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Atopic dermatitis (AD) is one of the most prevalent chronic inflammatory skin diseases in the world. It is characterized by recurrent eczematous lesions and intense itch, and many cytokines are involved in the pathogenesis of AD. Among them, much attention has been paid to interleukin 31 (IL-31) as an AD-associated itch mediator. IL-31 is mainly produced by CD4+ helper T cells and transmits the signals via a heterodimeric receptor composed of IL-31 receptor A (IL-31RA) and oncostatin M receptor (OSMR), both of which are expressed in dorsal root ganglion (DRG) neurons. However, the molecular mechanisms of how IL-31 is produced in helper T cells upon stimulation and transmits the itch sensation to the brain were largely unknown. Recently, by using original mouse models of AD, we have identified endothelial PAS domain 1 (EPAS1) and neurokinin B (NKB) as key molecules critical for IL-31 production and IL-31-mediated itch transmission, respectively. These molecules could be novel drug targets for AD-associated itch. This review highlights our recent findings, which show the functional significance of these molecules in the IL-31-induced itch sensation, referring to their application to drug development.

BACKGROUND Primary localized cutaneous amyloidosis (PLCA) is a chronic pruritic skin disorder. The genetic basis of familial (f)PLCA involves mutations in the oncostatin M receptor (OSMR) and interleukin-31 receptor A (IL31RA) genes, but the disease pathophysiology is not fully understood. AIM To investigate the OSMR mutation spectrum in patients with sporadic (s)PLCA/fPLCA, lichen/macular PLCA in mainland China. METHODS This study was carried out on 64 patients with sPLCA, along with 36 with fPLCA and 10 unaffected individuals collected from 23 unrelated Chinese families. Genomic DNA was extracted from peripheral blood samples. Mutation screening of 17 OSMR exons was performed by Sanger sequencing. RESULTS PLCA lesions are typically localized to the shins, forearm and back. Sequence analysis of OSMR exons demonstrated that the OSMR missense mutation rate in patients with fPLCA (63.89%) was significantly higher than that in patients with sPLCA (34.38%). The male/female ratio of patients carrying a homozygous OSMR mutation (0.29) was significantly lower than that of patients carrying a heterozygous OSMR mutation (1.08; P

The receptor gp130 is utilized by cytokines including interleukin 6, leukemia inhibitory factor, oncostatin M, cilary neurotrophic factor and cardiotrophin. It is essential for myocardial development and haematopoiesis during embryogenesis, and its role as a shared signal transducer among different cytokines explains their overlapping biological functions. Although gp130 contains a cytokine-binding homology region (CHR) analogous to the extracellular growth hormone receptor, the complexes that utilize gp130 are not simple dimerizations of receptors around a single cytokine but involve receptor interactions with additional sites on the ligand resulting in higher order complexes. Analysis by surface plasmon resonance of the binding of the immunoglobulin-like and CHR domains of the extracellular portion of gp130 to mutants of the cytokine oncostatin M reveal that the CHR forms the main binding site for oncostatin M by a classical site II interaction, but in addition a second interaction occurs involving the receptor's immunoglobulin-like domain and the cytokine's site III at the N-terminus of the D helix. The implications for complex formation are discussed.