Current Genomics, 2010, 11, 591-606 591 Genetics of Interleukin 1 Receptor-Like 1 in Immune and Inflammatory Diseases Loubna Akhabir and Andrew Sandford* Department of Medicine, University of British Columbia, UBC James Hogg Research Centre, Providence Heart + Lung Institute, Room 166, St. Paul's Hospital, 1081 Burrard Street, Vancouver, BC V6Z 1Y6, Canada Abstract: Interleukin 1 receptor-like 1 (IL1RL1) is gaining in recognition due to its involvement in immune/inflamma- tory disorders. Well-designed animal studies have shown its critical role in experimental allergic inflammation and human in vitro studies have consistently demonstrated its up-regulation in several conditions such as asthma and rheumatoid ar- thritis. The ligand for IL1RL1 is IL33 which emerged as playing an important role in initiating eosinophilic inflammation and activating other immune cells resulting in an allergic phenotype. An IL1RL1 single nucleotide polymorphism (SNP) was among the most significant results of a genome-wide scan inves- tigating eosinophil counts; in the same study, this SNP associated with asthma in 10 populations. The IL1RL1 gene resides in a region of high linkage disequilibrium containing interleukin 1 receptor genes as well as in- terleukin 18 receptor and accessory genes. This poses a challenge to researchers interested in deciphering genetic associa- tion signals in the region as all of the genes represent interesting candidates for asthma and allergic disease. The IL1RL1 gene and its resulting soluble and receptor proteins have emerged as key regulators of the inflammatory proc- ess implicated in a large variety of human pathologies We review the function and expression of the IL1RL1 gene. We also describe the role of IL1RL1 in asthma, allergy, cardiovascular disease, infections, liver disease and kidney disease. Received on: June 01, 2010 - Revised on: July 06, 2010 - Accepted on: August 23, 2010 Keywords: Asthma, genetics, IL1RL1, immunity, inflammation, respiratory, SNP. INTRODUCTION Interleukin 1 receptor-like 1 (IL1RL1), also called T1, ST2, DER4 and FIT-1, is a member of the interleukin 1 su- per-family [1] but does not bind interleukin 1 (IL1) [2]. IL1RL1 was an orphan receptor until the description of its ligand, interleukin-33 (IL33) in 2005 [3]. Since then, IL33 binding to IL1RL1 has been associated with a variety of dis- ease states and in particular to inflammatory processes as outlined in recent reviews [4, 5]. In the present review, we will focus mainly on the genetic associations of IL1RL1 with disease. IL1RL1 GENE AND PROTEINS The IL1RL1 gene is located in chromosome 2q12 and is composed of 11 exons [6]. A number of IL1 family members reside in the immediate vicinity of the IL1RL1 gene namely IL1R2, IL1R1, IL1RL2, IL18 receptor 1 (IL18R1) and IL18 receptor accessory protein (IL18RAP). The region spans about 300 kb and is in high linkage disequilibrium (LD) (Fig. 1). There is evidence for the involvement of the genes surrounding IL1RL1 in human and experimental disease, and therefore the causal locus responsible for genetic association signals from this region is difficult to determine. *Address correspondence to this author at the Department of Medicine, University of British Columbia, UBC James Hogg Research Centre, Providence Heart + Lung Institute, Room 166, St. Paul's Hospital, 1081 Burrard Street, Vancouver, B.C., V6Z 1Y6, Canada; Tel: (604) 806-9008; Fax: (604) 806-8351; E-mail: Andrew.Sandford@hli.ubc.ca The IL18R1 and IL18RAP genes code for the components of the heterodimeric IL18 receptor (the and chains, respectively). The cytokine IL18 is a modulator of innate and adaptive immune responses that acts by inducing T helper type 1 (Th1) cell differentiation and T and NK cell matura- tion or by activating IgE production and T helper type 2 (Th2) cell differentiation under specific cytokine milieus [10-12]. High levels of IL18 mRNA and protein were ob- served in lungs of smokers and COPD patients [13] and ex- pression of an alternatively-spliced variant of IL18R1 was associated with atopy [14]. IL18R1 expression was also higher in human primary keratinocytes derived from skin lesions of psoriasis and atopic dermatitis patients compared with healthy controls [15]. IL18 signaling has been impli- cated in host defense [16] and rheumatoid arthritis [17]. Ad- ditionally, genetic association data have implicated the IL18 receptor genes in asthmatic and allergic phenotypes [18, 19]. Expression of IL1RL1 The gene transcription is initiated at two separate pro- moters: a proximal promoter and a distal promoter. The al- ternative usage of these two promoters leads to differential 3’ processing of the mRNA isoforms [7, 8]. Three known isoforms are produced: isoform 1 which codes for IL1RL1 isoform A (aka ST2L), a long membrane-bound protein, iso- form 2 which codes for IL1RL1 isoform B (aka sST2), a short soluble protein and a third isoform which codes for IL1RL1 isoform C (aka vST2) [9], a variant membrane- anchored form of the protein. The soluble form of IL1RL1 1389-2029/10 $55.00+.00 ©2010 Bentham Science Publishers Ltd.