IL-33 was first described in 2005 and, along with IL-1 and IL-18, belongs to the IL-1 cytokine family [2]. IL-33, similar to its other family members IL-1 and IL-18, has been shown to promote Th2 cytokine responses [2, 80, 118-121]. Members of the IL-1 family are expressed as prodomains and only become functionally mature proteins following proteolytic processing by caspase-1. Consistent with other IL-1 family members, Schmitz et al. [2] demonstrated that in vitro incubation of IL-33 with caspase-1 yielded an 18 kDa mature protein from a 30 kDa precursor. IL-33, like other members of the IL-1 family, shares the IL-1/FGF β-trefoil fold structural motif consisting of 12 β-strands forming a single domain [122, 123]. Interestingly, IL-33 has also been ascribed transcriptional repressor properties based on nuclear localization to heterochromatin and using a yeast two-hybrid system, it was shown that IL-33 repressed transcription in a manner consistent with IL-33 associating with heterochromatin [124]. Despite this work, the functional significance of IL-33 nuclear localization and the role this phenomenon plays in the context of immunity or inflammation is not fully understood.
IL-33 is produced by ECs and has been implicated in the promotion of Th2 cytokine associated responses, although IL-33 has also been shown to inhibit proinflammatory cytokine responses. IL-33 treatment was found to reduce atherosclerotic plaque size, the number of infiltrating macrophages and T cells and production of IFN-γ [125]. In
addition, IL-33 signaling has also been reported to regulate T. gondii-mediated
inflammation [126] and has been linked to inflammatory bowel disease (IBD) [127] and lupus [128]. The link between IL-33 and Th2 cytokine production was formed from in vivo studies, in which administration of IL-33 to mice resulted in increased expression of IL-4, -5, and -13, elevated serum levels of IgE and IgA and additional hallmarks for type 2 inflammation including increased goblet cell hyperplasia, mucus secretion and eosinophilia [2].
While data suggest that IL-33 promotes Th2 responses in vivo, in the systems tested, IL- 33 does not appear to be strictly required for the initiation of Th2 cytokine-mediated
responses in vitro [129] or in vivo [130]. IL-33 expression is induced following infection
with Trichuris [80], and administration of recombinant IL-33 early during infection
conferred resistance to normally susceptible Trichuris-infected AKR mice [80], similar to the effects observed following early treatment with IL-25 [81], however, Hoshino et al. found no effect on the outcome of infection in mice deficient in IL-33 signaling [131].
Moreover, IL-33 treatment was insufficient to mediate expulsion of Trichuris in the
absence of adaptive immunity highlighting the necessity of CD4+ T cells for resistance. Interestingly, IL-33 treatment increased the expression of TSLP and TSLPR mRNA in the colons of Trichuris-infected mice [80] demonstrating a potential association between two cytokines known to drive Th2 cytokine responses.
Increased expression of the IL-33 receptor (T1/ST2) has been reported in the serum of patients with asthma [132] and in mouse models of airway inflammation [133]. Further, two studies have demonstrated that neutralization of T1/ST2 resulted in the decreased levels of IL-4 and IL-5 in the bronchio-alveolar lavage fluid (BAL) and a reduction in eosinophil infiltration in an airway inflammation model [134, 135]. However, another report found no relationship between T1/ST2 expression and increased airway inflammation [131]. In support of the association between IL-33 and airway inflammation there was a recent report indicating that IL-33 induced airway hyperresponsiveness (AHR) associated with increased airway resistance and Th2 cytokine expression in the lungs [136].
Along with promoting protective Th2 cytokine responses, IL-33 can also have a pathologic role in vivo. Consistent with its ability to promote IL-13 production, IL-33 was found to be expressed in fibrotic liver tissue and promote collagen deposition [137], however, IL-33 was also expressed in the synovial joints of arthritis patients [138]. Moreover, blockade of T1/ST2 signaling attenuated inflammation observed in a mouse model of collagen-induced arthritis [138], highlighting a role for the IL-33 signaling pathway inflammatory diseases.
