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.

The specific IL-1 inhibitor from the human M20 cell line is distinct from the IL-1 receptor antagonist

Abstract: Several inhibitors of IL-1 have been described. Four appear to be the same: one purified from urine of patients with monocytic leukemia, another from IgG-stimulated monocytes, a third from PMA-induced U937 cels, and a fourth from keratinocytes. Because these IL-1 inhibitors compete with bona fide IL-1 for occupancy of IL-1 receptors, they are now called the IL-1 receptor antagonist (IL-1ra) or IL-1 receptor antagonist protein (IRAP). We have described another IL-1-specific inhibitor produced by the human myelomonocytic leukemia cell line, M20. This inhibitor specifically blocks IL-1-induced effects both in vitro and in vivo. In the present study, we compared the M20 IL-1 inhibitor with IL-1ra using neutralization in an IL-1 bioassay and immunoblotting with an anti-IL-1ra antibody that recognizes natural IL-1ra. Neutralization experiments, immunoblotting, and western blotting obtained after transfer from SDS-PAGE revealed that anti-IL-1ra does not recognize the M20 IL-1 inhibitor. In addition, the isoelectric point and molecular weight of the M20 IL-1 inhibitor were different from those of the IL-1ra. From these data, we conclude that the M20 IL-1 inhibitor is antigenically unrelated to the IL-1ra but is a distinct and specific IL-1 inhibitor.

Anti‐interleukin‐1 reactive cells in Hodgkin's disease

Abstract: Constitutional symptoms (or B-symptoms) of Hodgkin's disease may be mediated by interleukin 1 (IL-1), a product of macrophage-histiocytes. To further study this relation, the authors examined the cells that reacted with anti-human IL-1 antibody in biopsy specimens from 140 untreated patients with Hodgkin's disease (72 asymptomatic patients and 68 with B-symptoms). Fever was the most common symptom, present in 57 of the 68 patients. Anti-IL-1 reactive cells were observed in 62 cases. A positive staining reaction was observed in three types of cells: Reed-Sternberg and related (R-S) cells (33 cases); small to medium cells of undetermined origin (18); and granulocytes (11). The staining was negative in 78 cases, including 42 with B-symptoms. The majority of tumors (27/33) with positively stained R-S cells were from asymptomatic patients. Most tumors (14/18) with positively stained small to medium sized cells were from patients with B-symptoms. Large numbers of granulocytes were positively stained in five asymptomatic patients and six with B-symptoms. The immunohistochemical demonstration of IL-1-bearing cells in tumors does not correlate with the manifestation of constitutional symptoms in Hodgkin's disease.

Anti-inflammatory therapies in acute coronary syndromes: is IL-1 blockade a solution?

Abstract: This editorial refers to ‘The effect of interleukin-1 receptor antagonist therapy on markers of inflammation in non-ST elevation acute coronary syndromes: the MRC-ILA Heart Study’[†][1], by A.C. Morton et al. , on page 377 Elevation of circulating levels of C-reactive protein (CRP) at the time of hospital admission predicts a poor outcome in patients with an acute coronary syndrome (ACS) and is thought to reflect an important inflammatory component in the pathogenesis of this condition.1,2 C-reactive protein is also the preferred systemic inflammatory biomarker for risk stratification in heart disease.3 The link between inflammation and ACS is complex. Atherosclerosis, the primary cause of ACS, is a chronic inflammatory disease of coronary arteries,4 but exacerbations of the inflammatory process within the atherosclerotic plaque may lead to plaque rupture with thrombosis and subsequent myocardial ischaemia.5 Myocardial injury following an ischaemic event is an additional source for a local and systemic inflammatory response; importantly, the intensity of the systemic response is also a predictor of adverse events.6 There are therefore at least three potential sources of inflammation in ACS: (i) the baseline chronic inflammation seen in patients at risk and related to hypercholesterolaemia, diabetes, obesity, and others; (ii) the inflammatory events within the atherosclerotic plaques; and (iii) the systemic inflammatory response to ischaemic myocardial injury ( Figure 1 ). As such it is not surprising that inflammatory biomarkers predict adverse outcomes. Observational data and experimental studies reveal several candidate mediators; the role of each in patients with ACS is, however, unknown. The great majority of clinical studies are limited to associations between biomarker levels and outcomes, without any possibility of determining … [1]: #fn-2

Interleukin 4 (IL) 4 up-regulates gene and surface IL 1 receptor type I in murine T helper type 2 cells.

Abstract: The T cell-derived cytokine interleukin (IL) 4 is known to increase the proliferative response of T cells stimulated with IL 1. IL 4 is also an autocrine growth factor for type II T helper cells (Th2) cells. In the present studies, we examined the effect of murine recombinant IL 4 on the expression of the IL 1 receptor type I (IL 1RtI) in murine Th2 cell lines at the mRNA and surface level. Using a specific anti-murine IL 1RtI monoclonal antibody and flow microfluorometry, we found that IL 4 increased the surface expression of IL 1RtI in a dose-dependent manner. In D10S cells, a subline of the Th2 cell line D10.G4.1, 50-500 pg/ml IL 4 up-regulated the receptor 1.8- to 3.2-fold (p less than 0.05). This up-regulation was also seen at the mRNA level. The effect was not due to increased stability of the mRNA, since IL 4 did not modify the half-life of IL 1RtI mRNA. IL 4 also up-regulated IL 1RtI on CDC25 cells, another Th2 cell line. However, we did not observe an effect of IL 4 on gene expression of IL 1RtI in BALB/c 3T3 fibroblasts. IL 2 and IL 4 showed an additive effect in up-regulating IL 1RtI and D10S cells. These studies indicate that IL 4 up-regulates IL 1RtI in murine Th2 cells by increasing gene expression for IL 1RtI without affecting mRNA stability. Thus, IL 4 production by Th2 cells may amplify the immune response via up-regulation of IL 1RtI.

Antibodies to IL-1β

Abstract: The subject invention concerns a nucleic acid comprising a nucleotide sequence encoding human interleukin-1 (IL-1), and fragments thereof, and the polypeptides and peptides obtained. Specifically, the subject invention comprises the cloning of a cDNA synthesized by reverse transcription of poly(A)RNA isolated from adherent human monocytes stimulated with bacterial endotoxin. The subject invention further concerns antibodies that are immunoreactive with human IL-1β proteins. Human IL-1 is useful to induce the production of IL-2 by activated T-cells; it also acts on B-cells and NK-cells.

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.