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.

Interleukin-1 and its receptor.

Abstract: Interleukin-1 (IL-1) is a polypeptide that is produced during infection, injury, or immunologic challenge. There are two molecular forms, IL-1-beta and IL-1-alpha, and despite only a 26% amino acid homology, both forms induce a wide variety of biological changes. These include systemic effects such as fever, sleep, ACTH release, and increased sodium excretion. In vitro, IL-1 activates T and B lymphocytes and induces a variety of lymphokines, interferons, and other cytokines, particularly tumor necrosis factor, for the induction of inflammatory changes such as prostaglandin synthesis, activation of endothelial cells, and bone resorption. Despite the broad range of tissue targets, IL-1 receptors have been described primarily on lymphocyte lines and fibroblasts. A feature of these studies is the low numbers of receptor sites and a relatively low-affinity binding. There is also evidence for the existence of a second class of high-affinity receptors. Molecular weights of IL-1 receptors vary with the cell source; these have been demonstrated with molecular weight of 80, 70, and 60 kDa. In general, there is a discrepancy between receptor number and affinity and biological responses to IL-1. One explanation for the mechanism of action of IL-1, particularly on T cells, is the requirement for cross-linking of two membrane proteins. In some cells, the binding of IL-1 to putative receptors may be fast and transient, accounting for activation of intracellular responses without a measureable biological response (such as increased DNA synthesis). IL-1 activation of cells is an important biological response, and its mechanism remains in an unexplored domain.

Interleukin-32 induces the differentiation of monocytes into macrophage-like cells

Abstract: After emigration from the bone marrow to the peripheral blood, monocytes enter tissues and differentiate into macrophages, the prototype scavenger of the immune system. By ingesting and killing microorganisms and removing cellular debris, macrophages also process antigens as a first step in mounting a specific immune response. IL-32 is a cytokine inducing proinflammatory cytokines and chemokines via p38-MAPK and NF-κB. In the present study, we demonstrate that IL-32 induces differentiation of human blood monocytes as well as THP-1 leukemic cells into macrophage-like cells with functional phagocytic activity for live bacteria. Muramyl dipepide (MDP), the ligand for the intracellular nuclear oligomerization domain (NOD) 2 receptor, has no effect on differentiation alone but augments the monocyte-to-macrophage differentiation by IL-32. Unexpectedly, IL-32 reversed GM-CSF/IL-4-induced dendritic cell differentiation to macrophage-like cells. Whereas the induction of TNFα, IL-1β, and IL-6 by IL-32 is mediated by p38-MAPK, IL-32-induced monocyte-to-macrophage differentiation is mediated through nonapoptotic, caspase-3-dependent mechanisms. Thus, IL-32 not only contributes to host responses through the induction of proinflammatory cytokines but also directly affects specific immunity by differentiating monocytes into macrophage-like cells.

Induction of human interleukin-1 by a product of Staphylococcus aureus associated with toxic shock syndrome.

Abstract: Certain strains of Staphylococcus aureus associated with toxic shock syndrome elaborate material that induces human blood monocytes to secrete interleukin-1 (IL-1). IL-1 was detected both by its ability to cause fever in rabbits using the leukocytic pyrogen (LP) assay and by its mitogenic activity towards thymocytes in the so-called lymphocyte-activating factor (LAF) assay. Anti-human IL-1 prevents the manifestation of both activities. Filtrates of control strains of S. aureus manifest neither activity. Thus, culture filtrates derived from toxic shock syndrome (TSS)-associated strains cause biphasic fever in rabbits when injected intravenously. The fever lasts several hours. Plasma taken at the peak of the fever and injected into a second set of rabbits produces a brief monophasic fever typical of LP. Further, human monocytes release LP when incubated with TSS filtrates in vitro. The monocyte products also stimulate the proliferation of mouse thymocytes in the presence of phytohemagglutinin in a manner characteristic of LAF. A bacterial filtrate is much less effective without an intermediate incubation with monocytes. The stimulation of monocyte IL-1 production is easily quantified, provides a simple method of assaying the TSS toxin, and since it involves human cells, is directly relevant to the human disease. The assay was used to monitor the purification of TSS toxin. Only 0.1 ng/ml of the purified material is required to induce monocyte IL-1 production. It is thus more potent than endotoxin. In contrast to endotoxin, its effect is not blocked by polymyxin B. We conclude that in TSS the sudden fever and probably other components of the acute phase response may be attributed to a massive release of IL-1.

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.