IL-33 amplifies both Th1- and Th2-type responses through its activity on human basophils, allergen-reactive Th2 cells, iNKT and NK Cells

Abstract

IL-33 is an IL-1 family member recently identified as the ligand for T1/ST2 (ST2), a member of the IL-1 receptor family. ST2 is stably expressed on mast cells and T(h)2 effector T cells and its function has been studied in the context of T(h)2-associated inflammation. Indeed, IL-33 induces T(h)2 cytokines from mast cells and polarized mouse T cells and leads to pulmonary and mucosal T(h)2 inflammation when administered in vivo. To better understand how this pathway modulates inflammatory responses, we examined the activity of IL-33 on a variety of human immune cells. Human blood-derived basophils expressed high levels of ST2 receptor and responded to IL-33 by producing several pro-inflammatory cytokines including IL-1 beta, IL-4, IL-5, IL-6, IL-8, IL-13 and granulocyte macrophage colony-stimulating factor. Next, utilizing a human T(h)2-polarized T cell culture system derived from allergic donor blood cells, we found that IL-33 was able to enhance antigen-dependent and -independent T cell responses, including IL-5, IL-13 and IFN-gamma production. IL-33 activity was also tested on V alpha 24-positive human invariant NKT (iNKT) cells. In the presence of alpha-galactosylceramide antigen presentation, IL-33 dose dependently enhanced iNKT production of several cytokines, including both IL-4 and IFN-gamma. IL-33 also directly induced IFN-gamma production from both iNKT and human NK cells via cooperation with IL-12. Taken together, these results indicate that in addition to its activity on human mast cells, IL-33 is capable of activating human basophils, polarized T cells, iNKT and NK cells. Moreover, the nature of the responses elicited by IL-33 suggests that this axis may amplify both T(h)1- and T(h)2-oriented immune responses.

IL‐33‐activated dendritic cells are critical for allergic airway inflammation

“…The cytokine expression pattern of T cells polarized by IL-33-activated DCs differs from classical Th2 cells by the absence of IL-4 production. An atypical Th2 subset upon IL-33 activation has been reported, which is independent of IL-4, GATA3 and TCR engagement [26,29].…”

“…IL-33 signals through a heterodimeric membrane receptor composed of ST2 and the IL-1R1 accessory protein and activates basophils [20,21], mast cells [22,23], eosinophils [24,25], NK and NKT cells [26], Th2 lymphocytes [5,27] and macrophages [14]. In accordance with its Th2 functions, administration of IL-33 into naive mice induces severe inflammation in the lung and digestive tract with elevated levels of IL-4, IL-5 and IL-13, splenomegaly and increased serum Ig [10].…”

“…The cytokine expression pattern of T cells polarized by IL-33-activated DCs differs from classical Th2 cells by the absence of IL-4 production. An atypical Th2 subset upon IL-33 activation has been reported, which is independent of IL-4, GATA3 and TCR engagement [26,29].The contribution of IL-33 on asthma symptoms by its direct action on mast cells, basophils, eosinophils and Th2 cells has been Figure 7. IL-33 enhances allergic airway inflammation induced by OVA-pulsed DCs.…”

IL-33 is expressed in human osteoblasts, but has no direct effect on bone remodeling

“…IL-33 appears to be predominantly expressed in vivo in endothelial and epithelial cells [20,21], but IL-33 expression may be induced by inflammatory signals in other cell types [11,22]. Cell targets of IL-33 include polarized Th2 cells [11,23,24], mast cells [15,25], basophils [24,26], and dendritic cells [27,28]. Besides these ST2-receptor mediated effects, IL-33 is able to translocate into the nucleus, where it may display transcriptional functions.…”

The enigmatic processing and secretion of interleukin-33

“…8,9 As a nuclear factor, the intracellular functions of IL-33 remain to be further clarified, although overexpression studies suggested a role as a transcriptional repressor. 10 As an extracellular cytokine, binding of IL-33 to the ST2 receptor activates nuclear factor-kB and mitogen-activated protein kinases, [3][4][5]11 and is involved in the polarization of T cells towards the Th2 cell phenotype 2,6,7,[11][12][13][14] and in activation of mast cells, [15][16][17][18][19][20] bosophils, 14,[20][21][22][23][24] eosinophils, [24][25][26] and natural killer cells. 14,27 IL-33 must be present extracellularly in order to play the crucial role in inflammatory, infectious and autoimmune diseases including anaphylactic shock, asthma, rheumatoid arthritis, atherosclerosis, systemic sclerosis and cardiovascular diseases.…”