Mutations in cryopyrin: bypassing roadblocks in the caspase 1 inflammasome for interleukin-1beta secretion and disease activity.

Unlike the release of tumor necrosis factor (TNF ), there are several roadblocks to the release of interleukin-1 (IL-1 ), beginning with the transcription of the IL1B gene and ending with the exit of the active cytokine from the cell. There is also the additional roadblock of the high level of synthesis and secretion of the naturally occurring IL-1 receptor antagonist (IL1Ra), with its tight binding to the IL-1 receptor type I and an affinity higher than that of either IL-1 or IL-1 . If these roadblocks are not enough to limit the activity of IL-1 , there is nature’s decoy mechanism, which consists of the preferential binding of the cell surface IL-1 receptor type II to IL-1 , preventing it from triggering the signal-transducing type I receptor. The soluble form of the type II receptor also prevents active IL-1 from engaging the signaling receptor by forming an inactive complex with the soluble IL-1 receptor accessory protein, which is constitutively produced in the liver. The facilitation of IL-1 processing by the caspase 1 inflammasome through ATP activation of the P2X7 receptor can also be viewed as a potential roadblock to the activity of IL-1 . It seems clear that in the evolution of cytokines, some cytokines, such as IL-6 and IL-1Ra, are quickly driven from the cell by the Golgi machinery, whereas others encounter a series of roadblocks that limit their activity. The most revealing justifications for nature’s wisdom in placing several roadblocks to IL-1 activity are the consequences of the effects of IL-1 in the loss of insulin-producing pancreatic beta cells (1) and the manifestations of autoinflammatory syndromes, diseases that carry a portfolio of destructive inflammation (2–4). Familial Mediterranean fever (5) and hyper-IgD syndrome (6) are also classified as autoinflammatory diseases because of the poor control of the processing and secretion of IL-1 . In this issue of Arthritis and Rheumatism (7), the study reported by Gattorno and coworkers offers important new lessons about these roadblocks. The investigators studied the release of IL-1 from primary blood monocytes obtained from patients with chronic infantile neurologic, cutaneous, articular (CINCA) syndrome (known in North America as neonatal-onset multisystem inflammatory disease [NOMID]) and from a patient with Muckle-Wells syndrome (MWS). These 2 syndromes, as well as familial cold-induced autoinflammatory syndrome (FCAS), are the primary examples of dysregulated processing and secretion of IL-1 . The investigators also studied the effects of in vivo treatment with anakinra, a recombinant human IL-1Ra. Specifically, the study examined the secretion of IL-1 from peripheral blood monocytes obtained from the patients before and during treatment with anakinra. The study focused on the function of the IL-1 “inflammasome” (more appropriately termed the caspase 1 inflammasome) and the effect of mutations in cryopyrin, the protein of the NALP3 gene (8). The lessons learned from these studies provide new insights into the tight control of the processing and secretion of IL-1 . While the syndromes studied are rare, the mechanisms revealed by these studies have broad implications for how evolution favored the restriction of biologic responses to IL-1 by placing several roadblocks to its egress from the cell. The clinical manifestations of these syndromes are characterized by recurrent fevers, neutrophilic leukocytosis, rashes, deforming arthritis, and high serum levels of acute-phase reactants. Progressive deafness, Supported by NIH grant AI-15614. Charles A. Dinarello, MD: University of Colorado Health Sciences Center, Denver. Dr. Dinarello has received consulting fees (less than $10,000) from Amgen and has given expert testimony for which he received a fee (less than $10,000) from Chiron. Address correspondence and reprint requests to Charles A. Dinarello, MD, University of Colorado Health Sciences Center, 4200 East Ninth Avenue B168, Denver, CO 80262. E-mail: cdinarello@mac.com. Submitted for publication May 13, 2007; accepted in revised form May 18, 2007.