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  • Review Article
  • Published:

Treating inflammation by blocking interleukin-1 in a broad spectrum of diseases

Nature Reviews Drug Discovery volume 11, pages 633–652 (2012)Cite this article

Subjects

Key Points

  • Interleukin-1 (IL-1) is a master cytokine in the pathogenesis of several diseases, inducing multiple pathways of inflammation.

  • Inflammation is part of every disease, acute or chronic. Diseases in which monocytes and/or macrophages and neutrophils have a dominant role are called autoinflammatory diseases. By contrast, diseases in which T lymphocytes have a major role are termed autoimmune diseases.

  • Autoimmune diseases are treated with glucocorticoids, immunosuppressive drugs as well as various anti-cytokine-based therapeutics that target the immune system. Autoinflammatory diseases are uniquely responsive to IL-1-blocking therapies and are less responsive to immunosuppressors.

  • There are two forms of IL-1: IL-1α and IL-1β. Both trigger inflammation by binding to the same receptor.

  • The IL-1 receptor antagonist anakinra binds to the IL-1 receptor and blocks the activity of both IL-1α and IL-1β.

  • A broad spectrum of acute and inflammatory diseases are treated with anakinra.

  • Neutralizing monoclonal antibodies to IL-1α, IL-1β and the IL-1 receptor have been developed to decrease the activity of IL-1.

  • An orally active inhibitor of caspase 1, the enzyme that processes IL-1β into an active cytokine, has also been developed.

  • Blocking IL-1 in individuals with rare inherited diseases reverses generalized as well as local inflammation.

  • Common inflammatory diseases such as arthritis, gout, type 2 diabetes, dry eye syndrome and heart failure are also responsive to IL-1 blocking.

  • The future of IL-1 drug development will involve an expansion of disease indications through controlled trials.

Abstract

Interleukin-1 (IL-1) is a highly active pro-inflammatory cytokine that lowers pain thresholds and damages tissues. Monotherapy blocking IL-1 activity in autoinflammatory syndromes results in a rapid and sustained reduction in disease severity, including reversal of inflammation-mediated loss of sight, hearing and organ function. This approach can therefore be effective in treating common conditions such as post-infarction heart failure, and trials targeting a broad spectrum of new indications are underway. So far, three IL-1-targeted agents have been approved: the IL-1 receptor antagonist anakinra, the soluble decoy receptor rilonacept and the neutralizing monoclonal anti-IL-1β antibody canakinumab. In addition, a monoclonal antibody directed against the IL-1 receptor and a neutralizing anti-IL-1α antibody are in clinical trials.

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Figure 1: Initiation of sterile inflammation by IL-1α following an ischaemic event.
Figure 2: Role of IL-1β in sterile inflammation.

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Acknowledgements

The authors thank A. Abbate, M. Donath, E. Furline, R. Gall, L. Joosten, S. Marshall, T. Mandrup-Poulsen, M. G. Netea, B. Pilström, A. Solinger, J. Simard, C. J. Tack, P. Tyrrel, C. Ungerth, E. J. van Asseldonk and B. van Tassel for their assistance with this article. This work is supported by grants from the US National Institutes of Health (AI-15614, AR-45584, CA-04 6934 (to C.A.D.)) and a VIDI grant from the Netherlands Research Fund (to A.S.).

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  1. Department of Medicine, University of Colorado Denver, Aurora, 80045, Colorado, USA

    Charles A. Dinarello

  2. Department of Medicine, University Medical Center Nijmegen, Nijmegen, HB 6500, The Netherlands

    Charles A. Dinarello, Anna Simon & Jos W. M. van der Meer

Authors
  1. Charles A. Dinarello
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  2. Anna Simon
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  3. Jos W. M. van der Meer
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Corresponding author

Correspondence to Charles A. Dinarello.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Table S1

Broad Spectrum of Diseases Responsive to Anakinra (PDF 310 kb)

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FURTHER INFORMATION

ClinicalTrials.gov website

Glossary

IL-1 receptor antagonist

(IL-1Ra). A naturally occurring protein that is structurally similar to interleukin-1 (IL-1), and inhibits IL-1α and IL-1β activity by blocking the IL-1 receptor.

Monoclonal antibody

A type of antibody that recognizes and binds to a single specific epitope of the antigen of interest. For example, canakinumab is a monoclonal antibody that binds to a specific location on interleukin-1β (IL-1β). Monoclonal antibodies are used clinically to neutralize cytokines and cytokine receptors.

Chimeric

Composed of two unrelated components. A fusion of the naturally occurring interleukin-1 receptor antagonist (IL1-Ra) with IL-1β is an example of a chimeric molecule.

Caspase 1

An intracellular enzyme that cleaves the inactive interleukin-1β (IL-1β) precursor to form an active molecule. Caspase 1 is activated by the inflammasome.

Type 2 diabetes

Diabetes resulting from the loss of insulin-producing cells by an inflammatory process. Type 2 diabetes is an autoinflammatory disease caused by interleukin-1 (IL-1)-mediated inflammation.

CANTOS

Canakinumab Anti-inflammatory Thrombosis Outcome Study; a trial testing canakinumab for lowering the risk of myocardial infarction, stroke and cardiovascular deaths in high-risk patients.

Type 1 diabetes

Diabetes resulting from the loss of insulin-producing cells following an immune attack. Type 1 diabetes is an autoimmune disease.

