Caspase-1: Past and Future of this Major Player in Cell Death and Inflammation

Inflammation is a major physiological process required for the detection of pathogens and their elimination from an organism.It is triggered by the innate immune system that gets activated through the recognition of danger- or pathogen-associatedmolecular patterns by protein complexes called inflammasomes. The activation of inflammasomes does not only eliminatethe replicative niche of pathogens by inducing infected cells’ death (called pyroptosis) but also leads to the secretion of proinflammatory cytokines such as Interleukin-1β (IL-1β) and IL-18, which in turn triggers the recruitment of other immune cellsto the infection site and mediates communication with neighboring resident cells. The cysteine aspartate protease Caspase-1is the common effector enzyme of different inflammasomes and is responsible for the maturation of Gasdermin D and IL-1βrequired for the induction of pyroptosis and the secretion of IL-1β through the Gasdermin D pores. Several gain of functionmutations in inflammasome forming receptor proteins including Caspase-1 were associated with severe auto-immune andauto-inflammatory diseases pointing out the necessity of the tight regulation of these complexes. In this review, we focusedon Caspase-1 that is at the crossroad of inflammatory cell death and IL-1β secretion. We describe its discovery, Caspase-1activator signals, its substrates and the inhibitors that have been designed. We also discuss ongoing research that revealsnovel unexpected roles for this protease. This review is a good reference not only for the beginners in innate immunity andinflammation but also provides an update on Caspase-1’s biology for more advanced researchers.

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1. Murphy K, Travers P, Walport M, Janeway C. Janeway’s immunobiology (8th ed.) 2012 New York: Garland Science.
2. Sadik CD, Luster AD. Lipid-cytokine chemokine cascades orchestrate leukocyte recruitment in inflammation. J Leukoc Biol 2012; 91: 207-15.
3. Mantovani A, Dinarello CA, Molgora M, Garlanda C. Interleukin-1 and related cytokines in the regulation of inflammation and immunity. Immunity 2019; 50: 778-95.
4. Monteleone M, Stow JL, Schroder K. Mechanisms of unconventional secretion of IL-1 family cytokines. Cytokine 2015; 74: 213-8.
5. Agostini L, Martinon F, Burns K, McDermott MF, Hawkins PN, Tschopp J. NALP3 forms an IL-1beta-processing inflammasome with increased activity in Muckle-Wells autoinflammatory disorder. Immunity 2004; 20: 319-25.
6. Martinon F, Burns K, Tschopp J. The inflammasome: a molecular platform triggering activation of inflammatory Caspases and processing of proIL-beta. Mol Cell 2002;10(2):417-26.
7. Kayagaki N, Stowe IB, Lee BL, O’Rourke K, Anderson K, Warming S, et al. Caspase-11 cleaves gasdermin D for non-canonical inflammasome signalling. Nature 2015; 526: 666-71.
8. Shi J, Zhao Y, Wang K, Shi X, Wang Y, Huang H, et al. Cleavage of GSDMD by inflammatory Caspases determines pyroptotic cell death. Nature 2015; 526: 660-5.
9. Evavold CL, Ruan J, Tan Y, Xia S, Wu H, Kagan JC. The pore-forming protein Gasdermin D regulates interleukin-1 secretion from living macrophages. Immunity 2018; 48: 35-44.
10. Park, H, Bourla AB, Kastner DL, Colbert RA, Siegel RM. Lighting the fires within: the cell biology of autoinflammatory diseases. Nat Rev Immunol 2012; 12: 570–80.
11. Cerretti DP, Kozlosky CJ, Mosley B, Nelson N, Van Ness K, Greenstreet TA, et al. Molecular cloning of the interleukin-1 beta converting enzyme. Science 1992; 256: 97-100.
12. Kayagaki N, Warming S, Lamkanfi M, Vande Walle L, Louie S, Dong J, et al. Non-canonical inflammasome activation targets Caspase-11. Nature 2011; 479: 117-21.
13. Saleh M, Vaillancourt JP, Graham RK, Huyck M, Srinivasula SM, Alnemri ES, et al. Differential modulation of endotoxin responsiveness by human Caspase-12 polymorphisms. Nature 2004; 429: 75-9.
