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BACKGROUND: The vast majority of patients with high-grade gliomas (HGG) over-express interleukin 4 (IL4)-independent binding sites for IL13 in situ. In addition, mutated IL13-based cytotoxins directed specifically toward glioma-associated sites are arguably the most active anti-glioma agents. Two IL13 receptor (R) proteins were identified: (1) IL13R alpha', a component of the signaling, heterodimeric high-affinity receptor for IL13 that is shared with IL4, and (2) IL13R alpha, a monomeric, IL4-independent receptor. MATERIALS AND METHODS: We analyzed gene expression of IL13R alpha, IL13R alpha' and that of IL4Rbeta, which is the other subunit of the shared IL13/4 receptor. The study was conducted with 40 human normal adult tissues, 20 discrete regions of the central nervous system (CNS), 7 fetal tissues, several cultured cell lines, and surgical CNS specimens. RESULTS: The most striking feature of the IL13R alpha gene expression was the virtual lack of its transcripts within the CNS. Furthermore, only the testes exhibited a prominent presence of the mRNA for IL13R alpha among peripheral organs. In contrast, the components of the shared IL13/4 receptor were readily detected both in the CNS and in vital organs, such as liver, heart, lungs, and gastrointestinal tract. CONCLUSIONS: The results strongly support a need to redirect IL13 towards its more restrictive, IL4-independent, receptor for glioma diagnosis and therapies. Moreover, the gene for IL13R alpha resides on chromosome X. Since IL13R alpha is (1) a cancer-associated protein, (2) virtually restricted to testes among normal tissues, and (3) its gene is on chromosome X, IL13R alpha is unexpectedly categorized as a cancer/testis antigen. Our findings make IL13R alpha even more attractive as a target for variety of approaches in glioma molecular management.