New insights into the mechanism of IL-1b maturation Kimberly Burns, Fabio Martinon and Ju Èrg Tschopp  The pro-in¯ammatory cytokine IL-1b is initially synthesised in an inactive precursor form and therefore requires processing by caspase-1 for activation. Recently, several investigators have identi®ed a number of proteins that are implicated in caspase-1 activation, and other proteins that negatively regulate both caspase-1 activation and IL-1b processing have also been identi®ed. Drugs that target these components may have therapeutic bene®ts for in¯ammatory diseases. Addresses Institute of Biochemistry, University of Lausanne, Chemin des Boveresses 155, CH-1066 Epalinges, Switzerland  e-mail: jurg.tschopp@ib.unil.ch Current Opinion in Immunology 2003, 15:26±30 This review comes from a themed issue on Innate immunity Edited by Ruslan Medzhitov and Christine A Biron 0952-7915/03/$ ± see front matter ß 2003 Elsevier Science Ltd. All rights reserved. DOI 10.1016/S0952-7915(02)00017-1 Abbreviations ASC apoptosis-associated speck-like protein containing a CARD CARD caspase recruitment domain ICE IL-1b converting enzyme IL interleukin Ipaf ICE-protease activating factor LPS lipopolysaccharide LRR leucine-rich repeat NALP1 Nacht, LRR and PYD containing protein 1 PI proteinase inhibitor PYD Pyrin domain RIP2 receptor interacting protein 2 TLR Toll-like receptor TNF tumour necrosis factor Introduction IL-1b is a pro-in¯ammatory cytokine produced by acti- vated macrophages and monocytes. It functions in the generation of systemic and local responses to infection, injury and immunological challenges by generating fever, activating lymphocytes and promoting infusion of leuko- cytes into the sites of injury or infection (reviewed by [1]). It is the primary cause of chronic and acute in¯ammation and, as an endogenous pyrogen, it is a key player in the febrile response [2,3]. IL-1b affects almost every cell type. It exerts its activities extracellularly by binding to a high af®nity receptor, IL-1RI. Upon IL-1b binding, the IL-1RI aggregates with a related polypeptide chain (IL-1RAcP), thereby triggering the formation of a membrane proximal signalling complex that activates IkB kinase (IKK) and mitogen-activated protein kinase (MAPK) pathways [4]. This leads to the activationofthetranscriptionfactorsnuclearfactor(NF)-kB and AP-1, resulting in the induction of genes encoding chemokines, cytokines, acute-phase proteins, cell adhe- sion molecules and enzymes involved in the production of small pro-in¯ammatory substances [5]. IL-1b faces a challenge not encountered by most other secreted polypeptides because of the absence of a signal peptide. Its passage through the classical secretory path- way (i.e. endoplasmic reticulum to Golgi) is therefore precluded. IL-1b is instead translated in the cytosol, where it gains access to the extracellular environment [6±9]. Further complicating its production, IL-1b is initially synthesised as an inactive 31 kDa precursor molecule (proIL-1b) that must be proteolytically pro- cessed to generate the active mature 17 kDa form, which is the major form delivered to the extracellular environ- ment [10]. The mechanism by which IL-1b is processed and secreted is not well understood, but recent devel- opments in this ®eld provide new insights into the processing of proIL-1b and will be the focus of this review. Production of IL-1b requires two distinct stimuli: priming and processing/secretion The synthesis, processing and release of mature IL-1b are tightly regulated events. proIL-1b is generally not detected in unstimulated monocytes and macrophages, but must be induced at the transcriptional level [11]. This synthesis is under the control of transcription factors activated in many cell types when challenged with microbes, microbial products and other environmental stimuli that necessitate the engagement or ampli®cation of in¯ammatory responses. Multiple signalling pathways areinvolvedinthetranscriptionalupregulationofproIL-1b, including pathways triggered by IL-1b itself, by other in¯ammatory cytokines, such as TNF, or by various Toll- like receptor (TLR) ligands, such as lipopolysaccharide (LPS), which signals via TLR4 [1]. These signals can also be mimicked by phorbol 12-myristate 13-acetate (PMA) treatment [12]. However, in the absence of a secondary or `secretion' stimulus, processing of proIL-1b and release of mature IL-1b is generally inef®cient, resulting either in the retention or degradation of proIL-1b. There are multiple agents that induce the post-translational processing of proIL-1b, such as nigericin, hypotonic stress, bacterial toxins (e.g. Shigella ¯exneri protein IpaB), antimicrobial 26 Current Opinion in Immunology 2003, 15:26±30 www.current-opinion.com