Interleukin-1 in the pathogenesis and treatment of inflammatory diseases

Abstract

More than any other cytokine family, the IL-1 family of ligands and receptors is primarily associated with acute and chronic inflammation. The cytosolic segment of each IL-1 receptor family member contains the Toll-IL-1-receptor domain. This domain is also present in each Tolllike receptor, the receptors that respond to microbial products and viruses. Since Toll-IL-1-receptor domains are functional for both receptor families, responses to the IL-1 family are fundamental to innate immunity. Of the 11 members of the IL-1 family, IL-1␤ has emerged as a therapeutic target for an expanding number of systemic and local inflammatory conditions called autoinflammatory diseases. For these, neutralization of IL-1␤ results in a rapid and sustained reduction in disease severity. Treatment for autoimmune diseases often includes immunosuppressive drugs whereas neutralization of IL-1␤ is mostly anti-inflammatory. Although some autoinflammatory diseases are due to gain-of-function mutations for caspase-1 activity, common diseases such as gout, type 2 diabetes, heart failure, recurrent pericarditis, rheumatoid arthritis, and smoldering myeloma also are responsive to IL-1␤ neutralization. This review summarizes acute and chronic inflammatory diseases that are treated by reducing IL-1␤ activity and proposes that disease severity is affected by the anti-inflammatory members of the IL-1 family of ligands and receptors. (Blood. 2011;117(14):3720-3732) IntroductionSince the 1996 publication in Blood of "Biologic Basis for Interleukin-1 in Disease," 1 there have been several major advances in understanding a role for IL-1 in the pathogenesis of disease. Because of its property as a hematopoietic factor, IL-1 was administered to patients to improve recovery after BM transplantation (human responses to IL-1 were reviewed in detail in 1996). 1 Effective in reducing the duration of thrombocytopenia and leukopenia, recipients of IL-1 therapy experienced unacceptable signs and symptoms of systemic inflammation, including hypotension. Therefore, attention was initially focused on blocking IL-1 activity in sepsis with the use of the naturally occurring IL-1 receptor antagonist (IL-1Ra), now known by its generic name anakinra. There were 3 controlled trials of anakinra in human sepsis. Although in each trial there was a reduction in 28-day all-causes mortality compared with placebo-treated patients, the reductions did not reach statistical significance. 2 The failure of blocking IL-1 to significantly reduce mortality in septic shock is not unusual, because most anticytokines and anti-inflammatory agents have also failed in sepsis trials (reviewed in Eichacker et al 3 ).Subsequently, attention focused on blocking IL-1 in noninfectious, chronic inflammatory conditions, such as rheumatoid arthritis. Anakinra is approved for reducing the signs and symptoms of rheumatoid arthritis and slows the progressive joint destructive characteristics of the disease. Anakinra has also been administered to patients with smoldering/indolent myeloma at high risk o...

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Les inflammasomes

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“…IL-1 type cytokines, including both IL-1α and IL-1β, mainly control the pro-inflammatory reactions in response to pathogen-induced tissue injury [1]. The major sources of the secreted IL-1α and IL-1β are the cells of the innate immune system [1].…”

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