title: Identification of constitutively active interleukin 33 (IL-33) splice variant.
abstract: IL-33/IL-1F11 is a new member of the IL-1 family ligand and provokes T helper-type immune responses. IL-33 is the ligand of ST2 and IL-1 receptor accessory protein (IL-1RAcP) that triggers nuclear factor-κ light chain enhancer of activated B cells (NF-κB) and MAPK signaling. We discovered a novel short splice variant of IL-33 that was termed spIL-33. The new spIL-33 lacks exon 3 containing a proposed caspase-1 cleavage site. We isolated spIL-33 cDNA from the Huh7 human hepatocarcinoma cell line and expressed the recombinant spIL-33 protein in Escherichia coli. The recombinant spIL-33 and pro-IL-33 were not cleaved by caspase-1, unlike IL-18 (IL-1F4). The recombinant spIL-33 was constitutively active, and spIL-33-induced inflammatory cytokine production was caspase-1-independent in HMC-1 and Raw 264.7 cells. The recombinant spIL-33 induced the phosphorylation of IL-1 receptor-associated kinase (IRAK1), NF-κB, p38 MAPK, p44/42 MAPK, and JNK in a time- and dose-dependent manner. Anti-ST2 monoclonal antibody specifically blocked the spIL-33-induced cytokine production. In this study, we identified and characterized a new IL-33 splice variant, which was a constitutively active IL-33 isoform. The existence of constitutively active spIL-33 suggests that the biological activity of IL-33 could be triggered by diverse stimulations during immune responses. Further investigation of the spIL-33 expression pattern may contribute to understanding the involvement of IL-33 in inflammatory disorders.
authors: Laboratory of Cytokine Immunology, Medical Immunology Center, Konkuk University, Seoul, Korea.
authors: Jaewoo
authors: J
authors: Hong
authors: Suyoung
authors: S
authors: Bae
authors: Hyunjhung
authors: H
authors: Jhun
authors: Siyoung
authors: S
authors: Lee
authors: Jida
authors: J
authors: Choi
authors: Taebong
authors: T
authors: Kang
authors: Areum
authors: A
authors: Kwak
authors: Kwangwon
authors: K
authors: Hong
authors: Eunsom
authors: E
authors: Kim
authors: Seunghyun
authors: S
authors: Jo
authors: Soohyun
authors: S
authors: Kim
mesh_terms: D017398:Alternative Splicing / Q000502:physiology*; D000818:Animals; D001483:Base Sequence; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D053592:Interleukin-1 Receptor-Associated Kinases / Q000235:genetics / Q000378:metabolism; D000067596:Interleukin-33; D007378:Interleukins / Q000096:biosynthesis* / Q000235:genetics; D019169:Jurkat Cells; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D008969:Molecular Sequence Data; D010766:Phosphorylation / Q000502:physiology; D020033:Protein Isoforms / Q000096:biosynthesis / Q000235:genetics; D011498:Protein Precursors / Q000096:biosynthesis* / Q000235:genetics; D051381:Rats; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000235:genetics; D020298:U937 Cells
chemical_list: C506536:IL33 protein, human; C506535:Il33 protein, mouse; D000067596:Interleukin-33; D007378:Interleukins; D020033:Protein Isoforms; D011498:Protein Precursors; D011994:Recombinant Proteins; C507768:IRAK1 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases; C507769:Irak1 protein, mouse; D020929:Mitogen-Activated Protein Kinase Kinases