The Expanding Family of Interleukin-1 Cytokines and Their Role in Destructive Inflammatory Disorders

Understanding cytokine immunobiology is central to the development of rational therapies for destructive inflammatory diseases such as rheumatoid arthritis (RA) and periodontitis. The classical interleukin-1 (IL-1) family cytokines, IL-1alpha and IL-1beta, as well as IL-18, play key roles in inflammation. Recently, other members of the IL-1 family have been identified. These include six cytokines whose genes are located downstream of the genes for IL-1alpha and IL-1beta on chromosome 2 (IL-1F5-10) and also IL-33, which is the ligand for ST2, a member of the IL-1R/Toll-like receptor (TLR) receptor superfamily. IL-1F6, IL-1F8 and Il-1F9 are agonists and, along with their receptor IL-1Rrp2, are highly expressed in epithelial cells suggesting a role in immune defence in the skin and the gastrointestinal (GI) tract including the mouth. Synovial fibroblasts and articular chondrocytes also express IL-1Rrp2 and respond to IL-1F8, indicating a possible role in RA. IL-33 is associated with endothelial cells in the inflamed tissues of patients with RA and Crohn's disease, where it is a nuclear factor which regulates transcription. IL-33 is also an extracellular cytokine: it induces the expression of T helper 2 (Th2) cytokines in vitro and in vivo as well as histopathological changes in the lungs and GI tract of mice. Therapeutic agents which modify IL-1 cytokines (e.g. recombinant IL-1Ra) have been used clinically and others are at various stages of development (e.g. anti-IL-18 antibodies). This review highlights the emerging data on these novel IL-1 cytokines and assesses their possible role in the pathogenesis and therapy of destructive inflammatory disorders such as RA and periodontitis.