Introduction to the interleukin‐1 family of cytokines and receptors: Drivers of innate inflammation and acquired immunity (2017)

This article introduces a series of reviews covering The IL-1 cytokine and receptor family appearing in Volume 281 of Immunological Reviews. More than any other family, the IL-1 Family of 11 cytokines and 10 receptors provides the host with an endogenous innate immune system, whereas the family of Toll-like receptors (TLR) provides the host with an exogenous innate system. Both endogenous and exogenous families evoke nearly the same biological effects because they share the same functional Toll-IL-1 receptor (TIR) domain of their respective receptors.1 In addition to innate inflammation, the IL-1 and TLR families assist the acquired immune system. Ninety-five percent of living organisms use innate immune mechanisms for survival, whereas only five percent depend on T- and B-cell functions. This volume of Immunological Reviews begins with an Overview of the IL-1 Family with emphasis on the role of the family in the treatment of disease (Figure 1).1 Two members of the IL-1 Family used to treat inflammatory diseases, the IL-1 receptor antagonist (IL-1Ra) and the IL-18 binding protein (IL-18BP), are discussed. Clinical trials with antibodies to IL-1β, IL-1α, IL-1 Receptor type 1 (IL-1R1), IL-18, and IL-33 are also discussed in the Overview. Following the Overview, the volume examines the perennial issue of the role of inflammatory cytokines as mediators of disease contrasted to the role of cytokines in host defense. The review entitled “The Role of the Interleukin-1 Family in Trained Immunity”2 provides the reader with basic concepts of how the IL-1 Family contributes to trained immunity, a component of innate immunity and sometimes termed innate memory. Trained immunity affords protection to microbial challenges before the evolution of T and B cells. In this review, there are examples of large-scale epidemiologic studies of BCG vaccination as well as to basic in vitro and animal studies. Following the review on trained immunity, there is “Interleukin-1 Gene Polymorphism and Susceptibility to Disease”.3 This is a comprehensive study, as it provides the reader with a condensation of a large number of single-nucleotide polymorphisms (SNP's) in the family and their relationship to disease risk. The SNPs in IL-1 Family are timely data because of the emerging role of the IL-1 Family for cancer risk. The review “IL-1 and IL-1 Regulatory Pathways in Cancer Progression and Therapy”4 is a cutting-edge review by the authors who initiated the field of inflammation and cancer progression. After many years characterizing tumor-associated macrophages,5 those studies have now been validated with the therapeutic success of checkpoint inhibitors in cancer therapy. With the milestone study of neutralizing IL-1β for 4 years,6 IL-1β blockade can now be classified as a safe, non-toxic, effective checkpoint inhibitor. The volume is weighted toward IL-1β because of the central place IL-1β holds in autophagy, the NLRP3 and AIM2 inflammasomes, the clinical efficacy of IL-1β neutralization, and the potential of oral NLRP3 inhibitors to specifically reduce IL-1β-mediated inflammation and cancer progression. In addition to NLRP3 and AIM2 inflammasomes, the NLRC4 inflammasome provides new information on its role in enteric infections and IL-18. This section begins with the pivotal role of IL-1β as presented in “Autophagy Limits Activation of the Inflammasomes”,7 a topic that is fundamental to the reviews on inflammasomes. There are four reviews that address the unique properties of inflammasomes. Inflammasome activation by the filamentous oligomerization of the macromolecular complex containing ASC is visible in cells and called “specks.” In “The Intra- and Extracellular Functions of ASC Specks”,8 we learn of how specks function to promote the autocleavage of the caspase-1 precursor. The NLRP3 inflammasome is affected by and regulates several cellular metabolites, an area that has recently gained attention as it links the metabolic derangements of macrophage-mediated inflammation to the metabolic derangements of cancer. The metabolic upheaval that was described by Warburg in cancer cells is reviewed in “Metabolic Regulation of NLRP3”.9 In “The AIM2 Inflammasome: Sensor of Pathogens and Cellular Perturbations”,10 the importance of this inflammasome to bacterial and viral diseases provides new concepts on how the cell senses endogenous DNA. The NLRC4 inflammasome has a special place in this volume. In “The NLRC4 Inflammasome”,11 we read that mutations in this inflammasome results are autoinflammatory diseases mediated by IL-18. The next section in this volume provides the reader with reviews on specific cytokines in the IL-1 Family. IL-1β is discussed in the Overview and the reviews on autophagy and inflammasomes. A unique role for IL-1α in disease is presented in “Function and Regulation of IL-1α in Inflammatory Diseases and Cancer”.12 As the field of cytokine-based therapies continues to impact on clinical medicine, blocking IL-1α is a rapidly evolving strategy for skin diseases and cancer.13-16 Although, in many ways, IL-18 and IL-1β are closely related, IL-18 does not copy IL-1β activity. The immunological and clinical significance of IL-18 is broadly addressed in “Interleukin-18: Biological Properties and Role in Disease”.17 IL-33 has special place in the IL-1 Family because this cytokine was unknown for many years. Nevertheless, using IL-1 Receptor Family ST2 (now IL-1R4), considerable advances were made on IL-33 as having a major role in the Th2 responses. Similar to IL-1α, IL-33 has a role in the nucleus. These two properties of IL-33 are reviewed in “Interleukin-33: a Nuclear Cytokine from the IL-1 Family”.18 Five cytokines the IL-1 Family were discovered by in silico research methods using DNA databases. The IL-36 Subfamily is comprised of IL-36α, IL-36β, IL-36γ as well as the IL-36 receptor antagonist (IL-36Ra). This Subfamily is reviewed in “Regulation and Function of Interleukin-36 Cytokines,19 a timely assessment of these new members of the IL-1 Family. IL-37 is a unique member of the IL-1 Family, as this cytokine is a fundamental inhibitor of innate inflammation as well as of acquired immunity. As the first assessment of the function of IL-37 in 2010,20 reports on IL-37 during the past 7 years have risen remarkably. An update of this cytokines is presented in “Suppression of Inflammation and Acquired Immunity by IL-37”.21 IL-38 is the most recent member of the IL-1 Family to be characterized. IL-38 and IL-37 exploit the ligand binding chains of the IL-36 receptor and the IL-18 receptor, respectively and recruit two previous orphan coreceptors, IL-1R8 and IL-1R9, respectively. IL-38, like IL-37, suppresses innate inflammation and its role in immune responses and inflammation are presented in “Biology of IL-38 and its Role in Disease”.22 The volume closes with two reviews on the IL-1 Family of receptors. The IL-1 Receptor Family has a long history that began in 1988 with the identification of the IL-1R1,23 followed by the report of homology of IL-1R1 with the Drosophila Toll protein24 and completed in 1995 with discovery of the coreceptor, IL-1R3.25 Recently, IL-1R1 binding to IL-1β and the formation of signaling complex with IL-1R3 have been resolved.26 The binding of IL-1β, IL-1827, and IL-3328 to their respective ligand binding chains is similar, and in each case, ligand binding results in a conformational change in structure of the receptor, which allows the coreceptor to bind and form the trimeric complex. The ligands never make contact with their coreceptors. The entire IL-1 Family of Receptors is presented in a comprehensive review “The Family of Interleukin-1 Receptors”.29 In “Tuning Inflammation and Immunity by the Negative Regulators IL-1R2 and IL-1R8”,30 the function of the two negative receptors of the IL-1 family and their role in health and disease are reviewed. These studies are supported by NIH Grant AI-15614 and The Interleukin Foundation, Denver, Colorado, USA. The author declares no conflict of interest.