The IL-1 family and inflammatory diseases.
IL-1 and its related family member IL-18 are primarily proinflammatory cytokines by their ability to stimulate the expression of genes associated with inflammation and autoimmune diseases. For IL-1 (IL-1alpha and IL-1beta), the most salient and relevant properties are the initiation of cyclooxygenase type 2 (COX-2), type 2 phospholipase A and inducible nitric oxide synthase (iNOS). This accounts for the large amount of prostaglandin-E2 (PGE2), platelet activating factor and nitric oxide (NO) produced by cells exposed to IL-1 or in animals or humans injected with IL-1. Another important member of the proinflammatory IL-1 family is IL-18. IL-18 is also an important player in autoimmune disease because of its ability to induce IFNgamma, particularly in combination with IL-12 or IL-15. Both IL-1 and IL-18 increase the expression of adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1) on mesenchymal cells and vascular-cell adhesion molecule-1 (VCAM-1) on endothelial cells. This latter property promotes the infiltration of inflammatory and immunocompetent cells into the extravascular space. IL-1 and IL-18 are also an angiogenic factors by increasing the expression of vascular endothelial growth factor; IL-1 and IL-18 thus play a role in pannus formation and blood vessel supply. The strongest case for the importance of IL-1 in disease processes come from the administration of the IL-1 receptor antagonist, also a member of the IL-1 family and IL-18 binding protein (IL-18BP), a constitutively expressed and secreted protein that binds and neutralizes IL-18. Data from the human genome project have revealed other members of the IL-1 family. However, these appear to be antagonists rather than agonists. IL-1 also acts as an adjuvant during antibody production and stimulates bone marrow stem cells for differentiation in the myeloid series. IL-1 is distinct from tumor necrosis factor (TNF); IL-1 and TNFalpha share several biological properties but the salient difference is that TNF receptor signaling induces programmed cell death whereas IL-1 receptor signaling does not. In fact, IL-1 is a hematopoietic growth factor and IL-1 was administered to humans to reduce the nadir of white blood cells and platelets in patients during bone-marrow transplantation. This property, of IL-1 is not observed in the responses to TNFalpha. Furthermore, in animal models of destructive rheumatoid arthritis, IL-1 is necessary but TNFalpha is not.
Department of Medicine, University of Colorado Health Sciences Center, 4200 East Ninth Ave., B168, Denver, CO 80262, USA.
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Dinarello
D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology*; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000276:immunology; D006801:Humans; D007375:Interleukin-1 / Q000276:immunology*; D020382:Interleukin-18 / Q000276:immunology*; D007527:Isoenzymes / Q000276:immunology; D008024:Ligands; D008565:Membrane Proteins; D051379:Mice; D009569:Nitric Oxide / Q000276:immunology; D019001:Nitric Oxide Synthase / Q000276:immunology; D052247:Nitric Oxide Synthase Type II; D010741:Phospholipases A / Q000276:immunology; D010972:Platelet Activating Factor / Q000276:immunology; D011451:Prostaglandin-Endoperoxide Synthases / Q000276:immunology; D017472:Receptors, Interleukin-1 / Q000276:immunology*
D007375:Interleukin-1; D020382:Interleukin-18; D007527:Isoenzymes; D008024:Ligands; D008565:Membrane Proteins; D010972:Platelet Activating Factor; D017472:Receptors, Interleukin-1; D009569:Nitric Oxide; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D010741:Phospholipases A; D015232:Dinoprostone