Is IL-1 a good therapeutic target in the treatment of arthritis?
Inflammation is an important homeostatic mechanism that limits the effects of infectious agents. However, inflammation might be self-damaging and therefore has to be tightly controlled or even abolished by the organism. Interleukin 1 (IL-1) is a crucial mediator of the inflammatory response, playing an important part in the body's natural responses and the development of pathological conditions leading to chronic inflammation. While IL-1 production may be decreased or its effects limited by so-called anti-inflammatory cytokines, in vitro IL-1 inflammatory effects are inhibited and can be abolished by one particularly powerful inhibitor, IL-1 receptor antagonist (IL-1Ra). Recent research has shown that in the processes of rheumatoid arthritis (RA) IL-1 is one of the pivotal cytokines in initiating disease, and IL-1Ra has been shown conclusively to block its effects. In laboratory and animal studies the inhibition of IL-1 by either antibodies to IL-1 or IL-1Ra proved beneficial to the outcome. Because of its beneficial effects in many animal disease models, IL-1Ra has been used as a therapeutic agent in human patients. The recombinant form of IL-1Ra, anakinra (Kineret, Amgen) failed to show beneficial effects in septic shock and displays weak effects in RA patients. However, IL-1 blockade by anakinra is dramatically effective in systemic-onset juvenile idiopathic arthritis, in adult Still's disease and in several autoinflammatory disorders, most of the latter being caused by mutations of proteins controlling IL-1beta secretion. Importantly, to be efficacious, anakinra required daily injections, suggesting that administered IL-1Ra displays very short-term effects. Better IL-1 antagonists are in the process of being developed.
Burger
Danielle
D
Clinical Immunology Unit, Division of Immunology and Allergy, Department of Internal Medicine, University Hospital, 24 rue Micheli-du-Crest, CH-1211 Geneva 14, Switzerland. danielle.burger@hcuge.ch
Dayer
Jean-Michel
JM
Palmer
Gaby
G
Gabay
Cem
C
D000818:Animals; D001168:Arthritis / Q000188:drug therapy*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000503:physiopathology; D004195:Disease Models, Animal; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein / Q000502:physiology / Q000627:therapeutic use; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000502:physiology; D053583:Interleukin-1beta / Q000187:drug effects / Q000378:metabolism; D018123:Receptors, Interleukin / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000502:physiology
D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D053583:Interleukin-1beta; D018123:Receptors, Interleukin