Interleukin-33

Interleukins (from Latin/Greek inter = between; leukos = white; kinein = to move) are a group of endogenous, short-chain regulatory proteins (cytokines) of the immune system (IL1-IL38). Interleukins are mediators for the induction, progression and control of T-cell-mediated cytotoxic immune reactions and B-cell activation (antibody production). They are mainly produced and secreted by stimulated leukocytes, monocytes and macrophages. To date, around 38 different interleukins have been clearly identified. Each cytokine in the interleukin group is nomenclaturally assigned a number for its classification (IL-1 to IL-38 - as of 2017).

Some structurally related substances have been grouped into families. Their members often have a similar function or are involved in the fine regulation of immune reactions, for example by regulating the synthesis of related interleukins.

Interleukin-33 (IL-33) is a proinflammatory cytokine that in humans is encoded by the IL-33 gene (located on chromosome 9p24.1) .

Interleukin-33 is a member of the 11-member interleukin-1 superfamily, a cytokine family characterized by its particular beta-fold structure, a conserved molecular structure that is also characteristic of the cytokines interleukin-1alpha, interleukin-1beta, interleukin-1Ra and interleukin-18 .

The interleukin (IL)-1 family includes 7 pro-inflammatory agonists (IL-1alpha, IL-1βbeta, IL-18, IL-33, IL-36alpha, IL-36beta, IL-36gamma) and 4 defined (anti-inflammatory) antagonists (IL-1Ra, IL-36Ra, IL-37, and IL-38/Palomo J et al. 2015).

Interleukin-33 is a cytokine with a dual function. In addition to its chromatin-associated function, it is constitutively expressed in healthy endothelial cells, as it acts as DAMP after its release into the extracellular space of cells in the context of immunological, non-silent (relevant) cell death(necrosis or pyroptosis) and drives cytokine production in natural helper cells, Th2 lymphocytes, mast cells, basophils, eosinophils, invariant natural killer and natural killer T cells. Interleukin-33 is involved in allergic and partasitic inflammatory reactions.

The cytokine induces various cytokines such as interleukin-4 via activation of T helper 2 cells (Th2). Interleukin-33 binds to the receptor ST2 (IL1RL1) and to the "interleukin-1 receptor accessory protein" IL1RAP. This activates type 2 cytokines (especially interleukin-5 and interleukin-13) via the NF-kappaB and MAP kinase signaling pathways. IL-33 is rapidly oxidized and thus neutralized after its release.

Interleukin-33 is expressed by a large number of different cell types such as fibroblasts, mast cells, dendritic cells, macrophages, osteoblasts, endothelial cells and various epithelial cells.

IL-33 induces type 2 cytokines in T-helper cells, mast cells, eosinophil and basophil granulocytes (these cytokines were originally called NF-HEV "nuclear factor (NF) in high endothelial venules" HEVs). Also in epithelial cells and endothelia (Nabe 2014).

Remarkably, interleukin-33 acts in a dual manner, intracellularly as a "nuclear factor" (binds to DNA) and further, extracellularly as a cytokine (Martin NT et al. 2016).

IL-33 is associated with various diseases, such as bronchial asthma, allergic rhinosinusitis, atopic eczema and endometriosis. IL-33 is also associated with itchy skin diseases. It has been postulated that IL-33-blocking therapeutics can be used as anti-allergic agents.

The cytokine also plays a protective role in intestinal parasitic infections (Nunes T et al. 2014). It is overexpressed in Behcet's disease (Hamzaoui K et al. 2015).

Interleukin-33 is also released during the first stretching of the lungs immediately after birth. The cytokine activates immune cells in the lung tissue.

IL-33 reduces the expression of filaggrin and claudin-1, which leads to a reduction in the barrier function of the skin. However, the destruction of the barrier leads to percutaneous exposure to allergens or the release of IL-33. IL-33 is therefore a common starting point for the itch-scratch cycle of atopic dermatitis (Imai Y 2019).

1. Balato A et al. (2016) Interleukin-33: increasing role in dermatological conditions. Arch Dermatol Res 308:287-296. Martin NT et al.(2016) Interleukin 33 is a guardian of barriers and a local alarmin. Nat Immunol 17:122-131.

2. Imai Y (2019) Interleukin-33 in atopic dermatitis. J Dermatol Sci 96:2-7.

3. Hamzaoui K et al. (2015) Interleukin-33 and Behçet disease: Another cytokine among others. Hum Immunol 76(:301-306.
4. Nabe T (2014) Interleukin (IL)-33: new therapeutic target for atopic diseases. J Pharmacol Sci 126:85-91.
5. Nunes T et al. (2014) Interleukin-33 and inflammatory bowel diseases: lessons from human studies. Mediators Inflamm 2014:423957.
6. Makrinioti H et al. (2014) Role of interleukin 33 in respiratory allergy and asthma. Lancet Respir Med 2:226-237.

7. Palomo J et al. (2015) The interleukin (IL)-1 cytokine family--Balance between agonists and antagonists in inflammatory diseases. Cytokine 76:25-37.

8. Pei C et al. (2014) Emerging role of interleukin-33 in autoimmune diseases. Immunology 141:9-17.