Interleukin-33: a regulator of basophils

The cytokine network controlling basophils has been extended to interleukin-33. This commentary provides an update and summary on this emerging concept.

It is well appreciated that growth and function of mast cells and basophils are regulated by a network of cytokines and other ligands, and that both cell types express a unique array of cell surface receptors mediating ligand-specific responses in health and disease.¹  Interleukin (IL)–33 is a novel immunoregulatory cytokine that has been identified as a ligand of the orphan IL-1 family receptor T1/ST2.^2,3  Similar to IL-1 and IL-18, IL-33 is synthesized as a precursor molecule that is cleaved by caspase-1.³  IL-33 is produced and released primarily by endothelial cells. Based on the nuclear repressor activity of the cytokine and the antagonistic properties of its receptor (ST2), it has been assumed that IL-33 could decrease inflammation, thereby opposing the activity of IL-1 and/or other proinflamma-tory cytokines.⁴ 

However, during the past few years, IL-33 has been recognized as a potential proinflammatory cytokine that may act on various effector cells of the immune system, including mast cells, eosinophils, and basophils.^8-10  In this issue of Blood, Pekaric-Petkovic and colleagues provide evidence that IL-33 exerts multiple profound effects of human basophils.¹¹  In particular, IL-33 promotes histamine release provoked by IgE-dependent stimuli as well as the secretion of IL-4, IL-8, and IL-13.¹¹  The activation pattern induced by IL-33 is similar to that provoked by IL-3, the most potent basophil activator.¹  However, the signaling pathways activated by IL-33 in basophils are different from those triggered by IL-3. Whereas IL-3 primarily leads to the activation of the JAK/STAT pathway and ERK in basophils, IL-33 primarily activates the NFkB pathway and the p38 MAP kinase. In line with this observation, IL-33 did not mimic all effects of IL-3 on basophils. Likewise, in contrast to IL-3, IL-33 did not prime human basophils for C5a-induced LTC4 generation.¹¹ 

Other studies have recently confirmed that IL-33 is a regulator of human basophils.^8,10  One interesting effect of IL-33 on basophils is induction of CD11b, suggesting that IL-33 may also regulate basophil adhesiveness to endothelial cells (which can produce IL-33) and thus can enhance basophil-transmigration from blood into tissues.¹⁰  In addition, IL-33 may trigger migratory responses of human basophils.¹⁰ 

An unexpected finding in the study by Pecaric-Petkovic and colleagues was that basophils apparently express only trace amounts of IL-33 receptor T1/ST2 on their surface.¹¹  In fact, in resting basophils, the receptor was only detectable by polymerase chain reaction, not by flow cytometry. Nevertheless, the effects of IL-33 on basophils could be blocked by an antibody against ST2, suggesting a functional interaction on resting basophils.¹¹  So far, little is known about the regulation of expression of the IL-33 receptor (ST2) on basophils or other immune cells. When exposed to IL-3, basophils were found to up-regulate and thus display considerable amounts of surface ST2 protein.¹¹  These data suggest that IL-3 can regulate IL-33 responsiveness of basophils, and thus confirm that IL-3 is a major basophil regulator.¹  In addition, this observation predicted cooperative effects of IL-3 and IL-33 on basophils. Indeed, IL-3 and IL-33 were found to cooperate with each other in promoting cytokine (IL-4) secretion in human basophils.¹⁰ 

Basophils also express receptors for IL-1 and IL-18. However, in contrast to IL-33, neither IL-1 nor IL-18 were reported to exert major proinflammatory effects on human basophils, which is of interest since mouse basophils are responsive to IL-18. On the other hand, it is well known that mouse basophils differ from human basophils in many aspects, and the same holds true for mouse and human mast cells.¹ 

Apart from basophils, eosinophils and mast cells also appear to be IL-33 targets. ^5-10  With regard to mast cells, IL-33 apparently also promotes adhesion as well as secretion of mediators and cytokines.^5,6  Similarly, it has been described that IL-33 triggers eosinophil activation, expression of CD11b, and adhesion.^7,9  An interesting aspect is that IL-33 activates p38 in human blood eosinophils in the same way as in basophils, whereas other blood leukocytes are not activated by IL-33. All in all, it seems as if IL-33 is a major regulator and activator of (the secretory function of) immune cells that play a role in acute inflammation. The same regulator may also trigger the rapid recruitment of these cells into tissue sites (of inflammation) through increased adhesiveness and migration-induction. In addition, it has been shown that IL-33 promotes the survival of eosinophils and mast cells in vitro. Whether IL-33 can also promote basophil survival and differentiation of these cells (basophils, eosinophils) from their multipotent uncommitted progenitor cells, as has been described for IL-3,¹  remains at present unknown.

In summary, IL-33 is an emerging regulator of certain immune cells involved in allergic and other immediate inflammatory reactions, and thus may be a key cytokine in the pathogenesis of diseases in which activation of basophils, mast cells, and eosinophils plays an essential role, such as allergic or chronic inflammatory diseases. These observations may also provide the basis for the development of new anti-inflammatory drugs that target the expression, release, or function of IL-33 or IL-33 receptors.