Expression of IL-17B in neurons and evaluation of its possible role in the chromosome 5q-linked form of Charcot–Marie–Tooth disease Emma E. Moore a, * , Scott Presnell a , Ursula Garrigues a , Angele Guilbot b , Eric LeGuern b , Deborah Smith a , Lena Yao a , Theodore E. Whitmore a , Teresa Gilbert a , Theo D. Palmer c , Philip J. Horner d , Rolf E. Kuestner a a ZymoGenetics Inc, 1201 Eastlake Avenue East, Seattle, WA 98102, USA b Department of Neurology, Stanford University Medical Center, Stanford, CA 94305-5327, USA c Laboratory of Genetics, The Salk Institute, La Jolla, CA 92037, USA d INSERM U289, Federation de Neurologie, Ho ˆpital de la Salpe ˆtrie `re, Paris, France Received 16 January 2001; received in revised form 6 June 2001; accepted 19 June 2001 Abstract IL-17B is a recently identified homolog of IL-17. Northern analysis revealed that IL-17B mRNA is expressed at very high levels in spinal cord and at much lower and more variable levels in trachea, prostate, lung, small intestine, testes, adrenal, and pancreas. In developing mouse embryos IL-17B expression was first detected at day 11 and appeared to peak at day 15. In situ analysis of mouse spinal cord, dorsal root ganglia, and brain demonstrated that IL-17B mRNA is primarily expressed by the neurons. Immunohistochemical analysis of human spinal cord, dorsal root ganglia, cerebral cortex, cerebellum, and hippocampus demonstrated that IL-17B protein is primarily localized to the neuronal cell bodies and axons. Radiation hybrid mapping localized the IL-17B gene to a region on human chromosome 5q that is associated with a rare autosomal recessive form of Charcot–Marie–Tooth demyelinating disease. However, no changes were found in the coding regions, splice junctions, intron 1, or the 5 0 and 3 0 untranslated regions of IL-17B genes of patients affected with this disease. q 2002 Elsevier Science B.V. All rights reserved. Keywords: IL-17B; Charcot–Marie–Tooth disease; Neurons; Myelin 1. Introduction IL-17 is a cytokine that was originally identified due to its high homology (57%) to a viral protein encoded by the herpesvirus Saimiri gene 13 (HVS13) [1,2]. The expression of IL-17 appears to be restricted to activated memory CD4 1 T cells while its receptor is ubiquitously expressed and shows no homology to any known family of receptors [3,4]. Consistent with its expression in activated T cells, IL-17 displays a variety of proinflammatory and immune modulatory activities. For example, treatment of macro- phages, fibroblasts, or endothelial cells with IL-17 results in the elevation of NF-kB activity and increased expression of IL-6, IL-8, PGE2, and G-CSF [5–7]. The following observations suggest that IL-17 plays a central role in the pathogenesis of rheumatoid arthritis: (a) IL-17 levels are significantly elevated in synovial fluid from patients with rheumatoid arthritis, but not those with osteoarthritis [8,9], (b) IL-17 enhances the IL-1-induced production of IL-6 by synoviocytes [10], and (c) IL-17 induces the production of nitric oxide, IL-1b, IL-6, and stromolysin by articular chon- drocytes [11,12]. There is also mounting evidence that IL- 17 contributes to allograft rejection. This includes (a) the observation that IL-17 stimulates the functional differentia- tion of dendritic cell progenitors to mature antigen present- ing cells which can activate T cells [13] and (b) the finding that treatment with a soluble IL-17 receptor significantly prolongs the survival time following both vascularized and non-vascularized cardiac allografts [14]. Hence, antago- nists to IL-17 may be of therapeutic value in numerous pathological conditions. IL-17B, IL-17C, and IL-17E are three recently identified homologs of IL-17 that have been reported to show 26–28% amino acid identity to each other and to IL-17 [15–17]. In contrast to IL-17, these IL-17 homologs are not expressed in activated CD4 1 T cells, however, there is evidence that they may play a role in inflammatory and immune responses [15]. Fc fusion proteins of both IL-17B and IL-17C stimu- Neuromuscular Disorders 12 (2002) 141–150 0960-8966/02/$ - see front matter q 2002 Elsevier Science B.V. All rights reserved. PII: S0960-8966(01)00250-4 www.elsevier.com/locate/nmd * Corresponding author. Tel.: 11-206-442-6737; fax: 11-206-442-6608. E-mail address: mooreb@zgi.com (E.E. Moore).