592 Current Genomics, 2010, Vol. 11, No. 8 Akhabir and Sandford Fig. (1). Linkage disequilibrium in IL1RL1 and surrounding genes on chromosome 2q12 (102280 kb to 102500 kb) in the CEU HapMap population. corresponds to the extra-cellular domain of IL1RL1 isoform A except for nine amino-acids in the C-terminal region. IL1RL1 isoform A is mainly expressed on cells of hema- topoietic provenance, mainly T cells [20]. It has been shown that binding of IL1RL1 isoform A with its ligand on the sur- face of basophils, eosinophils and mast cells promotes their activation [21], increased adhesion and survival [22] and degranulation [23], respectively. IL33/IL1RL1 isoform A has also been shown to play a role in activating macrophages [24, 25]. The short form, IL1RL1 isoform B, is expressed by vari- ous cells including epithelial cells, endothelial cells, fibro- blasts and smooth muscle cells. This expression is aug- mented upon stimulation with IL1 , IL1 , TNF , LPS and other factors inducing cell stress such as cardiac infarction and hypoxia [26]. The tissue distribution of IL1RL1 isoform B seems to be relatively ubiquitous, with the highest levels of the secreted form found in the lung followed by the heart and the brain [27]. Several studies show that the membrane-bound IL1RL1 protein acts as a specific marker for Th2 cells [20]. In vitro blockade of IL1RL1 signaling with recombinant IL1RL1 protein to compete with the endogenous receptor resulted in the abrogation of differentiation to and activation of Th2, but not Th1, effector cells [28]. Interestingly, IL1RL1 has been found to play a considerable role in a newly discovered im- mune type2 effector leukocytes, known as nuocytes [29]. An IL13-GFP mouse model was utilized to define these as cells not corresponding to a previously known leukocyte lineage that express ICOS, IL1RL1 and IL25R [29]. The nuocytes’ function included the innate immune response to helminth infection with Nippostrongylus brasiliensis by secretion of high levels of IL13 in response to IL25 and IL33. The ligand for IL1RL1 is a recently discovered member of the interleukin 1 family: IL33 [3]. The signaling of IL1RL1 isoform A binding to IL33 results in the activation of the Mitogen-Activated Protein kinases ERK1, ERK2 and p38 and the subsequent activation of NF B [3, 23]. IL1RL1 isoform B corresponds to the extra-cellular domain of iso- form A and in vitro studies have shown that it can also bind IL33 and act as a decoy receptor inhibiting the activation of NF B [30] and the subsequent inflammatory response. This was confirmed in an animal model where introduction of soluble IL1RL1 decreased pro-inflammatory cytokine (IL4, IL5 and IL13) production in a murine asthma model after treatment with IL33. It was shown that this protective effect of the soluble IL1RL1 seems to be IL10 dependent in an animal model of ischemia reperfusion injury [31].