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Interleukin-33 in health and disease

Key Points

  • Broad expression in stromal and barrier tissue renders interleukin-33 (IL-33) a ubiquitous and crucial immune modulator that shapes type 1, type 2 and regulatory immune responses.

  • Although lacking a secretion sequence and sequestered in the nucleus, IL-33 is released and processed into highly active forms by various proteases.

  • IL-33 contributes to cytokine networks that not only control pathogen removal but also support tissue repair mediated by group 2 innate lymphoid cells and regulatory T cells.

  • The role of IL-33 is expected to continue to expand, modulating both protective and pathological immune responses.

  • Delivering or blocking IL-33 is emerging as a promising therapeutic strategy for maintaining immune homeostasis and protecting against infectious and inflammatory diseases.


Interleukin-33 (IL-33) — a member of the IL-1 family — was originally described as an inducer of type 2 immune responses, activating T helper 2 (TH2) cells and mast cells. Now, evidence is accumulating that IL-33 also potently stimulates group 2 innate lymphoid cells (ILC2s), regulatory T (Treg) cells, TH1 cells, CD8+ T cells and natural killer (NK) cells. This pleiotropic nature is reflected in the role of IL-33 in tissue and metabolic homeostasis, infection, inflammation, cancer and diseases of the central nervous system. In this Review, we highlight the molecular and cellular characteristics of IL-33, together with its major role in health and disease and the potential therapeutic implications of these findings in humans.

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Figure 1: The interleukin-33 gene and protein structure.
Figure 2: Regulation of IL-33 activity.
Figure 3: IL-33 signalling.
Figure 4: Effects of IL-33 activity in the lungs and gut.

Accession codes


Protein Data Bank


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F.Y.L is supported by the Wellcome Trust and the Medical Research Council, UK. J.-P.G. is supported by grants from Agence Nationale de la Recherche (ANR-12-BSV3-0005-01), Institut National du Cancer (INCA) and Fondation ARC. H.R.T. is supported by grants from the US National Institutes of Health, National Heart, Lung, and Blood Institutes (R01 HL122489) and the National Institute of Allergy and Infectious Diseases (R21 AI121981).

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Principal sources of nuclear IL-33 in human and mouse tissues (PDF 138 kb)


IL-1 family

A family of pro-inflammatory cytokines with 11 members, including IL-1β, IL-18 and IL-33. They stimulate the expression of integrins on leukocytes and endothelial cells, regulate and initiate inflammatory responses. They bind to heterodimeric receptors comprised of a specific receptor and a shared IL-1 receptor accessory protein and activate cell signalling through adaptor protein MYD88.

Group 2 innate lymphoid cells

A subset of innate lymphoid cells (ILCs) that produce type 2 cytokines, such as interleukin-5 and interleukin-13. Their development depends on the transcription factors retinoic acid receptor-related orphan receptor-α and GATA-binding protein 3. These cells contribute to tissue repair and parasite elimination, as well as to the development of asthma and allergy.


An endogenous molecule that is released after tissue injury and that promotes activation of the innate immune system. Excessive release of alarmins might promote uncontrolled inflammation and exacerbate tissue injury. Conversely, alarmins may have beneficial effects by activating the immune system to combat potential pathogens. Also called damage-associated molecular pattern (DAMP).


A programmed form of necrotic cell death mediated by receptor-interacting protein kinase 1 (RIPK1) and RIPK3. It can be induced by death receptors and by TIR-domain-containing adaptor protein inducing interferon-β (TRIF)-dependent Toll-like receptor 3 (TLR3) and TLR4 signalling. Inhibition of caspase 8 activation sensitizes cells to necroptosis.

Chronic obstructive pulmonary disease

(COPD). A group of diseases characterized by the pathological limitation of airflow in the airway, including chronic obstructive bronchitis and emphysema. It is most often caused by tobacco smoking, but can also be caused by other airborne irritants (such as coal dust) and occasionally by genetic abnormalities, such as α1-antitrypsin deficiency.

Graft versus host disease

(GVHD). Tissue damage in a recipient of allogeneic tissue (usually a bone-marrow transplant) that results from the activity of donor cytotoxic T lymphocytes that recognize the tissues of the recipient as foreign. GVHD varies markedly in extent, but it can be life threatening in severe cases. Damage to the liver, skin and gut mucosa are common clinical manifestations.

