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FLASH GENE

Symbol

IL33

contributors: mct/npt/pgu - updated : 27-02-2017

HGNC name	interleukin 33
HGNC id	16028

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

Location	9p24.1      Physical location : 6.241.677 - 6.257.982
Genatlas name	Alarmin
Synonym name	DVS27-related protein
	chromosome 9 open reading frame 26 (NF-HEV)
	interleukin-1 family member 11
	nuclear factor from high endothelial venules
Synonym symbol(s)	DVS27, NFEHEV, DKFZp586H0523, C9orf26, IL1F11, NFHEV, RP11-575C20.2, IL-33

DNA

TYPE	functioning gene
STRUCTURE	42.83 kb     7 Exon(s)

MAPPING

cloned

Y

linked

N

status

provisional

RNA

TRANSCRIPTS	type	messenger

text	a novel exon 2E is included in the alternatively spliced messenger RNAs and, it contains an open reading frame of 131 amino acids coding for a possible transmembrane protein (PMID: 23261461)

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_033439 8 - 2644 NP_254274 30 270 - 2007 17185418 NM_001199640 7 - 2592 NP_001186569 - 228 - 2007 17185418 NM_001199641 5 - 2340 NP_001186570 - 144 - 2007 17185418

EXPRESSION

Type

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Cardiovascular vessel aorta       Digestive liver         Nervous brain

cells

System Cell Pubmed Species Stage Rna symbol Cardiovascular endothelial not specific adipocyte not specific fibroblast not specific mast cell Homo sapiens

cell lineage

cell lines

fluid/secretion

at STAGE

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains

isoforms

Precursor

synthesized as a 30-kDa precursor (pro-IL-33). Pro-IL-33 is cleaved by caspase-1 into an 18-kDa mature form (mature IL-33)

HOMOLOGY

Homologene

FAMILY

IL1 cytokine family

CATEGORY

secretory

SUBCELLULAR LOCALIZATION	extracellular
	intracellular
	intracellular,nucleus,chromatin/chromosome
text	in the absence of pro-inflammatory stimuli, localizes to the nucleus

basic FUNCTION	may be involved in lung macrophage activation in clinical asthma
	CASP1, CASP8, and calpain are dispensable for IL33 release by macrophages
	host-protective against helminth infection and reduces atherosclerosis by promoting TH2-type immune responses
	may function as an endogenous danger signal or alarmin, similar to IL1A and HMGB1
	with its receptor, IL1RL1, may play important roles in eosinophil-mediated inflammation
	prevents cardiomyocyte apoptosis and improves cardiac function and survival after MI through IL1RL1 signaling
	have an important role in sensing damage in various infectious and inflammatory diseases
	may be an important cytokine in the initiation and perpetuation of inflammation
	crucial amplifier of mucosal and systemic innate, rather than acquired, immune responses
	seems to play a critical role in various types of innate-type inflammation in the lung and gut, whereas it is dispensable for acquired immune responses
	crucial as an alarmin for innate-type, but not acquired-type, tissue injury-related inflammatory responses such as LPS-induced endotoxin shock
	nuclear IL33 sequesters nuclear NFKB and reduces NFKB-triggered gene expression to dampen proinflammatory signaling
	proteolytic processing may play an important role in the regulation of IL33 activity during inflammation
	in the nucleus of endothelial cells participates in inflammatory reactions as a transcriptional regulator of RELA
	dual-function molecule that regulates gene expression in nuclei and, as a cytokine, conveys proinflammatory signals from outside of cells via its specific receptor IL1RL1
	IL33/IL1RL1 signaling plays an important role in regulating IL33 induced inflammatory responses in ocular surface
	may play a pivotal role in maintenance of cutaneous homeostasis and acceleration of normal wound healing
	predominantly induces type 2 immune responses and thus is protective against atherosclerosis and nematode infections but contributes to allergic airway inflammation
	IL33, may induce inflammatory molecule release from the glial cells and may play an important role in the pathogenesis of Alzheimer disease
	acts as an immunoadjuvant to enhance antigen-specific tumor immunity
	contributes to disease processes in association with Th1 and Th2 phenotypes
	cell-intrinsic role for the IL33/IL1RL1 axis in the regulation of apoptosis in mast cellls, identifying thereby a previously unappreciated pathway supporting expansion of the mast cellls population with inflammation
	IL33/IL1RL1 axis plays an essential role in the development of visceral adipose tissue Treg (VAT-Treg) cells
	IL33 and IL1RL1 function as a developmental switch to license thermogenesis during the perinatal period

CELLULAR PROCESS

PHYSIOLOGICAL PROCESS

PATHWAY

metabolism

signaling

	IL33/IL1RL1 pathway is critically involved in mammary tumor growth by facilitating expression of pro-angiogenic VEGFA in tumor cells and attenuating tumor necrosis
	IL33/IL1RL1 signaling may be involved in periapical inflammation and tissue fibrosis

a component

INTERACTION

DNA

RNA

small molecule

protein	ligand for the then orphan receptor IL1RL1
	likely dual functions (activation/termination) of PRTN3 in IL33 biological activity
	processed into mature bioactive forms by neutrophil elastase and cathepsin G
	endothelial nuclear IL33 is induced by NOTCH1 and DLL4 may be the dominant ligand responsible for this signaling
	TMED1 is required for optimal IL33-induced IL8 and IL6 production
	IFNG induces IL33 in keratinocytes and IL33 acts on activated T cells to further increase the release of IFNG, therefore contributing to drive skin inflammation towards chronic responses
	signals through its ligand-binding primary receptor IL1RL1 and IL1 receptor accessory protein (IL1RAP)
	IFNG directly controls IL33 protein level through a STAT1- and PSMB9-dependent mechanism
	upregulation of CSF2 and CSF1 production by endothelial cells, an effect that appears to be mediated by NFKB1 and to be independent of IL1, may be an additional mechanism through which IL33 contributes to inflammatory activation of the vessel wall
	PIBF1 expression by B cells is induced by the mucosal alarmin IL33

cell & other

REGULATION

induced by

by IL17A in epidermal keratinocytes, may be involved in the pathophysiology of inflammatory skin diseases, including psoriasis

ASSOCIATED DISORDERS

corresponding disease(s)

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function constitutional     --over   more abundantly expressed in the lung epithelial cells of asthma patients than those from healthy controls constitutional     --over   IL33 and IL1RL1 positive cells were also significantly increased in Alzheimer disease (AD) brains when compared to non-AD brains constitutional     --low   pre-eclampsia is associated with lower serum IL33 constitutional     --low   decreased levels of placental ADAMTS12 were found to be associated with intrahepatic cholestasis of pregnancy (ICP), suggesting a possible role of inflammation in the pathogenesis tumoral     --over   of IL33 expression in borderline and malignant epithelial ovarian tumours indicates its involvement in the development and progression of epithelial ovarian cancer (EOC), and its increased expression in less differentiated cancers suggests their association with poor prognosis in this category of tumours

Susceptibility

Variant & Polymorphism

Candidate gene
Marker
Therapy target	could be a new target for therapeutic intervention across a range of diseases
	System Type Disorder Pubmed immunology inflammatory   may provide new therapeutic targets for controlling mucosal eosinophilic inflammation cardiovascular aquired heart failure IL33/IL1RL1 not only represents a promising cardiovascular biomarker but also a novel mechanism of intramyocardial fibroblast-cardiomyocyte communication that may prove to be a therapeutic target for the prevention of heart failure

ANIMAL & CELL MODELS