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.

Keywords: AOSD; Autoimmune; Autoinflammatory; C-reactive protein; CAPS; CRP; DIRA; FCAS; FMF; HIDS; Inflammation; NLRP12; NLRP3; NOMID; PAPA; PASH; PFAPA; SAPHO; SJIA; TNF receptor associated periodic syndrome; TRAPS; adult onset Still's disease; cryopyrin autoinflammatory periodic syndromes; deficiency of IL-1Ra; familial Mediterranean fever; familial cold autoinflammatory syndrome; hyper IgD syndrome; neonatal onset multi-inflammatory diseases; nucleotide-binding domain and leucine-rich repeat pyrin containing 12; nucleotide-binding domain and leucine-rich repeat pyrin containing 3; periodic fever, aphthous stomatitis, pharyngitis, and adenitis; pyoderma-gangrenosum, acne, and suppurativa hidradenitis; pyogenic arthritis, pyoderma gangrenosum, and acne; synovitis, acne, pustulosis, hyperostosis and osteitis; systemic-onset juvenile idiopathic arthritis.

Fig. 1

Time line for milestones in clinical applications with IL-1 blocking therapeutics. HIDS, hyper IgD syndrome; CAPS, cryopyrin associated periodic syndromes; FMF, familial Mediterranean fever; TRAPS, TNF receptor associated periodic syndrome; MWS, Muckle–Wells syndrome; AOSD, adult onset Still disease; SJIA, systemic juvenile idiopathic arthritis; STEMI, ST segment elevated my myocardial infarction.

Fig. 2

Role of IL-1α and IL-1β in sterile inflammation. Event 1. With hypoxic damage in the necrotic area, dying cells loose membrane integrity. Event 2. With cellular necrosis, cell contents are released including the active IL-1α precursor [354]. Anti-IL-1α antibodies neutralize IL-1α at this step. Event 3. The IL-1α precursor binds to IL-1R1 on nearby resident macrophages; anakinra and anti-IL-1R1 antibodies prevent this event. With binding of the IL-1α precursor to the IL-1R1, synthesis of IL-1β precursor takes place, caspase-1 cleaves the precursor releasing active IL-1β. Anti-IL-1β blocks at this step. Triggered by IL-1α binding to the IL-1R1 on resident macrophages, chemokines are also released. Event 4. IL-1β activates capillaries in the ischemic tissues to express the intracellular adhesion molecule-1 (ICAM-1). Circulating blood neutrophils roll on the endothelium, adhere to ICAM-1 and enter the ischemic tissue via diapedesis [6]. Anakinra or anti-IL-1R1 prevents this event. Event 5. With resident macrophages releasing chemokines, a chemokine gradient forms, which facilitates the passage to blood neutrophils into the ischemic area. Event 6. The number of neutrophils increases into the area of the ischemic event and local IL-1 prolongs the survival of neutrophils at this step. Event 7. Neutrophils scavenge dying cells and release proteases that contribute the destruction of penumbral cells.