RETRACTED: The cytokine interleukin-33 mediates anaphylactic shock

Abstract

Anaphylactic shock is characterized by elevated immunoglobulin-E (IgE) antibodies that signal via the high affinity Fcε receptor (FcεRI) 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–κB 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.

Targeting ST2L Potentiates CpG-Mediated Therapeutic Effects in a Chronic Fungal Asthma Model

“…33 Anaphylactic shock appears to be one human condition that is characterized by the release of major amounts of IL-33 into the circulatory system. 47 In contrast, a few human plasma samples contained detectable levels of IL-33, although the amount of IL-33 detected in plasma samples from patients with moderate asthma was significantly greater than levels in control and other diseased samples. TLR ligand activation of DCs induced ST2L, sST2, and IL-33 transcript expression in our experimental model, but levels of IL-33 protein produced by these cells were less than the limits of detection of the ELISA used.…”

The Immune-Modulating Cytokine and Endogenous Alarmin Interleukin-33 Is Upregulated in Skin Exposed to Inflammatory UVB Radiation

“…In the skin, IL-33 is constitutively expressed in epidermal keratinocytes 35 and is significantly upregulated in inflamed skin samples of atopic dermatitis patients. 36 It has been hypothesized that IL-33 acts as a novel "alarmin" that is released in the full-length active form after tissue damage. 35,37 In this way, IL-33 acts as an endogenous danger signal that mediates the recruitment of innate immune cells to sites of infection or cellular damage.…”

Epithelial-derived IL-33 and its receptor ST2 are dysregulated in ulcerative colitis and in experimental Th1/Th2 driven enteritis

“…S7A). Analysis of individual data from T 0 until the end of the induction regimen (wk 14) showed differential modulation of the IL-33/sST2 axis when comparing UC vs. CD. In fact, after the induction phase at wk 14, IL-33 levels were decreased in the overall IBD group (P < 0.01) (Fig.…”

“…The IL-33/ST2 axis appears to play an important role in several chronic inflammatory disorders, including asthma, rheumatoid arthritis, and anaphylactic shock (13)(14)(15); however, in contrast to IL-1 and IL-18, which predominantly promote Th1-type responses, IL-33 mainly induces Th2 cytokines (i.e., IL-5 and IL-13) (7). Relevant to our study, IL-33 exerts specific effects in the gut, because mice treated with recombinant (r)IL-33 displayed epithelial hyperplasia and eosinophil/neutrophil infiltration in the colonic mucosa (7).…”