cells Review IL-1α Processing, Signaling and Its Role in Cancer Progression Jing Wen Chiu †, Zuhairah Binte Hanafi †, Lionel Chin Yong Chew † , Yu Mei * and Haiyan Liu * Immunology Programme, Department of Microbiology and Immunology, Life Sciences Institute, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117456, Singapore; [email protected] (J.W.C.); [email protected] (Z.B.H.); [email protected] (L.C.Y.C.) * Correspondence: [email protected] (Y.M.); [email protected] (H.L.); Tel.: +65-90878606 (Y.M.); +65-65166661 (H.L.); Fax: +65-67782684 (H.L.) † Equal contribution. Abstract: Interleukin-1α (IL-1α) is a major alarmin cytokine which triggers and boosts the inflam- matory responses. Since its discovery in the 1940s, the structure and bioactivity of IL-1α has been extensively studied and emerged as a vital regulator in inflammation and hematopoiesis. IL-1α is translated as a pro-form with minor bioactivity. The pro-IL-1α can be cleaved by several proteases to generate the N terminal and C terminal form of IL-1α. The C terminal form of IL-1α (mature form) has several folds higher bioactivity compared with its pro-form. IL-1α is a unique cytokine which could localize in the cytosol, membrane, nucleus, as well as being secreted out of the cell. However, the processing mechanism and physiological significance of these differentially localized IL-1α are still largely unknown. Accumulating evidence suggests IL-1α is involved in cancer pathogenesis. The role of IL-1α in cancer development is controversial as it exerts both pro- and anti-tumor roles in different cancer types. Here, we review the recent development in the processing and signaling of IL-1α and summarize the functions of IL-1α in cancer development. Keywords: interleukin-1α; IL-1R; protease; cancer Citation: Chiu, J.W.; Binte Hanafi, Z.; Chew, L.C.Y.; Mei, Y.; Liu, H. IL-1α 1. Introduction Processing, Signaling and Its Role in Interleukin-1 (IL-1) was first reported in 1943 when Valy Menkin isolated a pyrogenic Cancer Progression. Cells 2021, 10, 92. euglobulin from inflammatory exudates. This pyrogenic euglobulin, later named as pyrexin, https://doi.org/10.3390/ was found to be heat stable and induce biphasic fevers preceded by a marked leukopenia cells10010092 and significant latent period [1,2]. Since then, this substance has been identified and reported by scientists in different research fields and were given different names based on Received: 1 December 2020 its biological properties, such as endogenous pyrogen, leukocytic endogenous mediator, Accepted: 5 January 2021 lymphocyte activating factor, hemopoietin-1, mononuclear cell factor, proteolysis inducing Published: 7 January 2021 factor, catabolin and osteoclast activating factor [3]. In 1974, Dinarello et al. identified two chemically and biologically distinctive pyrogens derived from monocytes and neutrophils, Publisher’s Note: MDPI stays neu- respectively [4]. Another ten years later, these pyrogens were cloned from both human and tral with regard to jurisdictional clai- mouse and named as Interleukin-1 [5,6]. One year later, Carl J. March et al. successfully ms in published maps and institutio- isolated these two DNA encoding proteins sharing human IL-1 activity, and named them nal affiliations. as IL-1α and IL-1β, respectively [7]. Since then, the function of IL-1β has been extensively studied, while the biological processing and function of IL-1α were less well studied. In this review, we summarize the current understanding of IL-1α processing, signaling, function Copyright: © 2021 by the authors. Li- and its role in cancer progression. censee MDPI, Basel, Switzerland. This article is an open access article 2. The Biology of IL-1α distributed under the terms and con- 2.1. IL-1a Expression ditions of the Creative Commons At- IL-1α is constitutively expressed by many types of cells, including fibroblasts, hepato- tribution (CC BY) license (https:// cytes, keratinocytes, macrophages, dendritic cells, T cells, et cetera [8]. Although various creativecommons.org/licenses/by/ types of cells are known to produce IL-1α, endothelial and epithelial cells are the main 4.0/). Cells 2021, 10, 92. https://doi.org/10.3390/cells10010092 https://www.mdpi.com/journal/cells Cells 2021, 10, x FOR PEER REVIEW 2 of 19 Cells 2021, 10, 92 2 of 19 various types of cells are known to produce IL‐1α, endothelial and epithelial cells are the main source of IL‐1α under both physiological and pathological conditions. At steady state, the expressionsource level of IL-1 of ILα‐1underα is relatively both physiological low, whereas and upon pathological exposure conditions.to pathogens At steady state, or stress‐inducedthe stimulus, expression the level expression of IL-1 αofis IL relatively‐1α increases low, dramatically whereas upon to exposureinitiate in to‐ pathogens or flammatory responsesstress-induced [9]. stimulus, the expression of IL-1α increases dramatically to initiate inflam- matory responses [9]. 