Treating inflammation by blocking interleukin-1 in humans

Abstract

IL-1 is a master cytokine of local and systemic inflammation. With the availability of specific IL-1 targeting therapies, a broadening list of diseases has revealed the pathologic role of IL-1-mediated inflammation. Although IL-1, either IL-1α or IL-1β, was administered to patients in order to improve bone marrow function or increase host immune responses to cancer, these patients experienced unacceptable toxicity with fever, anorexia, myalgias, arthralgias, fatigue, gastrointestinal upset and sleep disturbances; frank hypotension occurred. Thus it was not unexpected that specific pharmacological blockade of IL-1 activity in inflammatory diseases would be beneficial. Monotherapy blocking IL-1 activity in a broad spectrum of inflammatory syndromes results in a rapid and sustained reduction in disease severity. In common conditions such as heart failure and gout arthritis, IL-1 blockade can be effective therapy. Three IL-1blockers have been approved: the IL-1 receptor antagonist, anakinra, blocks the IL-1 receptor and therefore reduces the activity of IL-1α and IL-1β. A soluble decoy receptor, rilonacept, and a neutralizing monoclonal anti-interleukin-1β antibody, canakinumab, are also approved. A monoclonal antibody directed against the IL-1 receptor and a neutralizing anti-IL-1α are in clinical trials. By specifically blocking IL-1, we have learned a great deal about the role of this cytokine in inflammation but equally important, reducing IL-1 activity has lifted the burden of disease for many patients.

Introduction

The importance of IL-1 as a master cytokine in inflammation comes from infants born with a loss of function mutation in the naturally occurring endogenous IL-1 receptor antagonist (IL-1Ra). IL-1Ra blocks the IL-1 receptor type 1 (IL-1R1), which is on all cells; therefore, systemic inflammation may come for either IL-1α or IL-1β. These infants succumb early in life with overwhelming sterile inflammation of the skin, joints and bone with large numbers of infiltrating neutrophils and high levels of interleukin-17 [1], [2]. The condition is called deficiency of interleukin-1 antagonist (DIRA) and daily treatment with anakinra rapidly reverses the inflammation and prevents a fatal outcome. Mice deficient in IL-1Ra are similarly affected in that these mice develop spontaneous inflammation such as a rheumatoid arthritis-like disease and can succumb to lethal arteritis. The best evidence for a role for either IL-1α or IL-1β in disease comes from specific blockade, as correlations of circulating levels and disease severity are not informative and do not establish causality. Even in the most severe IL-1β-mediated autoinflammatory diseases, IL-1β levels in the circulation increase only by factor of five [3].

There are two IL-1's. IL-1α is expressed as a precursor and is constitutively present in most cells of healthy subjects. The cytokine is found in normal keratinocytes of the skin, the epithelial cells of mucosal membranes throughout the body and the cells of organs such as the liver, lung and kidney. Platelets also contain IL-1α. The entire endothelium of the vasculature contains the IL-1α precursor and in membrane fragments from the endothelium termed “apoptotic bodies” [4]. These membrane fragments are active in inducing neutrophil infiltration [4] in several inflammatory conditions of the blood vessels termed vasculitis [5]. During ischemia, however, cell death by necrosis takes place and the IL-1α precursor is released [6], [7].

In contrast, IL-1β is not present in health or at levels not detected by standard assays. IL-1β is a product of blood monocytes, tissue macrophages and dendritic cells. The rate-limiting step in the production of IL-1β is transcription, but IL-1β mRNA requires an additional signal for synthesis. The stimulus can be a microbial product but cytokines, such as TNFα, IL-18, IL-1α or IL-1β itself induce IL-1β [8]. In fact, IL-1 induction of itself is part of the mechanism of “autoinflammation”. IL-1β is first synthesized as an inactive precursor but the precursor requires cleavage by caspase-1, an intracellular cysteine protease. Caspase-1 itself requires activation in order to process IL-1β into an active cytokine. The activation of caspase-1 proceeds following the oligomerization of a complex of intracellular proteins termed the “inflammasome” by the late Tschopp [9], [10]. With activation of caspase-1, the N-terminal amino acids are cut and mature IL-1β is readily secreted as an active cytokine. One of the components of the inflammasome termed “cryopyrin” (also termed NLRP3) plays a critical role in the secretion of IL-1β. A single amino acid mutation in cryopyrin [11] results in enhanced caspase-1 activity and greater secretion of IL-1β⋅ Increased production and secretion of IL-1β from blood monocytes is characteristic of a group of autoinflammatory diseases termed “cryopyrin associated periodic syndrome (CAPS)”.