Caspase-1, Caspase-8, and Calpain Are Dispensable for IL-33 Release by Macrophages1

In addition to IL-1 and IL-18, IL-33 was recently identified as a member of the IL-1 cytokine family. rIL-33 can promote production of Th2-type cytokines by Th2 cells and mast cells in vitro. Administration of rIL-33 to mice results in increases in IgE secretion and eosinophilic inflammation. However, the precise immune cell source of IL-33 remains unclear. Moreover, although recombinant pro-IL-33 is cleaved by recombinant caspase-1 in vitro, as are pro-IL-1β and pro-IL-18, the involvement of caspase-1 in pro-IL-33 cleavage remains controversial. In this study, we show that mouse peritoneal macrophages, but not splenic dendritic cells, produced IL-33 upon stimulation with LPS. Likewise, mouse bone marrow cell-derived cultured mast cells also produced a small, but significant amount of IL-33 via FcεRI cross-linking, but not in response to stimulation with LPS. To our surprise, IL-33 release was found even in caspase-1-deficient, caspase-8 inhibitor-treated, and calpain inhibitor-treated macrophages. These observations suggest that caspase-1-, caspase-8-, and calpain-independent IL-33 production by macrophages and/or mast cells may contribute to the pathogenesis of Th2-type allergic inflammation.

[1]  S. Cullen,et al.  Suppression of interleukin-33 bioactivity through proteolysis by apoptotic caspases. , 2009, Immunity.

[2]  J. Girard,et al.  The IL-1-like cytokine IL-33 is inactivated after maturation by caspase-1 , 2009, Proceedings of the National Academy of Sciences.

[3]  C. Gabay,et al.  Interleukin-33 Is Biologically Active Independently of Caspase-1 Cleavage* , 2009, The Journal of Biological Chemistry.

[4]  S. Janssens,et al.  Brief Definitive Report Stimulation of Toll-like Receptor 3 and 4 Induces Interleukin-1 ␤ Maturation by Caspase-8 , 2022 .

[5]  C. Gabay,et al.  IL‐1, IL‐18, and IL‐33 families of cytokines , 2008, Immunological reviews.

[6]  Ashley M. Miller,et al.  IL-33 reduces the development of atherosclerosis , 2008, The Journal of experimental medicine.

[7]  XuD HepworthMR LiewFY GrencisRK HumphreysNE.  IL-33, a potent inducer of adaptive immunity to intestinal nematodes. , 2008 .

[8]  S. Akira,et al.  IL‐33 induces IL‐13 production by mouse mast cells independently of IgE‐FcεRI signals , 2007 .

[9]  I. McInnes,et al.  IL‐33 is a chemoattractant for human Th2 cells , 2007, European journal of immunology.

[10]  M. Hayakawa,et al.  Soluble ST2 Blocks Interleukin-33 Signaling in Allergic Airway Inflammation* , 2007, Journal of Biological Chemistry.

[11]  Dirk E. Smith,et al.  Cutting Edge: The ST2 Ligand IL-33 Potently Activates and Drives Maturation of Human Mast Cells1 , 2007, The Journal of Immunology.

[12]  R. Kastelein,et al.  IL-1 Receptor Accessory Protein and ST2 Comprise the IL-33 Receptor Complex , 2007, The Journal of Immunology.

[13]  S. Galli,et al.  IL-33 can promote survival, adhesion and cytokine production in human mast cells , 2007, Laboratory Investigation.

[14]  Delphine A. Lacorre,et al.  IL-33, the IL-1-like cytokine ligand for ST2 receptor, is a chromatin-associated nuclear factor in vivo , 2007, Proceedings of the National Academy of Sciences.

[15]  尾本 陽一.  Human mast cell chymase cleaves pro-IL-18 and generates a novel and biologically active IL-18 fragment , 2006 .

[16]  J Fernando Bazan,et al.  IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines. , 2005, Immunity.

[17]  T. Kawakami,et al.  Mast Cell Survival and Activation by IgE in the Absence of Antigen: A Consideration of the Biologic Mechanisms and Relevance1 , 2005, The Journal of Immunology.

[18]  M. Sweet,et al.  T1/ST2--an IL-1 receptor-like modulator of immune responses. , 2004, Cytokine & growth factor reviews.

[19]  E. S. Baekkevold,et al.  Molecular characterization of NF-HEV, a nuclear factor preferentially expressed in human high endothelial venules. , 2003, The American journal of pathology.

[20]  Kim Bottomly,et al.  Lipopolysaccharide-enhanced, Toll-like Receptor 4–dependent T Helper Cell Type 2 Responses to Inhaled Antigen , 2002, The Journal of experimental medicine.

[21]  K. Takakura,et al.  Identification of Genes Differentially Expressed in Canine Vasospastic Cerebral Arteries after Subarachnoid Hemorrhage , 1999, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[22]  S. Akira,et al.  Caspase-1-independent, Fas/Fas ligand-mediated IL-18 secretion from macrophages causes acute liver injury in mice. , 1999, Immunity.

[23]  R. Klemenz,et al.  The IL-1 receptor-related T1 antigen is expressed on immature and mature mast cells and on fetal blood mast cell progenitors. , 1998, Journal of immunology.

[24]  C. Dinarello.  Interleukin‐1β, Interleukin‐18, and the Interleukin‐1β Converting Enzyme a , 1998 .

[25]  Andreas Radbruch,et al.  T1/ST2 is preferentially expressed on murine Th2 cells, independent of interleukin 4, interleukin 5, and interleukin 10, and important for Th2 effector function. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[26]  M. Su,et al.  Altered cytokine export and apoptosis in mice deficient in interleukin-1 beta converting enzyme. , 1995, Science.

[27]  C. Avnstorp,et al.  Interleukin‐1 , 1987 .