14. McArthur K, Kile BT. Apoptotic Caspases: Multiple or mistaken identities? Trends Cell Biol 2018; 28: 475-93.
15. Eckhart L, Declercq W, Ban J, Rendl M, Lengauer B, Mayer C, et al. Terminal differentiation of human keratinocytes and stratum corneum formation is associated with Caspase-14 activation. J Invest Dermatol 2000; 115: 1148-51.
16. Thul PJ, Åkesson L, Wiking M, Mahdessian D, Geladaki A, Ait Blal H, et al. A subcellular map of the human proteome. Science 2017; 356 pii: eaal3321.
17. Viganò E, Diamond CE, Spreafico R, Balachander A, Sobota RM, Mortellaro A. Human Caspase-4 and Caspase-5 regulate the one-step non-canonical inflammasome activation in monocytes. Nat Commun 2015; 6:8761.
18. Fischer H, Koenig U, Eckhart L, Tschachler E. Human Caspase 12 has acquired deleterious mutations. Biochem Biophys Res Commun 2002; 293, 722-6.
19. Nakagawa T, Zhu H, Morishima N, Li E, Xu J, Yankner BA, et al. Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-beta. Nature 2000; 403: 98-103.
20. Black RA, Kronheim SR, Cantrell M, Deeley MC, March CJ, Prickett KS, et al. Generation of biologically active interleukin-1 beta by proteolytic cleavage of the inactive precursor. J Biol Chem 1988; 263: 9437-42.
21. Kostura MJ, Tocci MJ, Limjuco G, Chin J, Cameron P, Hillman AG, et al. Identification of a monocyte specific pre-interleukin 1 beta convertase activity. Proc Natl Acad Sci U S A 1989; 86: 5227-31.
22. Thornberry NA, Bull HG, Calaycay JR, Chapman KT, Howard AD, Kostura MJ, et al. A novel heterodimeric cysteine protease is required for interleukin-1 beta processing in monocytes. Nature 1992; 356: 768-74.
23. Ayala JM, Yamin TT, Egger LA, Chin J, Kostura MJ, Miller DK. IL-1 beta-converting enzyme is present in monocytic cells as an inactive 45-kDa precursor. J Immunol 1994; 153: 2592-9.
24. Alnemri ES, Livingston DJ, Nicholson DW, Salvesen G, Thornberry NA, Wong WW, et al. Human ICE/CED-3 protease nomenclature. Cell 1996; 87: 171.
25. Li P, Allen H, Banerjee S, Franklin S, Herzog L, Johnston C, et al. Mice deficient in IL-1 beta-converting enzyme are defective in production of mature IL-1 beta and resistant to endotoxic shock. Cell 1995; 80: 401-11.
26. Kuida K, Lippke JA, Ku G, Harding MW, Livingston DJ, Su MS, et al. Altered cytokine export and apoptosis in mice deficient in interleukin-1 beta converting enzyme. Science 1995; 267: 2000-3.
27. Sandstrom A, Mitchell PS, Goers L, Mu EW, Lesser CF, Vance RE. Functional degradation: A mechanism of NLRP1 inflammasome activation by diverse pathogen enzymes. Science 2019; 364 pii: eaau1330.
28. Martinon F, Pétrilli V, Mayor A, Tardivel A, Tschopp J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 2006; 440: 237-41.
29. Kanneganti TD, Ozören N, Body-Malapel M, Amer A, Park JH, Franchi L, et al. Bacterial RNA and small antiviral compounds activate Caspase-1 through cryopyrin/Nalp3. Nature 2006; 440: 233-6.
30. Mariathasan S, Weiss DS, Newton K, McBride J, O’Rourke K, Roose-Girma M, et al. Cryopyrin activates the inflammasome in response to toxins and ATP. Nature 2006; 440: 228-32.
31. Özören N, Masumoto J, Franchi L, Kanneganti TD, Body-Malapel M, Ertürk I, et al. Distinct roles of TLR2 and the adaptor ASC in IL-1beta/IL-18 secretion in response to Listeria monocytogenes. J Immunol 2006; 176: 4337-42.
