Genetics of Interleukin 1 Receptor-Like 1 in Immune down the linkage signal and investigate specific SNP asso- ciations. This may lead to the identification of novel path- ways in diabetes. In summary, the available data on the involvement of IL1RL1 and its ligand IL33 in immune and autoimmune disorders are reasonably consistent; a clearer understanding of the balance between IL1RL1 isoform A/IL33, IL1RL1 isoform B/IL33 and its regulation is needed in order to make that axis a more attractive target for therapeutic intervention. Cardiovascular Disease In vitro and animal model studies have demonstrated that IL33/IL1RL1 isoform A signaling protects cardiomyocytes from apoptosis by suppressing Caspase 3 activity and pro- moting the expression of anti-apoptotic proteins in vitro and improves survival in experimental myocardial infarction (MI) animals [72]. Human studies have shown an increase of soluble IL1RL1 after myocardial stress or injury, and MI [26, 73]; the levels correlated with diastolic load [74], car- diac abnormalities on electrocardiogram (ECG) and poor prognosis in dyspneic and MI patients [75-77]. In a study following 150 patients admitted to hospital with acutely de- stabilized heart failure, multiple serum samples were col- lected between admission and discharge and soluble IL1RL1 levels were measured. The results showed that IL1RL1 iso- form B levels were a powerful predictor of 90-day mortality. Indeed, IL1RL1 isoform B serum levels are considered a reliable biomarker for heart failure [78, 79] as delineated by a recent review by Moore et al. [80]. A more recent study demonstrated for the first time that IL1RL1 isoform B could be used to predict left ventricular and infarct recovery after acute MI [81]. The company Critical Diagnostics in collaboration with the Brigham and Women’s Hospital in Boston has developed a diagnosis kit called Presage that uses soluble IL1RL1 lev- els for diagnosis and prognosis of cardiovascular disease. However, this kit is not yet approved by the FDA for clinical use. Many U.S. and international patents protect the use of IL1RL1 for the diagnosis and prognosis in cardiovascular disease. The fact that increased level of IL1RL1 is correlated with poor prognosis in different instances of cardiovascular dis- ease points to a role of soluble IL1RL1 as marker for the severity of the immune response. Increased IL1RL1 isoform B is indicative of an overwhelming immune response that is hard to control and thus leads to unfavorable outcome in cardiovascular disease patients, such as after an MI. Infections IL1RL1 isoform B levels correlate with sepsis severity and outcome [82]. A possible mechanism was recently de- scribed by Alves-Filho et al. [83]. Using the cecal ligation and puncture model in Balb-c mice [83], a widely used model for experimental sepsis, this group demonstrated that IL33 treatment was protective from peritonitis and enhanced bacterial clearance. Their data also show that the protective effect of IL33 treatment was achieved via the inhibition of a TLR-signaling-induced protein, GRK2. GRK2 plays a prominent role in sepsis as it down-regulates CXCR2 (a re- Current Genomics, 2010, Vol. 11, No. 8 595 ceptor for IL8, a chemokine that attracts neutrophils to infec- tion sites) thus leading to inefficient clearance of bacteria. In agreement with the role of IL1RL1 proteins in the promotion of Th2 responses, mRNA levels of both receptor and soluble forms of the IL1RL1 transcript were shown to be up-regulated in an animal model of Toxoplasma gondii para- sitic infection and this up-regulation correlated with protec- tion from the infection [84]. In addition, ST2-/- knockout mice demonstrated increased susceptibility and more severe disease compared to wild type mice as assessed by weight loss, increased parasite transcript levels and typical disease pathology [84]. In 2008, a small study of a Somali popula- tion reported an association of a SNP in the 3’UTR of IL18R1 (rs3213733) with variability in Rubella vaccine- induced humoral immunity [85]. It is interesting that the same SNP was recently shown to be associated with asthma in two different studies, in Mexican and Japanese popula- tions [47, 86]. As LD patterns differ between populations, this suggests a potential functional role of this SNP in regu- lating gene expression/function. Additional evidence for a role of the IL33/IL1RL1 axis in host defense comes from an animal study showing the pro- tective role of IL33 in intestinal infection with nematodes [87]. In summary, IL1RL1 confers protection from infection, which is consistent with its involvement in the Th2 immune response. The increase in IL1RL1 signaling skews T cells to Th2 and prevents a parasite-specific Th1 polarized response. Liver and Kidney Disorders In a candidate gene association study of the course of Hepatitis C in a Japanese population, 103 genes including IL1RL1 and IL18R1 were investigated [88]. SNPs in both these genes as well as other genes involved in immune re- sponses were significantly associated with serum levels of alanine aminotransferase (ALT). ALT levels are routinely used as a diagnostic test of liver function and elevated levels are an indicator of infections and other disorders. Neverthe- less, this group’s data were not corrected for multiple testing and need to be replicated in other populations. An over-expression of IL1RL1 and IL33 mRNA in fi- brotic liver was reported using mouse and human tissue sec- tions [89]. CONCLUDING REMARKS The IL1RL1 gene and its resulting soluble and receptor proteins have emerged as key regulators of the inflammatory process implicated in a large variety of human pathologies (see summary Table 1). IL1RL1 is important for both innate and adaptive immu- nity as IL1RL1 isoform A binding with its ligand IL33 leads to polarization of T helper cells into Th2 and also activates and promotes the degranulation of mast cells. The resulting inflammation is down-regulated by the soluble form of IL1RL1; levels of the latter are recognized as biomarkers for the severity of various conditions. Except for the functional analysis of the IL1RL1 SNP rs6543116 associated with asthma and atopic dermatitis [36, 53], there has been no functional analysis of the disease-associated variants in