Inhibition Of Interleukin-1 Activity Research Articles

Interleukin-1 Receptor Blockade Rescues Myocarditis-Associated End-Stage Heart Failure.

Support measures currently represent the mainstay of treatment for fulminant myocarditis, while effective and safe anti-inflammatory therapies remain an unmet clinical need. However, clinical and experimental evidence indicates that inhibition of the pro-inflammatory cytokine interleukin 1 (IL-1) is effective against both myocardial inflammation and contractile dysfunction. We thus evaluated treatment with the IL-1 receptor antagonist anakinra in a case of heart failure secondary to fulminant myocarditis. A 65-year-old man with T cell lymphoma developed fulminant myocarditis presenting with severe biventricular failure and cardiogenic shock requiring admittance to the intensive care unit and mechanical circulatory and respiratory support. Specifically, acute heart failure and cardiogenic shock were initially treated with non-invasive ventilation and mechanical circulatory support with an intra-aortic balloon pump. Nevertheless, cardiac function deteriorated further, and there were no signs of improvement. Treatment with anakinra, the recombinant form of the naturally occurring IL-1 receptor antagonist, was started at a standard subcutaneous dose of 100 mg/day. We observed a dramatic clinical improvement within 24 h of initiating anakinra. Prompt, progressive amelioration of cardiac function allowed weaning from mechanical circulatory and respiratory support within 72 h of anakinra administration. Recent studies point at inhibition of IL-1 activity as an attractive treatment option for both myocardial inflammation and contractile dysfunction. Furthermore, IL-1 receptor blockade with anakinra is characterized by an extremely rapid onset of action and remarkable safety and may thus be suitable for the treatment of patients critically ill with myocarditis.

698 Inhibition of Interleukin-1 activity improves coronary flow, endothelial function and aorticl wall properties: a randomized cross-over, placebo-controlled, trial

698 Inhibition of Interleukin-1 activity improves coronary flow, endothelial function and aorticl wall properties: a randomized cross-over, placebo-controlled, trial

Therapeutic Prospects for Modification of Interleukin-1 Activity in Arthritis

Interleukin-1 (IL-1) is a major proinflammatory cytokine that is implicated in the pathogenesis of rheumatoid arthritis and osteoarthritis, together with other cytokines such as tumour necrosis factor-α. IL-1 is produced in the inflamed synovial tissue, where it contributes to synovial inflammation and proliferation, to bone and cartilage degradation and to systemic symptoms. Inhibition of IL-1 activity is a promising therapeutic approach in arthritis. Some existing antiarthritic agents, such as corticosteroids or methotrexate, are thought to exert part of their beneficial activity by interfering with IL-1 activity. However, IL-1 production may be specifically targeted by inhibiting the recently discovered IL-1β converting enzyme (ICE). Furthermore, it is possible to specifically block IL-1 at the effector level, using natural antagonists of IL-1 such as the soluble forms of the IL-1 receptor (IL-1sR) or the IL-1 receptor antagonist (IL-1Ra). In animal studies, IL-1Ra exerts antiarthritic effects in animal models following systemic administration or local gene transfer therapy to the joint. Phase I and phase II clinical trials have been completed in rheumatoid arthritis using IL-1Ra and IL-1sR. These agents were generally well tolerated and exhibited some beneficial effect. More studies are now being undertaken to fully investigate the clinical potential of these new therapeutic agents, either alone or in combination.

The effects of methotrexate on the production and activity of interleukin-1.

To explore the possibility that the mechanism of action of methotrexate (MTX) in rheumatoid arthritis (RA) is related to modulation of interleukin-1 (IL-1), the effects of MTX on IL-1 production and activity were evaluated. Human peripheral blood mononuclear cells and murine peritoneal and splenic cells were stimulated by lipopolysaccharide to produce IL-1. No inhibition of IL-1 synthesis or secretion caused by MTX treatment could be demonstrated either in vitro or in vivo, in patients with RA or in mice treated with MTX. We did show, however, that MTX had an inhibitory effect on IL-1 activity in 2 assays that demonstrate 2 different functions of IL-1. In a 2-step assay using LBRM-33-1A5 (1A5) and CTLD cells, MTX inhibited the secretion of IL-2 by 1A5 lymphoma cells in response to phytohemagglutinin and IL-1. In an assay using D10.G4.1 (D10) cells, MTX inhibited IL-1-induced proliferation of the D10 T cell clone. No effect of the drug on IL-2 activity was observed. The results demonstrate that MTX is capable of inhibiting some IL-1 activities without affecting IL-1 production or secretion. We propose that the inhibition of IL-1 activity or IL-1-dependent events may be one of the mechanisms of action of MTX in RA.