The cytokine interleukin-33 mediates anaphylactic shock.
Anaphylactic shock is characterized by elevated immunoglobulin-E (IgE) antibodies that signal via the high affinity Fc epsilon receptor (Fc epsilonRI) to release inflammatory mediators. Here we report that the novel cytokine interleukin-33 (IL-33) potently induces anaphylactic shock in mice and is associated with the symptom in humans. IL-33 is a new member of the IL-1 family and the ligand for the orphan receptor ST2. In humans, the levels of IL-33 are substantially elevated in the blood of atopic patients during anaphylactic shock, and in inflamed skin tissue of atopic dermatitis patients. In murine experimental atopic models, IL-33 induced antigen-independent passive cutaneous and systemic anaphylaxis, in a T cell-independent, mast cell-dependent manner. In vitro, IL-33 directly induced degranulation, strong eicosanoid and cytokine production in IgE-sensitized mast cells. The molecular mechanisms triggering these responses include the activation of phospholipase D1 and sphingosine kinase1 to mediate calcium mobilization, Nuclear factor-kappaB activation, cytokine and eicosanoid secretion, and degranulation. This report therefore reveals a hitherto unrecognized pathophysiological role of IL-33 and suggests that IL-33 may be a potential therapeutic target for anaphylaxis, a disease of considerable unmet medical need.
Pushparaj
Peter N
PN
Division of Immunology, Infection and Inflammation, Glasgow Biomedical Research Centre, University of Glasgow, Scotland, United Kingdom.
Tay
Hwee Kee
HK
H'ng
Shiau Chen
SC
Pitman
Nick
N
Xu
Damo
D
McKenzie
Andrew
A
Liew
Foo Y
FY
Melendez
Alirio J
AJ
D000707:Anaphylaxis / Q000276:immunology*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D015550:Cell Degranulation; D018925:Chemokines / Q000096:biosynthesis; D016207:Cytokines / Q000096:biosynthesis; D003872:Dermatitis / Q000276:immunology; D015777:Eicosanoids / Q000096:biosynthesis; D005260:Female; D006801:Humans; D007073:Immunoglobulin E / Q000276:immunology; D000067596:Interleukin-33; D007378:Interleukins / Q000502:physiology*; D008297:Male; D008407:Mast Cells / Q000166:cytology; D051379:Mice; D016328:NF-kappa B / Q000096:biosynthesis
D018925:Chemokines; D016207:Cytokines; D015777:Eicosanoids; C506536:IL33 protein, human; C506535:Il33 protein, mouse; D000067596:Interleukin-33; D007378:Interleukins; D016328:NF-kappa B; D007073:Immunoglobulin E; D002118:Calcium