32. Poyet JL, Srinivasula SM, Tnani M, Razmara M, Fernandes-Alnemri T, Alnemri ES. Identification of Ipaf, a human Caspase-1-activating protein related to Apaf-1. J Biol Chem 2001; 276: 28309-13.
33. Sutterwala FS, Mijares LA, Li L, Ogura Y, Kazmierczak BI, Flavell RA. Immune recognition of Pseudomonas aeruginosa mediated by the IPAF/NLRC4 inflammasome. J Exp Med 2007; 204: 3235- 45.
34. Hornung V, Ablasser A, Charrel-Dennis M, Bauernfeind F, Horvath G, Caffrey DR, et al. AIM2 recognizes cytosolic dsDNA and forms a Caspase-1-activating inflammasome with ASC. Nature 2009; 458: 514-518.
35. Fernandes-Alnemri T, Yu JW, Datta P, Wu J, Alnemri ES. AIM2 activates the inflammasome and cell death in response to cytoplasmic DNA. Nature 2009; 458: 509-13.
36. Khare S, Dorfleutner A, Bryan NB, Yun C, Radian AD, de Almeida L, et al. An NLRP7-containing inflammasome mediates recognition of microbial lipopeptides in human macrophages. Immunity 2012; 36: 464-76.
37. Minkiewicz J, de Rivero Vaccari JP, Keane RW. Human astrocytes express a novel NLRP2 inflammasome. Glia 2013; 61: 1113-21.
38. Shi J, Zhao Y, Wang Y, Gao W, Ding J, Li P, et al. Inflammatory Caspases are innate immune receptors for intracellular LPS. Nature 2014; 514: 187-92.
39. Hagar JA, Powell DA, Aachoui Y, Ernst RK, Miao EA. Cytoplasmic LPS activates Caspase-11: implications in TLR4-independent endotoxic shock. Science 2013; 341: 1250-3.
40. Yang D, He Y, Muñoz-Planillo R, Liu Q, Núñez G. Caspase-11 requires the pannexin-1 channel and the purinergic P2X7 pore to mediate pyroptosis and endotoxic shock. Immunity 2015; 43:923-32.
41. Sollberger G, Strittmatter GE, Kistowska M, French LE, Beer HD. Caspase-4 is required for activation of inflammasomes. J Immunol 2012; 188: 1992-2000.
42. Yuan J, Shaham S, Ledoux S, Ellis HM, Horvitz HR. The C. elegans cell death gene ced-3 encodes a protein similar to mammalian interleukin-1 beta-converting enzyme. Cell 1993; 75: 641-52.
43. Miura M, Zhu H, Rotello R, Hartwieg EA, Yuan J. Induction of apoptosis in fibroblasts by IL-1 beta-converting enzyme, a mammalian homolog of the C. elegans cell death gene ced-3. Cell 1993; 75: 653-60.
44. Pei H, Li C, Adereth Y, Hsu T, Watson DK, Li R. Caspase-1 is a direct target gene of ETS1 and plays a role in ETS1-induced apoptosis. Cancer Res 2005; 65: 7205-13.
45. Winter RN, Rhee JG, Kyprianou N. Caspase-1 enhances the apoptotic response of prostate cancer cells to ionizing radiation. Anticancer Res 2004; 24: 1377-86.
46. Guo H, Pétrin D, Zhang Y, Bergeron C, Goodyer CG, LeBlanc AC. Caspase-1 activation of Caspase-6 in human apoptotic neurons. Cell Death Differ 2006; 13: 285-92.
47. Philip NH, Dillon CP, Snyder AG, Fitzgerald P, Wynosky-Dolfi MA, Zwack EE, et al. Caspase-8 mediates Caspase-1 processing and innate immune defense in response to bacterial blockade of NF-κB and MAPK signaling. Proc Natl Acad Sci U S A 2014; 111: 7385-90.
48. Exline MC, Justiniano S, Hollyfield JL, Berhe F, Besecker BY, Das S, et al. Microvesicular Caspase-1 mediates lymphocyte apoptosis in sepsis. PLoS One 2014; 9:in press.
49. Tsuchiya K, Nakajima S, Hosojima S, Thi Nguyen D, Hattori T, et al., Caspase-1 initiates apoptosis in the absence of gasdermin D. Nat Commun 2019; 10:2091.