IL-1α precursor

Interleukin-1α (IL-1α) is first synthesized in the cell as a larger molecule, termed a precursor. The IL-1α precursor is active, but undergoes shortening to form a more active molecule, often called the 'mature' protein.

Alarmin

A term used to describe an active molecule (such as interleukin-1α) that is ready to induce inflammation.

Tumour necrosis factor

(TNF). A highly inflammatory cytokine that has overlapping properties with interleukin-1.

Autoinflammation

An inflammatory process by which more inflammation arises from endogenous products of inflammation. For example, interleukin-1 (IL-1) induces more IL-1.

IL-1β precursor

Interleukin-1β (IL-1β) is first synthesized in the cell as a larger molecule, termed a precursor. It undergoes shortening to form a more active molecule, often called the 'mature' protein.

Inflammasome

An assembly of intracellular proteins that activate caspase 1.

Deficiency of interleukin-1 receptor antagonist

(DIRA). An inherited disease caused by a mutation in the interleukin-1 receptor antagonist (IL-1Ra). DIRA is a systemic and lethal disease present at birth.

Gout

A disease caused by the formation of crystals of uric acid in the joints, particularly in the foot. It is highly painful and associated with overnutrition.

Familial Mediterranean fever

(FMF). A systemic and local inflammatory disease characterized by recurrent bouts of fever and painful inflammation in the linings of the abdominal and chest walls of the body. FMF is an inherited disease.

Cryopyrin-associated periodic syndrome

(CAPS). A grouping of three syndromes: familial cold autoinflammatory syndrome (FCAS), Muckle–Wells syndrome and neonatal-onset multi-inflammatory disease (NOMID). CAPS is an inherited autoinflammatory disease.

NLRP3

NOD-, LRR- and pyrin domain-containing protein 3. Also called cryopyrin. This protein participates in the activation of caspase 1 and is a component of the inflammasome.

Amyloidosis

A destructive process caused by the deposition of amyloid fibrils. In inflammatory diseases, the condition is termed secondary amyloidosis.

TNF receptor-associated periodic syndrome

(TRAPS). An inherited disease caused by a mutation in the tumour necrosis factor (TNF) receptor; patients suffer from debilitating recurrent bouts of fever with local and systemic inflammation. TRAPS is an autoinflammatory disease.

Hyper-IgD syndrome

(HIDS). A genetic autoinflammatory disorder that is associated with high levels of immunoglobulin D in the blood. The disease is caused by a mutation in the enzyme mevalonate kinase. Patients experience 4–6 days of fever, muscle aches, a skin rash, painful mouth ulcers and swollen lymph nodes.

ST segment elevation myocardial infarction

(STEMI). A type of heart attack characterized by an elevation of the ST segment on the electrocardiogram. STEMI is the most dangerous type of heart attack.

Insulin resistance

A metabolic abnormality that is commonly present in type 2 diabetes, in which elevated blood insulin levels are ineffective in transporting glucose into the cells.

Pseudogout

Clinically similar to gout; a disease caused by the formation of phosphate crystals in the joints.

Osteoarthritis

The most common cause of arthritis (painful joints). Osteoarthritis is due to loss of the cartilage that cushions the joints. Proteoglycans comprise the flexible matrix of cartilage.

Rheumatoid arthritis

An autoimmune disease resulting in inflammation of the joints, in which the synovial membrane is thickened with inflammatory cells. Rheumatoid arthritis is a systemic disease affecting nearly all organs and is distinct from osteoarthritis, which affects only the joints.

Glucocorticoids

The preferred name for cortisone-like drugs. Also known as steroids. Prednisone is a synthetic glucocorticoid.

C-reactive protein

(CRP). A large protein produced by the liver in response to any infectious or inflammatory condition. It is commonly measured in the circulation as a marker of the severity of inflammation, particularly in patients with coronary artery disease.

Non-steroidal anti-inflammatory drugs

(NSAIDs). Oral drugs that are used to treat many inflammatory conditions. Ibuprofen is an example of an NSAID.

Gammopathy

The presence of elevated levels of a monoclonal antibody in the circulation. Gammopathies are part of multiple myeloma and Schnitzler syndrome.

Panuveitis

Inflammation in the eye: usually in either the front chamber (anterior uveitis) or the rear chamber (posterior uveitis). Uveitis reduces visual acuity and may result in blindness.

Graft-versus-host disease

A disease that occurs in patients following bone marrow transplantation, in which the newly transplanted donor bone marrow attacks the intestinal and skin cells of the recipient patient.

Ejection fraction

A term used to describe the amount (percentage) of blood that is pumped from the left ventricle of the heart. Patients with heart failure have a low (less than 40%) ejection fraction and therefore have limited physical ability.

Sensorineural deafness

Loss of hearing due to the inability of the cholear organ to sense vibrations and convert the vibrations into neural signals.

Multiple myeloma

A uniform form of cancer in which there is uncontrolled overproduction of antibody-producing cells that crowd the bone marrow's normal function to produce red blood cells, platelets and white blood cells.

Angiogenesis

Growth of blood vessels. In cancer, angiogenesis provides growing tumours with a blood supply. Drugs that inhibit angiogenesis are used to treat cancer.

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Dinarello, C., Simon, A. & van der Meer, J. Treating inflammation by blocking interleukin-1 in a broad spectrum of diseases. Nat Rev Drug Discov 11, 633–652 (2012). https://doi.org/10.1038/nrd3800

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