Interleukin‐18 in asthma and other allergies

The prevalence of atopic diseases such as bronchial asthma has increased over the last decades, making allergies a very serious public health problem. Allergic predisposition is regarded as a multifactorial condition whose onset and severity are influenced by both genetic and environmental factors [1]. The search for genes that contribute to the aetiology of allergic asthma has included several complete screens of the human genome and a number of association and linkage studies. One of the regions most consistently linked to asthma and/or its intermediary phenotypes, such as high total serum IgE levels and eosinophilia, is a region on chromosome 11q, which contains many loci that, on the basis of their functions, are candidate asthma-susceptibility genes [2, 3]. The study by Higa et al. [4] in this issue of Clinical and Experimental Allergy is a further example of such association and extends our present knowledge by investigating IL-18 gene polymorphisms in atopic asthma. Our understanding of the immunological processes leading to allergic asthma has improved greatly in recent years. The paradigm of antagonism between T helper (Th) lymphocyte subset and their cytokines, first described in the early 1990s [5], has resulted in the widely accepted hypothesis that atopy and asthma are ‘Th2 diseases’. In its simplest terms this hypothesis argues that a relative increase in Th2 responses in combination with a decrease in Th2 responses drives the allergic phenotype [6]. IL-18 belongs among those several factors, which are known to influence the balance of Th1/Th2 immune response. Interleukin-18, a member of the IL-1 family, was originally described as IFN-γ-inducing factor (IGIF) and it is generally considered a Th1-type response [7]. IL-18, in collaboration with IL-12, strongly induces type I cytokines such as INF-γ leading to the production of molecules destructive to tissues, including nitric oxide, reactive oxygen species and TNF-α. Interestingly, IL-18 is also capable of generating a Th2 cell response under certain conditions, as measured by the production of Th2 cytokines and initiation of allergic manifestation [8]. However, recent reports indicate that IL-18 can directly stimulate IL-4 production and histamine release from basophiles [9], enhance IL-4 and IL-13 production from both NK and T cells in synergy with IL-2 [10, 11], and induce IgE expression by B cells [12]. In addition, IL-18 has also been shown to indirectly induce B cell isotype switching to IgE and, together with its effects on Th2 cytokine production, has been demonstrated to play a role in allergic inflammation [13]. However, these reports demonstrated a pleiotropic role for IL-18 in Th1 and Th2 responses dependent on the cytokine milieu [14]. The possible functions of IL-18 at different levels of the allergic mechanisms were mainly analysed by in vitro and mice studies. Wild et al. [13] found that the intranasal application of IL-18 together with ragweed increased the production of ragweed-specific IgE and IgG1 in serum and production of BAL eosinophilia in a mouse model of allergic asthma, effects consistent with the support of a Th2 phenotype. Furthermore, intrapulmonary administration of IL-18 in mice was associated with increased eotaxin levels and eosinophilic recruitment in the airways [15]. Thus, IL-18 seems to drive the allergic inflammation by its ability to stimulate eosinophilia and IgE production in mice models. The IL-18-induced IgE accumulation in vivo was completely dependent on the IL-4/IL-4R system but not on IL-13 [12, 13]. IL-18 is synthesized as an inactive precursor (pro-IL-18), a 24-kDa polypeptide, and like IL-1β it is cleaved by the IL-1β-converting enzyme (ICE, also known as cysteine proteinase caspase-1) in a biologically active 18-kDa monomer [16]. A recent report suggests proteinase 3 as a possible alternative enzyme necessary for IL-18 processing [17]. Pro-IL-18 expression is widespread, including monocyte/macrophages, dendritic cells, Kupffer cells, keratinocytes, Langerhans cells, B cells and airway epithelial cells. IL-18 acts through the membrane receptors IL-18Rα and IL-184Rβ to transduce the signal into the nucleus. The genes for IL-18 and its receptor map to different chromosomes. The human IL-18 gene is located on chromosome 11q22.2-22.3 [18], and it is composed of six exons and five introns spanning about 19.5 kb. Several studies have demonstrated that increased IL-18 expression and serum levels are associated with allergic diseases. Tanaka et al. [19] recently described that serum IL-18 levels were elevated in patients with acute asthma and that these levels quickly decreased after treatment. Also Wong et al. [20] demonstrated increased IL-18 levels in patients with allergic asthma. Furthermore, Yoshizawa et al. [21] reported that significantly higher serum IL-18 levels were found in patients with atopic dermatitis than in control subjects, and that serum IL-18 levels were correlated with disease severity and with the number of eosinophils in peripheral blood. However, a recent report has demonstrated significantly higher concentrations of IL-18 in nasal secretion of persistent allergic rhinitis patients compared to healthy controls, with a slow increase