50. Gu Y, Wu J, Faucheu C, Lalanne JL, Diu A, Livingston DJ, et al. Interleukin-1 beta converting enzyme requires oligomerization for activity of processed forms in vivo. EMBO J 1995; 14: 1923-31.
51. Walker NP, Talanian RV, Brady KD, Dang LC, Bump NJ, Ferenz CR, et al. Crystal structure of the cysteine protease interleukin-1 beta-converting enzyme: a (p20/p10)2 homodimer. Cell 1994; 78: 343-52.
52. Srinivasula SM, Poyet JL, Razmara M, Datta P, Zhang Z, Alnemri ES. The PYRIN-CARD protein ASC is an activating adaptor for Caspase-1. J Biol Chem 2002; 277: 21119-22.
53. Proell M, Gerlic M, Mace PD, Reed JC, Riedl SJ. The CARD plays a critical role in ASC foci formation and inflammasome signalling. Biochem J 2013; 449: 613-21.
54. Sahillioglu AC, Sumbul F, Ozoren N, Haliloglu T. Structural and dynamics aspects of ASC speck assembly. Structure 2014; 22: 1722-34.
55. Narayanan KB, Jang TH, Park HH. Self-oligomerization of ASC PYD domain prevents the assembly of inflammasome in vitro. Appl Biochem Biotechnol 2014; 172: 3902-12.
56. Narayanan KB, Park HH. Purification and analysis of the interactions of Caspase-1 and ASC for assembly of the inflammasome. Appl Biochem Biotechnol 2015; 175: 2883-94.
57. Gültekin Y, Eren E, Özören N. Overexpressed NLRC3 acts as an anti-inflammatory cytosolic protein. J Innate Immun 2015; 7: 25-36.
58. Thornberry NA, Rano TA, Peterson EP, Rasper DM, Timkey T, Garcia-Calvo M, et al. A combinatorial approach defines specificities of members of the Caspase family and granzyme B. Functional relationships established for key mediators of apoptosis. J Biol Chem 1997; 272: 17907-11.
59. Wilson KP, Black JA, Thomson JA, Kim EE, Griffith JP, Navia MA, et al. Structure and mechanism of interleukin-1 beta converting enzyme. Nature 1994; 370: 270-5.
60. Fantuzzi G, Dinarello CA. Interleukin-18 and interleukin-1 beta: two cytokine substrates for ICE (Caspase-1). J Clin Immunol 1999; 19: 1-11.
61. Ghayur T, Banerjee S, Hugunin M, Butler D, Herzog L, Carter A, et al. Caspase-1 processes IFN-gamma-inducing factor and regulates LPS-induced IFN-gamma production. Nature 1997; 386: 619-23.
62. Gu Y, Kuida K, Tsutsui H, Ku G, Hsiao K, Fleming MA, et al. Activation of interferon-gamma inducing factor mediated by interleukin-1beta converting enzyme. Science 1997; 275: 206-9.
63. Heilig R, Dick MS, Sborgi L, Meunier E, Hiller S, Broz P. The Gasdermin-D pore acts as a conduit for IL-1β secretion in mice. Eur J Immunol 2018; 48: 584-92.
64. Cayrol C, Girard JP. The IL-1-like cytokine IL-33 is inactivated after maturation by Caspase-1. Proc Natl Acad Sci U S A 2009; 106: 9021-6.
65. Chae JJ, Wood G, Richard K, Jaffe H, Colburn NT, Masters SL, et al. The familial Mediterranean fever protein, pyrin, is cleaved by Caspase-1 and activates NF-kappaB through its N-terminal fragment. Blood 2008; 112: 1794-1803.
66. Miggin SM, Pålsson-McDermott E, Dunne A, Jefferies C, Pinteaux E, Banahan K, et al. NF-kappaB activation by the Toll-IL-1 receptor domain protein MyD88 adapter-like is regulated by Caspase-1. Proc Natl Acad Sci U S A 2007; 104: 3372-7.
67. Lamkanfi M, Kanneganti TD, Van Damme P, Vanden Berghe T, Vanoverberghe I et al. Targeted peptidecentric proteomics reveals Caspase-7 as a substrate of the Caspase-1 inflammasomes. Mol Cell Proteomics 2008; 7: 2350-63.
