Ligands and Receptors of the Interleukin-1 Family in Immunity and Disease

IL-1 has served as a ground breaking molecule in immunology and it is now experiencing a renaissance. Originally the description of a cytokine acting at vanishingly low concentration on cells and organs as diverse as the hypothalamus (fever) and T cells (1) was without precedent in biology and paved the way to the whole field of cytokines and their pleiotropic mode of action. The discovery of the importance of IL-1 in defense against bacteria and of the Toll-IL-1 resistance (TIR, as originally defined) domain was upstream of the discovery of Toll-like receptors (2). Along the same line, the identification of MyD88 as the key adaptor in the IL-1 receptor signaling cascade (3) prompted its identification in Toll/TLR4 signaling (4, 5). The type II IL-1 receptor was identified as a decoy for IL-1, thus providing a new paradigm in receptor biology (6), subsequently extended to other cytokines and growth factors (7). Stunning from this strong roots, IL-1 has in recent years seen a renaissance. New relatives of IL-1 and IL1R have been identified and their function has been defined in innate and adaptive immune responses. IL-1 family members have emerged as key players in the differentiation of the main T helper subsets, Th1, Th2, and Th17. Finally, anti-IL-1 strategies have had a tremendous impact in autoinflammatory diseases and are being tested in a variety of clinical conditions. This volume brings together eight articles that are intended to provide a summary about IL-1 family ligand and receptors in inflammation and immunity. The eight articles are briefly described below. van de Veerdonk et al. focus their review on the IL-1 family of ligands, describe their biological functions and provide new insights in their biology (8). In particular they focus on the new IL1 family members, IL-37 and the cytokines belonging to the IL-36 subfamily and on the potency of blocking IL-1 in disease. Among the ligands, a special focus on the biology of IL-18 as well as its role in human disease is provided by the review by Dinarello et al. (9). IL-18 is synthesized as an inactive precursor requiring processing by caspase-1 into an active cytokine, similarly to IL-1β, and is constitutively present in nearly all cell types. The activity of IL-18 is balanced by the presence of a high affinity naturally occurring IL-18 binding protein (IL-18BP), which is now in clinical trials. Most members of the IL-1 family, including the master proinflammatory cytokine IL-1β, are leaderless proteins and are released from the cell though a “non-classical” pathway of secretion. Rubartelli et al. review current hypotheses on the mechanisms of externalization of IL-1 family members and discuss their relevance with respect to the different functions, as cytokines or as DAMPs, played by IL-1 family members (10). Members of IL-1R like receptor family include signaling molecules and negative regulators. In our review, we present the latter, which include the prototypic decoy receptor type 2 IL-1R and “receptors” with regulatory function, such as TIR8/SIGIRR (11). We suggest that the presence of multiple pathways of negative regulation of members of the IL-1/IL-1R family emphasizes the need for a tight control of members of this fundamental system, which mediates potentially devastating local and systemic inflammatory reactions. Voronov et al. present the role of IL-1 as a pleiotropic cytokine in the context of cancer (12). In their secreted form, IL-1α and IL1β are involved in tumorigenesis and tumor invasiveness, whereas IL-1α, when expressed on the cell membrane, stimulates antitumor cell immunity. Differential patterns of IL-1α and IL-1β expression and function have been observed in different tumors, thus the authors suggest that better understanding of the role of IL-1α and IL-1β in distinct malignancies will enable the application of novel IL-1 modulation approaches in cancer patients as an adjunct to conventional approaches. Lopetuso et al. discuss the dichotomous functions of IL1 family members, such as IL-1, IL-1Ra, IL-18, and IL-33, in gastrointestinal-related inflammatory disorders, depending on the phase of disease or homeostasis and show that IL-37 is emerging as a potent anti-inflammatory cytokine which downregulates colitis (13). In addition, they present data on IL-1 family members suggesting novel pathogenic hypotheses and translational implications for inflammatory bowel disease (IBD) and inflammation-associated colorectal cancer. The review by Federici et al. presents inherited autoinflammatory diseases secondary to mutations of proteins of the intracellular pathways deputed to the activation and secretion of IL-1β (14). The authors show that the understanding of the molecular pathways involved in these disorders has clarified that similar pathogenic mechanisms play also a crucial role in sustaining inflammation in several multi-factorial inflammatory disorders and opened new perspectives for the treatment of these autoinflammatory disorders based on IL-1 blockers. Finally, Santarlasci et al. discuss the involvement of IL-1α and IL-1β in the differentiation, activation, and maintenance or survival of the different Th cell subsets (15). Indeed, the differential