during the course of the pollen season [22]. In addition, Tanaka et al. [23] indicated that NC/Nga mice that were used in a mouse model of AD produced much higher amounts of IL-18 than control mice, likewise as dermatitis patients compared to healthy volunteers. In contrast to previous findings, Ho et al. [24] described significantly lower in situ IL-18 levels in BAL fluid from patients with asthma. Further, Cameron et al. [25] found that hybridization expression or IL-18 in airway epithelium of patients with asthma not receiving corticosteroids was decreased compared with healthy controls. Intriguingly, Habu et al [26] indicated that NC/Nga mice that were used in a mouse model of AD produced much lower amounts of IL-18 after in vivo LPS stimulation than BALB mice. It is in accordance with findings by Higashi et al. [27], who noted that monocytes from atopic dermatitis patients produced lower IL-18 levels. Their findings are in contrast with another study where IL-18 secretion from mononuclear cells of patients with bronchial asthma and atopic dermatitis was significantly higher than that in non-allergic controls [28]. Although the production of IL-18 is affected by many factors, individual differences could also be caused by genetic polymorphisms. It is tempting to speculate that polymorphisms in the IL-18 gene could affect the balance between Th1 and Th2 cytokine responses. This could mediate higher susceptibility to allergic asthma in individuals carrying alleles with higher activity and vice versa in individuals with lower activity alleles. Previously, the human IL-18 promoter region was cloned and screened for possible polymorphisms. Three single-nucleotide polymorphisms were detected in the promoter, and two polymorphisms in the 5′-non-translated regions of the IL-18 gene and one of the promoter variants had a lower activity than the others after stimulation with PMA/ionomycin [29]. In accordance with this, in the current issue of Clinical and Experimental Allergy, Higa et al. [4] examined whether or not polymorphisms occurred in the coding region of the IL-18 gene and, if so, whether there was a relation between polymorphism and asthma. They detected one new polymorphism in the coding region of the IL-18 gene linked with substitution A to C at position 105, but this polymorphism was silent. This group compared 497 patients with asthma (221 children and 276 adult asthmatics) with a control group (N=85 adults), and the increase of the frequency of the A allele was found to be associated with increased susceptibility to disease. There was also an increase of IL-18 levels in patients with allergic asthma compared with the control group, but no significant relation was detected between the IL-18 levels and genotypes of 105A/C polymorphism. Our understanding of disease pathogenesis is dependent on our current understanding of pathophysiology and on the available technology. Recent advances in molecular biology techniques have allowed a rapid and accurate identification of polymorphisms in various genes that may be important for determining the susceptibility to allergic disorders. The strengths of the present study are the plausibility of the hypothesis. The well-established roles of IL-18 in inflammation are consistent with the biology of allergic asthma. The increased plasma concentrations of IL-18 in asthmatic patients are also in accordance with the majority of results of the previous studies showing elevated circulating levels of IL-18 cytokine in patients with allergic diseases [19–23]. Relatively small control groups and the unclear functional importance of the IL-18 silent polymorphism are the disadvantages of this study. The results of the subgroup analysis involving a small fraction of the total population in this study must be interpreted cautiously. If a variant shows a frequency difference between cases and controls, there are two possible explanations. First, it may be a real effect. That is, the variant is either a risk factor or in linkage disequilibrium with a risk factor. The second possibility, however, is that the results could be due to population stratification. If the cases and controls are drawn from subpopulations that have differences in disease incidence, then any marker showing an allele frequency difference between subpopulations will show an allele frequency difference between the patients and the controls. In order to exclude this possibility, authors studied the allele frequency of an additional locus (β2-adrenergic receptor (ADR)-16-Arg/Gly polymorphism); its allele frequency from patients with asthma was similar to that from controls. At present, the available data do not point towards a contribution of IL-18 A allele to susceptibility to allergic asthma. At best, an IL-18 gene variant may be assigned as a possible marker for disease susceptibility in this population. Although the data from Japanese population clearly call for confirmation in other ethnic groups as well as in prospective studies, Higa's study represents an important first step in this new exciting approach to understanding a role of the IL-18 gene in allergic diseases. The identification of susceptibility or causative genes is a crucial step for the development of diagnosis, treatment and prevention of disease.