68. Trompet S, de Craen J, Slagboom P, Shepherd J, Blauw GJ, Murphy MB, et al. Genetic variation in the interleukin-1 beta-converting enzyme associates with cognitive function. The PROSPER study. Brain 2008; 131: 1069-77.
69. Blankenberg S, Godefroy T, Poirier O, Rupprecht HJ, Barbaux S, Bickel C, et al. Haplotypes of the Caspase-1 gene, plasma Caspase-1 levels, and cardiovascular risk. Circ Res 2006; 99: 102-8.
70. Luksch H, Romanowski MJ, Chara O, Tüngler V, Caffarena ER, Heymann MC, et al. Naturally occurring genetic variants of human Caspase-1 differ considerably in structure and the ability to activate interleukin-1β. Hum Mutat 2013; 34: 122-31.
71. Soung YH, Jeong EG, Ahn CH, Kim SS, Song SY, Yoo NJ, et al. Mutational analysis of Caspase 1, 4, and 5 genes in common human cancers. Hum Pathol 2008; 39: 895-900.
72. Kim YR, Kim KM, Yoo NJ, Lee SH. Mutational analysis of CASP1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and 14 genes in gastrointestinal stromal tumors. Hum Pathol 2009; 40: 868-71.
73. Kim MS, Park SW, Kim YR, Lee JY, Lim HW, Song SY, et al. Mutational analysis of Caspase genes in prostate carcinomas. APMIS 2010; 118: 308-12.
74. Winter RN, Kramer A, Borkowski A, Kyprianou N. Loss of Caspase-1 and Caspase-3 protein expression in human prostate cancer. Cancer Res 2001; 61: 1227-32.
75. Pan YL, Liu W, Gao CX, Shang Z, Ning LJ, Liu X. CASP-1, -2 and -5 gene polymorphisms and cancer risk: A review and meta-analysis. Biomed Rep 2013; 1: 511-6.
76. Vázquez-Higuera JL, Rodríguez-Rodríguez E, Sánchez-Juan P, Mateo I, Pozueta A, Martínez-García A, et al. Caspase-1 genetic variation is not associated with Alzheimer’s disease risk. BMC Med Genet 2010; 11: in press.
77. Ona VO, Li M, Vonsattel JP, Andrews LJ, Khan SQ, Chung WM, et al. Inhibition of Caspase-1 slows disease progression in a mouse model of Huntington’s disease. Nature 1999; 399: 263-7.
78. Li M, Ona VO, Guégan C, Chen M, Jackson-Lewis V, Andrews LJ, et al. Functional role of Caspase-1 and Caspase-3 in an ALS transgenic mouse model. Science 2000; 288: 335-9.
79. Friedlander RM, Gagliardini V, Hara H, Fink KB, Li W, MacDonald G, et al. Expression of a dominant negative mutant of interleukin-1β converting enzyme in transgenic mice prevents neuronal cell death induced by trophic factor withdrawal and ischemic brain injury. J Exp Med 1997; 185: 933-40.
80. Hara H, Friedlander RM, Gagliardini V, Ayata C, Fink K, Huang Z, et al. Inhibition of interleukin 1beta converting enzyme family proteases reduces ischemic and excitotoxic neuronal damage. Proc Natl Acad Sci U S A 1997; 94: 2007-12.
81. Hara H, Fink K, Endres M, Friedlander RM, Gagliardini V, Yuan J, et al. Attenuation of transient focal cerebral ischemic injury in transgenic mice expressing a mutant ICE inhibitory protein. J Cereb Blood Flow Metab 1997; 17: 370-5.
82. Guo Y, Kyprianou N. Restoration of transforming growth factor beta signaling pathway in human prostate cancer cells suppresses tumorigenicity via induction of Caspase-1-mediated apoptosis. Cancer Res 1999; 59: 1366-71.
83. Hu B, Elinav E, Huber S, Booth CJ, Strowig T, Jin C, et al. Inflammation-induced tumorigenesis in the colon is regulated by Caspase-1 and NLRC4. Proc Natl Acad Sci U S A 2010; 107: 21635-40.
