The interleukin-1 families of cytokines and receptors: therapeutic potential for immunomodulation and the treatment of inflammatory disorders

Abstract

The interleukin (IL)-1 cytokine family includes 11 distinct members that are related in their genomic and protein structures. The initial members of this family, IL-1α and IL-1β, were discovered over two decades ago and are now considered as prototypic pro-inflammatory cytokines. Their activity is downregulated by a third family member, termed IL-1-receptor antagonist (IL-1ra). Another IL-1 family cytokine that was also identified early on is IL-18, an agonist cytokine possessing potent immunostimulatory activities. Subsequently, sequence homology searches in DNA databases led to the discovery of genes that encode additional family members. IL-1 cytokines exert their function through structurally related cell surface receptors that have a Toll/IL-1 receptor (TIR) module in their intracellular region and one to three copies of immunoglobulin (Ig)-like domains in their extracellular region. At present, 11 members of the IL-1 receptor family are known. A hallmark of IL-1 receptor signalling, which is mediated via the TIR domain, is the activation of the transcription factor NF-κB and the mitogen-activated protein kinases (MAPK). Owing to their possible roles in immune disease mechanisms, IL-1 and its relatives have long been considered as potential targets of therapeutic intervention in inflammatory and autoimmune conditions. Strong evidence for the importance of IL-1 in pathogenic inflammation was recently provided by the clinical use of a recombinant form of human IL-1ra for the treatment of rheumatoid arthritis and certain autoinflammatory syndromes. The discovery and characterisation of the IL-1 families of cytokines and receptors, as well as the exploration of their therapeutic potential, has generated a large body of patent literature over the past few years. Here, this literature is reviewed and discussed in the context of current research findings.

Keywords::

• anti-inflammatory therapy
• cytokines
• genetic polymorphism
• IL-1α
• IL-1β
• IL-1ra
• IL-18
• IL-33
• IL-1 family
• immunostimulation
• immunosuppression
• rheumatoid arthritis