Abstract
Interleukin-1 (IL-1) is the prototypical inflammatory cytokine: two distinct ligands (IL-1α and IL-1β) bind the IL-1 type 1 receptor (IL-1R1) and induce a myriad of secondary inflammatory mediators, including prostaglandins, cytokines, and chemokines. IL-1α is constitutively present in endothelial and epithelial cells, whereas IL-1β is inducible in myeloid cells and released following cleavage by caspase-1. Over the past 30 years, IL-1-mediated inflammation has been established in a broad spectrum of diseases, ranging from rare autoinflammatory diseases to common conditions such as gout and rheumatoid arthritis (RA), type 2 diabetes, atherosclerosis, and acute myocardial infarction. Blocking IL-1 entered the clinical arena with anakinra, the recombinant form of the naturally occurring IL-1 receptor antagonist (IL-1Ra); IL-1Ra prevents the binding of IL-1α as well as IL-1β to IL-1R1. Quenching IL-1-mediated inflammation prevents the detrimental consequences of tissue damage and organ dysfunction. Although anakinra is presently approved for the treatment of RA and cryopyrin-associated periodic syndromes, off-label use of anakinra far exceeds its approved indications. Dosing of 100 mg of anakinra subcutaneously provides clinically evident benefits within days and for some diseases, anakinra has been used daily for over 12 years. Compared to other biologics, anakinra has an unparalleled record of safety: opportunistic infections, particularly Mycobacterium tuberculosis, are rare even in populations at risk for reactivation of latent infections. Because of this excellent safety profile and relative short duration of action, anakinra can also be used as a diagnostic tool for undefined diseases mediated by IL-1. Although anakinra is presently in clinical trials to treat cancer, this review focuses on anakinra treatment of acute as well as chronic inflammatory diseases.
Highlights
Historical Background of IL-1 and IL-1 receptor antagonist (IL-1Ra)The history of interleukin 1 (IL-1) dates back to the purification of the endogenous fever-producing protein called leukocytic pyrogen, as reviewed in Dinarello (2015)
Specific mutations in diseases such as familial Mediterranean fever (FMF) and cryopyrin-associated periodic syndrome (CAPS) result in deregulated release of active IL-1β, which is clinically manifested as periodic fevers with systemic and local inflammation
Chronic inflammation is central to the pathogenesis of atherosclerosis (Libby et al, 2002), and IL-1 promotes the formation, growth, and rupture of vascular atherosclerotic plaques, which account for ischemic cardiovascular complications (Peiro et al, 2017; Buckley and Abbate, 2018)
Summary
The history of interleukin 1 (IL-1) dates back to the purification of the endogenous fever-producing protein called leukocytic pyrogen, as reviewed in Dinarello (2015). The specific biologic activity of purified human leukocytic pyrogen was first reported in 1977 as the induction of fever in rabbits at 10 ng/kg (Dinarello et al, 1977). There was an endotoxin-inducible suppressor “factor” inhibiting IL-1-mediated thymocyte proliferation in the circulation (Dinarello et al, 1981) Subsequent to this observation, others reported the presence of a “specific” inhibitor of IL-1 bioactivity in supernatants of human monocytes (Arend et al, 1985) and in the serum and urine of children with systemic juvenile arthritis (Prieur et al, 1987). As stated in our review (Cavalli and Dinarello, 2018), in 1981 we described a circulating suppressor factor from humans during experimental endotoxemia as assayed for specific inhibition of IL-1 activity in vitro (Dinarello et al, 1981). Unrestricted activation of caspase-1 and secretion of IL-1β lead to systemic and multi-organ sterile inflammation, which characterizes autoinflammatory diseases (Hoffman and Wanderer, 2011)
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