Myeloproliferative neoplasms

A group of diseases of the bone marrow in which excess cells are produced as a result of clonal genetic changes. It was previously known as myeloproliferative diseases. The increased number of blood cells may not cause any symptoms but may increase the risk of thrombosis.

M2 macrophages

Also known as alternatively-activated macrophages, M2 macrophages differentiate in response to interleukin-4 (IL-4) or IL-13 and are thought to mediate T helper 2-type immune responses, such as protection from parasites and wound healing. They are typically defined by their expression of arginase 1, the mannose receptor CD206 and the IL-4 receptor α-chain, and they can produce large amounts of IL-10.

Apolipoprotein E-deficient mice

A widely used mouse model that is prone to develop atherosclerosis because the mice have high levels of types of atherogenic lipoprotein called remnant lipoproteins. This lipoprotein abnormality is cause by the genetic absence of apolipoprotein E (APOE), which normally clears remnant lipoproteins from the bloodstream by interacting with hepatocytes.

B1 cells

An innate-like population of B cells that is mainly found in the peritoneal and pleural cavities of mice. B1 cell precursors develop in the fetal liver and omentum. B1 cells recognize self components as well as common bacterial antigens and secrete antibodies of low affinity and broad specificity.


A common disease of the tendon, characterized by tenderness on palpitation and pain, often when exercising or with movement. Tendinopathy is most frequently seen in tendons of athletes either before or after an injury resulting from tensile overload, tendon cell-related collagen synthesis disruption or load-induced ischaemia.

Dextran sodium sulfate (DSS)-induced acute colitis

A commonly used experimental model of colitis induced in mice by ingestion of the sulfated polysaccharide DSS. This model causes acute colonic epithelial damage and inflammation via unknown mechanisms.

T cell transfer-induced colitis

A commonly used mouse model of inflammatory bowel disease based on the disruption of T cell homeostasis. Adoptive transfer of CD4+CD45RBhi T cells (naive T cells) from healthy wild-type mice into syngeneic recipients that lack T cells and B cells induces a pan-colitis and small bowel inflammation at 5–8 weeks following cell transfer, with varying degrees of weight loss and diarrhoea and loose stools. This model allows the examination of the early immunological events associated with the induction of gut inflammation as well as the perpetuation of disease.

White adipose tissue

One of the two types of adipose tissue found in mammals (the other being brown adipose tissue). In healthy, non-overweight humans, It composes 20% in men and 25% in women of body weight. White adipose tissue cells contain a single large fat droplet, which forces the nucleus to be squeezed into the thin rim at the periphery. It is used as a store of energy and also acts as a thermal insulator, helping to maintain body temperature.

Brown adipose tissue

Comprising both cells that share a common embryological origin with muscle cells, and are found in large deposits, and beige cells that develop from white adipocytes, which are stimulated by the sympathetic nervous system and are found interspersed in white adipose tissue. Brown adipocytes contain numerous small fat droplets and a high number of iron-containing mitochondria, which gives them their brown appearance. The primary function is thermoregulation.

ApcMin/+ mouse model

A mouse strain that carries a point mutation in one adenomatous polyposis coli (Apc) allele and spontaneously develops intestinal adenomas. It is used as a model for human familial adenomatous polyposis and for human sporadic colorectal cancer.

Conditioning protocols

(Also known as a preparative regimen). Treatments involving a combination of chemotherapy, radiation therapy and/or immunosuppressive medications that are designed not only to destroy residual malignant cells but also to provide space for donor stem cell engraftment and to provide immunosuppression to prevent host rejection of the donor stem cells.


Phagocytic cells of myeloid origin that are involved in the innate immune response in the central nervous system. Microglia are thought to be the major brain-resident macrophages.

APP/PS1 mice

Also known as APPswePS1de9 mice. A commonly used mouse model of Alzheimer disease. These double-transgenic mice are generated by incorporation of a murine or human amyloid precursor protein (Mo/HuAPP695swe) and a mutant human presenilin 1 (PS1-dE9) both directed to neurons of the central nervous system. These mice develop β-amyloid deposits in the brain, cognitive impairment and have a high incidence of seizures by 6–7 months of age.

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Liew, F., Girard, JP. & Turnquist, H. Interleukin-33 in health and disease. Nat Rev Immunol 16, 676–689 (2016).

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