1.4.1 Cellular sources and regulation of IL-33 expression
Expression of IL-33 mRNA has been reported in tissues such as the CNS, lymph nodes, lung, skin, and colon, and in dendritic cells, macrophages, lung ECs and adipocytes [2, 41, 139], however, both helminth and influenza infections have been reported to increase production of IL-33 [80, 139]. Infection with Trichuris increased IL-33 mRNA with peak expression reported at day 3 post-infection compared to naïve controls [80]
(Fig. 1B). This infection-induced increase in IL-33 appears to be transient and temporal, suggesting a regulatory pathway to dampen its production following induction of immune responses. In addition, the H3N1-strain of influenza was also reported to increase IL-33 production from alveolar macrophages. Interestingly, while lung ECs were reported to produce IL-33 under homeostatic conditions, their production levels of IL-33 remained unchanged following flu infection [139].
1.4.2 Cellular targets and IL-33-T1/ST2 signaling
IL-33 signals through T1/ST2, a receptor closely related to IL-1R1 and IL-18Rα [140- 142], but it does not bind IL-1 or IL-18. This receptor family is characterized by the presence of an intracellular Toll-IL-1R (TIR) domain [143, 144], and requires two components for effective signaling: a ligand binding chain and a second subunit, which mediates the downstream signaling events but does not physically interact with the ligand itself (reviewed in [145]) (Fig. 2B). Both a membrane form and soluble form of T1/ST2 exist in vivo [146, 147], however, the function of the soluble form of T1/ST2 is unclear. One potential role is to function as a decoy receptor, thus regulating constitutive IL-33 signaling in vivo (Fig. 2B). In its membrane form, T1/ST2 is present on Th2 polarized cells and mast cells independently of IL-4 [134, 148, 149]. IL-33 was
found to associate with T1/ST2 [2], and receptor ligation resulted in activation of NF-κB
[2]. IL-1R accessory protein (IL-1RAcP) was subsequently identified as the second component of the functional IL-33R complex, as treatment with IL-33 did not induce a Th2 cytokine response in the absence of IL-1RAcP [150]. Therefore, the IL-33 signaling receptor complex is comprised of T1/ST2 and IL-1RAcP (Fig. 2B). Furthermore, MyD88 and TRAF6, as well as IL-1R associated kinase 4 (IRAK4), form a complex with IL-33
and T1/ST2 to mediate further downstream signaling events. IL-33 stimulation has also
been demonstrated to result in the phosphorylation of ERK1/2, p38, and IκBα (Fig. 2B).
T1/ST2 is expressed by Th2 cells and mast cells. Incubation of Th2 cells with IL-33
increased production of IL-5 and IL-13 and reduced production of IFN-γ [2]. Additionally,
mature mast cells and their precursors express T1/ST2 and treatment of human mast
cells or CD34+ mast cell progenitors [108] with IL-33, but not IL-18, resulted in increased
survival and cytokine production even in the absence of stem cell factor (SCF) [149].
Furthermore, Ho et al. demonstrated that murine mast cells responded to IL-33 in a
MyD88-dependent manner [151]. Similar increases in cytokine production observed in basophils following treatment with IL-33 were also shown to require MyD88 [136, 152]. These studies suggest that MyD88 plays an important role in IL-33-mediated cytokine production in innate cell populations. Interestingly, inclusion of TSLP into IL-33- containing cultures could enhance cytokine production from mast cells [108], supporting
a synergistic relationship between IL-33 and TSLP. Recent reports have also
demonstrated that IL-33 stimulation can promote macrophages to adopt an alternative
activation phenotype, characterized by expression of the mannose receptor and IL-4Rα
[153] and demonstrated effects of IL-33 on basophils [12, 136, 154], eosinophils [155] and recently identified innate cell populations (discussed in Chapter 1.7), termed natural helper cells, nuocytes and innate type 2 helper cells [13-15].
Collectively, these findings illustrate the ability of TSLP and IL-33 to promote Th2 cytokine responses and type 2 inflammation in vivo by targeting multiple cell populations, however, more recent data suggests that TSLP and IL-33 elicit distinct innate cell populations to influence Th2 cell differentiation. Moreover, the cellular mechanisms
used by TSLP and IL-33 to promote Th2 cytokine responses represent viable targets for therapeutics aimed at modulating Th2 cytokine-mediated inflammation associated with asthma, allergic disorders and helminth infections.