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.

Cytokines as endogenous pyrogens

Abstract: Cytokines are pleiotropic molecules mediating several pathologic processes. Long before the discovery of cytokines as immune system growth factors or as bone marrow stimulants, investigators learned a great deal about cytokines when they studied them as the endogenous mediators of fever. The terms "granulocytic" or "endogenous pyrogen" were used to describe substances with the biologic property of fever induction. Today, we recognize that pyrogenicity is a fundamental biologic property of several cytokines and hence the clinically recognizeable property of fever links host perturbations during disease with fundamental perturbations in cell biology. In this review, the discoveries made on endogenous pyrogens are revisited, with insights into the importance of the earlier work to the present-day understanding of cytokines in health and in disease.

Gene expression, synthesis, and secretion of interleukin 18 and interleukin 1β are differentially regulated in human blood mononuclear cells and mouse spleen cells

Abstract: Interleukin (IL)-18, formerly called interferon γ (IFN-γ)-inducing factor, is biologically and structurally related to IL-1β. A comparison of gene expression, synthesis, and processing of IL-18 with that of IL-1β was made in human peripheral blood mononuclear cells (PBMCs) and in human whole blood. Similar to IL-1β, the precursor for IL-18 requires processing by caspase 1. In PBMCs, mature but not precursor IL-18 induces IFN-γ; in whole human blood stimulated with endotoxin, inhibition of caspase 1 reduces IFN-γ production by an IL-1β-independent mechanism. Unlike the precursor for IL-1β, precursor for IL-18 was expressed constitutively in PBMCs and in fresh whole blood from healthy human donors. Western blotting of endotoxin-stimulated PBMCs revealed processed IL-1β in the supernatants via an caspase 1-dependent pathway. However, in the same supernatants, only unprocessed precursor IL-18 was found. Unexpectedly, precursor IL-18 was found in freshly obtained PBMCs and constitutive IL-18 gene expression was present in whole blood of healthy donors, whereas constitutive IL-1β gene expression is absent. Similar to human PBMCs, mouse spleen cells also constitutively contained the preformed precursor for IL-18 and expressed steady-state IL-18 mRNA, but there was no IL-1β protein and no spontaneous gene expression for IL-1β in these same preparations. We conclude that although IL-18 and IL-1β are likely members of the same family, constitutive gene expression, synthesis, and processing are different for the two cytokines.

Glucocorticoids inhibit transcriptional and post-transcriptional expression of interleukin 1 in U937 cells.

Abstract: We investigated effects of corticosteroids on interleukin 1 (IL-1) production in monocyte-like tumor cell line, U937. Release of IL-1 activity by bacterial toxin-stimulated cells was completely blocked by 10 nM dexamethasone (Dex). We examined the question whether corticosteroids suppress IL-1 production by blocking transcription of IL-1 mRNA, or by blocking IL-1 synthesis at a post-transcriptional step. Northern blot hybridization analysis indicated that Dex, 10 nM, completely blocked accumulation of IL-1 beta-encoding mRNA in U937 cells. Dex-mediated inhibition of IL-1 release appeared to be glucocorticoid receptor-mediated and was abrogated by progesterone. In addition, Dex at high concentrations could inhibit post-transcriptional synthesis of IL-1 by prestimulated U937 cells. Although Dex, 500 nM, did not change IL-1 mRNA levels in prestimulated cells, it completely blocked IL-1 release and induced a transient increase in cellular cyclic adenosine 3',5'-monophosphate (cAMP) levels. Dex-mediated inhibition of IL-1 release in prestimulated cells is likely to occur via increased levels of cAMP, which have been shown to block post-transcriptional IL-1 synthesis. Our results indicate that glucocorticoids suppress IL-1 synthesis by two distinct mechanisms, blocking transcription of IL-1 mRNA during monocyte activation, and blocking post-transcriptional IL-1 synthesis via cAMP.

Consensus conference definitions for sepsis, septic shock, acute lung injury, and acute respiratory distress syndrome: time for a reevaluation.

Abstract: Definitions for sepsis, septic shock, acute lung injury (ALI), and acute respiratory distress syndrome (ARDS) were developed by consensus conferences with the goal of achieving standardization of terminology and improved homogeneity of patient populations in clinical studies. Although such definitions have been useful in epidemiologic investigations, the criteria specified by the consensus conferences are broad and insufficiently specific to address the problem of heterogeneous mechanisms leading to clinical syndromes. An important challenge is to progress from clinical syndromes, as presently defined, to more specific entities that are delineated by alterations in specific immunologic or biochemical pathways. Such mechanistic definitions will provide more homogeneous groups of patients who can be identified at early stages of their clinical course. This approach encourages focused investigation of pathways leading to organ system dysfunction and death and, also, provides an efficient framework for the development of new therapies useful in critically ill patients.

An update on human interleukin-1: from molecular biology to clinical relevance

Abstract: Interleukin-1 (IL-1) represents a family of polypeptides with a wide range of biological activities. At least two dissimilar gene products have been cloned; there are probably more. The human IL-1 family plays an important role in the pathogenesis of many diseases and functions as a key mediator of the host response to various infectious, inflammatory, and immunologic challenges. Recombinant mouse (pI 5) and recombinant human (pI 7) IL-1's are being used to confirm the multiple biological properties of IL-1's but considerable investigation is required before the specific activities (biological units per milligram of protein) are established for each human IL-1 form. Some IL-1 biological activities such as the induction of hepatic acute-phase protein synthesis have been demonstrated in invertebrates predating the evolution of lymphocytes. IL-1 is highly inflammatory and increases the concentration of metabolites of arachidonic acid, most notably prostaglandin E2, in brain, muscle, chondrocytes, and synovial fibroblasts. The synthesis of leukotrienes also is involved in the mechanism of its action on certain tissues. The cloning and expression of human IL-1 genes will expand our understanding of IL-1 in various diseases through improved detection systems and the use of cDNA probes; the development of IL-1 antagonists, as well as the use of IL-1 as an immunomodulator, is presently being considered.

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.