84. Celardo I, Grespi F, Antonov A, Bernassola F, Garabadgiu AV, Melino G, Amelio I. Caspase-1 is a novel target of p63 in tumor suppression. Cell Death Dis. 2013; 4:e645.
85. Yan W, Chang Y, Liang X, Cardinal JS, Huang H, Thorne SH, et al. High-mobility group box 1 activates Caspase-1 and promotes hepatocellular carcinoma invasiveness and metastases. Hepatology 2012; 55: 1863-75.
86. Estrov Z, Talpaz M. Role of interleukin-1 beta converting enzyme (ICE) in acute myelogenous leukemia cell proliferation and programmed cell death. Leuk Lymphoma 1997; 24: 379-91.
87. Zaki MH, Boyd KL, Vogel P, Kastan MB, Lamkanfi M, Kanneganti TD. The NLRP3 inflammasome protects against loss of epithelial integrity and mortality during experimental colitis. Immunity 2010; 32:379-91.
88. Man SM, Zhu Q, Zhu L, Liu Z, Karki R, Malik A, et al. Critical Role for the DNA Sensor AIM2 in Stem Cell Proliferation and Cancer. Cell 2015; 162:45-58.
89. Zhong FL, Mamaï O, Sborgi L, Boussofara L, Hopkins R, Robinson K, et al. Germline NLRP1 mutations cause skin inflammatory and cancer susceptibility syndromes via inflammasome activation. Cell 2016; 167:187-202.e17.
90. Dowds TA, Masumoto J, Zhu L, Inohara N, Núñez G. Cryopyrin-induced interleukin 1beta secretion in monocytic cells: enhanced activity of disease-associated mutants and requirement for ASC. J Biol Chem 2004; 279: 21924-8.
91. Omenetti A, Carta S, Delfino L, Martini A, Gattorno M, Rubartelli A. Increased NLRP3-dependent interleukin 1β secretion in patients with familial Mediterranean fever: correlation with MEFV genotype. Ann Rheum Dis 2014; 73: 462-9.
92. Yüksel Ş, Eren E, Hatemi G, Sahillioğlu AC, Gültekin Y, Demiröz D, et al. Novel NLRP3/cryopyrin mutations and pro-inflammatory cytokine profiles in Behçet’s syndrome patients. Int Immunol 2014; 26: 71-81.
93. Joosten LA, Netea MG, Fantuzzi G, Koenders MI, Helsen MM, Sparrer H, et al. Inflammatory arthritis in Caspase 1 gene-deficient mice: contribution of proteinase 3 to Caspase 1-independent production of bioactive interleukin-1beta. Arthritis Rheum 2009; 60: 3651-62.
94. Sikora J, Mielczarek-Palacz A, Kondera-Anasz Z. Imbalance in cytokines from interleukin-1 family - role in pathogenesis of endometriosis. Am J Reprod Immunol 2012; 68: 138-45.
95. Vincent JA, Mohr S. Inhibition of Caspase-1/interleukin-1beta signaling prevents degeneration of retinal capillaries in diabetes and galactosemia. Diabetes 2007; 56: 224-30.
96. Wang H, Capell W, Yoon JH, Faubel S, Eckel RH. Obesity development in Caspase-1-deficient mice. Int J Obes (Lond) 2014; 38: 152-5.
97. Ray CA, Black RA, Kronheim SR, Greenstreet TA, Sleath PR, Salvesen GS, et al. Viral inhibition of inflammation: cowpox virus encodes an inhibitor of the interleukin-1 beta converting enzyme. Cell 1992; 69: 597-604.
98. Dobó J, Swanson R, Salvesen GS, Olson ST, Gettins PG. Cytokine response modifier a inhibition of initiator Caspases results in covalent complex formation and dissociation of the Caspase tetramer. J Biol Chem 2006; 281: 38781-90.
99. Bump NJ, Hackett M, Hugunin M, Seshagiri S, Brady K, Chen P, et al. Inhibition of ICE family proteases by baculovirus antiapoptotic protein p35. Science 1995; 269: 1885-8.