2.2. IL‐1α Processing 2.2. IL-1a Processing IL‐1α is translated into a 31‐kDa precursor form (pro‐IL‐1α). The pro‐IL‐1α contains IL-1α is translated into a 31-kDa precursor form (pro-IL-1α). The pro-IL-1α contains a nuclear localization signal (NLS) site which leads the pro‐IL‐1α translocation into the a nuclear localization signal (NLS) site which leads the pro-IL-1α translocation into the nucleus. IL‐1α also contains several post‐translational modification sites: (1) pro‐IL‐1α nucleus. IL-1α also contains several post-translational modification sites: (1) pro-IL-1α can can be phosphorylated at Ser90; (2) pro‐IL‐1α can be myristoylated at Lys82; and (3) be phosphorylated at Ser90; (2) pro-IL-1α can be myristoylated at Lys82; and (3) pro-IL-1α pro‐IL‐1α can be acetylated at Lys82 [10–13]. So far, the mechanisms and functions of can be acetylated at Lys82 [10–13]. So far, the mechanisms and functions of these post- these post‐translational modifications are not well understood. The pro‐IL‐1α could also translational modifications are not well understood. The pro-IL-1α could also be cleaved be cleaved by severalby several protease protease to a to17 a‐kDa 17-kDa mature mature form form and anda 16‐ akDa 16-kDa N terminal N terminal form form named as named as propiecepropiece [14]. [The14]. Themature mature form form of IL of‐1 IL-1α hasα has higher higher biology biology activity activity compared compared to the pro-IL- to the pro‐IL‐11α αasas its its binding affinityaffinity toto its its receptor receptor is is several several folds folds higher higher than than the the pro-IL-1 α [15]. So pro‐IL‐1α [15]. far,So far, elastase, elastase, cathepsin cathepsin G, proteinase-3, G, proteinase calpain,‐3, calpain, granzyme granzyme B, mast B, mast cell chymase, cell caspase-5, chymase, caspasecaspase-11‐5, caspase and‐11 thrombin and thrombin have been have identified been identified as the pro-IL-1 as the αprocleavage‐IL‐1α proteases [16] cleavage proteases(Figure [16]1 ).(Figure 1). Figure 1. OverviewFigure 1. Overview of IL-1α ofstructure. IL‐1α structure. Human Human IL-1α consistsIL‐1α consists of 271 of amino 271 amino acids acids including including an nuclear an nu‐ localization signal (NLS)clear domain. localization IL-1α signalcan be (NLS) cleaved domain. by various IL‐1α can proteases, be cleaved such by asvarious elastase, proteases, granzyme such B, as caspase-5, elastase, thrombin, chymase andgranzyme calpain. B, IL-1 caspaseα also‐5, undergoes thrombin, post-translational chymase and calpain. modification, IL‐1α also including undergoes acetylation, post‐translational myristoylation as well as phosphorylation.modification, including acetylation, myristoylation as well as phosphorylation. 2.2.1. Elastase, Cathepsin G and Proteinase‐3 2.2.1. Elastase, Cathepsin G and Proteinase-3 Neutrophils are the most abundant circulating leucocytes and play a vital role in Neutrophils are the most abundant circulating leucocytes and play a vital role in clearing pathogens through phagocytosis and destruction of microorganisms via granule clearing pathogens through phagocytosis and destruction of microorganisms via granule proteases [17]. The azurophil granule contains three major serine proteases: human leu‐ proteases [17]. The azurophil granule contains three major serine proteases: human cocyte elastase, cathepsin G and proteinase‐3 [18]. Elastase has long been recognized as leucocyte elastase, cathepsin G and proteinase-3 [18]. Elastase has long been recognized as IL‐1β‐processingIL-1 proteaseβ-processing and remains protease unclear and remains whether unclear it could whether also process it could IL‐ also1α [19]. process IL-1α [19]. In 2011, AfoninaIn et 2011, al. first Afonina reported et al. that first elastase reported could that cleavage elastase couldpro‐IL cleavage‐1α in vitro pro-IL-1 whenα in vitro when incubating the recombinantincubating the IL recombinant‐1α with elastase. IL-1α Thewith elastase elastase. cleaves The elastase IL‐1α at cleaves the Ala101 IL-1α at the Ala101 site, generatingsite, a more generating biological a more functional biological mature functional form mature of IL‐1 formα compared of IL-1α withcompared the with the pro- pro‐IL‐1α [20]. IL-1Recently,α [20]. the Recently, other two the neutrophils other two neutrophils-derived‐derived serine proteases: serine proteases:cathepsin G cathepsin G and and proteinase‐proteinase-33 have also been have implicated also been implicated to cleave pro to cleave‐IL‐1α pro-IL-1under theα under in vitro the incuin vitro‐ incubation bation condition.condition. Incubation Incubation of pro‐ ofIL‐ pro-IL-11α withα cathepsinwith cathepsin G and G andproteinase proteinase-3‐3 in vitroin vitro generated a generated a smallersmaller processed processed form form of of IL IL-1‐1α αcomparedcompared with with that that processed processed by by elastase [21].