-18 BP is not the soluble receptor for IL-18 but rather a distinct molecule, which appears to be distantly related to the IL-1 receptor type II, both structurally and functionally, and hence represents part of the IL-1 family of receptors.

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.