100. Zhou Q, Krebs JF, Snipas SJ, Price A, Alnemri ES, Tomaselli KJ, et al. Interaction of the baculovirus anti-apoptotic protein p35 with Caspases. Specificity, kinetics, and characterization of the Caspase/ p35 complex. Biochemistry 1998; 37: 10757-65.
101. Garcia-Calvo M, Peterson EP, Leiting B, Ruel R, Nicholson DW, Thornberry NA. Inhibition of human Caspases by peptide-based and macromolecular inhibitors. J Biol Chem 1998; 273: 32608-13.
102. Stosić-Grujicić S, Basara N, Dinarello CA. Modulatory in vitro effects of interleukin-1 receptor antagonist (IL-1Ra) or antisense oligonucleotide to interleukin-1 beta converting enzyme (ICE) on acute myeloid leukaemia (AML) cell growth. Clin Lab Haematol 1999; 21: 173-85.
103. Stack JH, Beaumont K, Larsen PD, Straley KS, Henkel GW, Randle JC, et al. IL-converting enzyme/Caspase-1 inhibitor VX-765 blocks the hypersensitive response to an inflammatory stimulus in monocytes from familial cold autoinflammatory syndrome patients. J Immunol 2005; 175: 2630-4.
104. Wannamaker W, Davies R, Namchuk M, Pollard J, Ford P, Ku G, et al. (S)-1-((S)-2-{[1-(4-amino-3-chloro-phenyl)-methanoyl]-amino}- 3,3-dimethyl-butanoyl)-pyrrolidine-2-carboxylic acid ((2R,3S)-2- ethoxy-5-oxo-tetrahydro-furan-3-yl)-amide (VX-765), an orally available selective interleukin (IL)-converting enzyme/Caspase-1 inhibitor, exhibits potent anti-inflammatory activities by inhibiting the release of IL-1beta and IL-18. J Pharmacol Exp Ther 2007; 321: 509-16.
105. Zhang Y, Liu L, Liu YZ, Shen XL, Wu TY, Zhang T, et al. NLRP3 inflammasome mediates chronic mild stress-induced depression in mice via neuroinflammation. Int J Neuropsychopharmacol 2015; 18:pii: pyv006.
106. Ravizza T, Noé F, Zardoni D, Vaghi V, Sifringer M, Vezzani A. Interleukin converting enzyme inhibition impairs kindling epileptogenesis in rats by blocking astrocytic IL-1beta production. Neurobiol Dis 2008; 31: 327-33.
107. Maroso M, Balosso S, Ravizza T, Iori V, Wright CI, French J, et al. Interleukin-1β biosynthesis inhibition reduces acute seizures and drug resistant chronic epileptic activity in mice. Neurotherapeutics 2011; 8: 304-15.
108. Siegmund B, Zeitz M. Pralnacasan (vertex pharmaceuticals). IDrugs 2003; 6: 154-8.
109. Rudolphi K, Gerwin N, Verzijl N, van der Kraan P, van den Berg W. Pralnacasan, an inhibitor of interleukin-1beta converting enzyme, reduces joint damage in two murine models of osteoarthritis. Osteoarthritis Cartilage 2003; 11: 738-46.
110. Loher F, Bauer C, Landauer N, Schmall K, Siegmund B, Lehr HA, et al. The interleukin-1 beta-converting enzyme inhibitor pralnacasan reduces dextran sulfate sodium-induced murine colitis and T helper 1 T-cell activation. J Pharmacol Exp Ther 2004; 308: 583-90.
111. Bauer C, Loher F, Dauer M, Mayer C, Lehr HA, Schönharting M et al. The ICE inhibitor pralnacasan prevents DSS-induced colitis in C57BL/6 mice and suppresses IP-10 mRNA but not TNF-alpha mRNA expression. Dig Dis Sci 2007; 52: 1642-52.
112. Ross J, Brough D, Gibson RM, Loddick SA, Rothwell NJ. A selective, non-peptide Caspase-1 inhibitor, VRT-018858, markedly reduces brain damage induced by transient ischemia in the rat. Neuropharmacology 2007; 53: 638-42.
113. Coll RC, Robertson AA, Chae JJ, Higgins SC, Muñoz-Planillo R, Inserra MC, et al. A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases. Nat Med 2015; 21: 248-55.