Helicobacter pylori outer membrane vesicles induce expression and secretion of oncostatin M in AGS gastric cancer cells.

Helicobacter pylori, a human pathogen that colonizes the stomach of 50% of the world's population, is associated with gastritis, gastric adenocarcinoma, and mucosa-associated lymphoid tissue (MALT) lymphoma. Diseases are characterized by severe inflammatory responses in the stomach that are induced by various chemokines and cytokines. Recently, oncostatin M (OSM), an IL-6 family cytokine, was detected in early gastric cancer biopsies. In this study, we showed that Helicobacter pylori induced secretion of OSM and overexpression of its type II receptor OSMRß (OSM/OSMRß) in a human gastric adenocarcinoma cell line (AGS) over 24 h of infection. Furthermore, we showed that the induction of OSM and OSMRß was carried out by heat-sensitive Helicobacter pylori outer membrane vesicle (OMV) protein. Collectively, our results established, for the first time, a direct relation between Helicobacter pylori OMVs and the OSM/OSMRß signaling axis.

Increased levels of the soluble oncostatin M receptor (sOSMR) and glycoprotein 130 (sgp130) in systemic sclerosis patients and associations with clinical parameters.

OBJECTIVE: The objective of the present study was to evaluate the serum levels of soluble oncostatin M (OSM), OSM receptor (sOSMR) and glycoprotein130 (sgp130) in patients with systemic sclerosis (SSc), and the possible associations and correlations with clinical parameters. METHODS: Serum levels of OSM, sOSMR and sgp130 were evaluated by ELISA in eighty-four SSc patients and eighty-four healthy volunteers. RESULTS: SSc patients had significantly elevated levels of sOSMR and sgp130 when compared with healthy individuals (p < 0.0001 and p = 0.025, respectively). Diffuse cutaneous SSc and limited cutaneous SSc patients also presented higher levels of sOSMR when compared with healthy individuals (p = 0.003 and p = 0.0001, respectively). Patients with digital ulcers presented higher levels of sOSMR when compared to those without ulcers (p = 0.034). However, sOSMR levels were lower in patients with esophageal dysfunction than patients without this involvement (p = 0.038). OSM levels were undetectable in serum from SSc patients and healthy volunteers. CONCLUSION: Serum levels of sOSMR and sgp130 are elevated in patients with systemic sclerosis. In addition, associations were observed with important clinical manifestations, suggesting that sOSMR is a candidate biomarker of this disease. More studies are needed to clarify the functions of IL-6 family cytokines in systemic sclerosis.

Novel IL31RA gene mutation and ancestral OSMR mutant allele in familial primary cutaneous amyloidosis.

Primary cutaneous amyloidosis (PCA) is an itchy skin disorder associated with amyloid deposits in the superficial dermis. The disease is relatively common in Southeast Asia and South America. Autosomal dominant PCA has been mapped earlier to 5p13.1-q11.2 and two pathogenic missense mutations in the OSMR gene, which encodes the interleukin-6 family cytokine receptor oncostatin M receptor beta (OSMRbeta), were reported. Here, we investigated 29 Taiwanese pedigrees with PCA and found that 10 had heterozygous missense mutations in OSMR: p.D647V (one family), p.P694L (six families), and p.K697T (three families). The mutation p.P694L was associated with the same haplotype in five of six families and also detected in two sporadic cases of PCA. Of the other 19 pedigrees that lacked OSMR pathology, 8 mapped to the same locus on chromosome 5, which also contains the genes for 3 other interleukin-6 family cytokine receptors, including interleukin-31 receptor A (IL31RA), which can form a heterodimeric receptor with OSMRbeta through interleukin-31 signaling. In one family, we identified a point mutation in the IL31RA gene, c.1562C>T that results in a missense mutation, p.S521F, which is also sited within a fibronectin type III-like repeat domain as observed in the OSMR mutations. PCA is a genetically heterogeneous disorder but our study shows that it can be caused by mutations in two biologically associated cytokine receptor genes located on chromosome 5. The identification of OSMR and IL31RA gene pathology provides an explanation of the high prevalence of PCA in Taiwan as well as new insight into disease pathophysiology.

Oncostatin M receptor-beta mutations underlie familial primary localized cutaneous amyloidosis.

Familial primary localized cutaneous amyloidosis (FPLCA) is an autosomal-dominant disorder associated with chronic skin itching and deposition of epidermal keratin filament-associated amyloid material in the dermis. FPLCA has been mapped to 5p13.1-q11.2, and by candidate gene analysis, we identified missense mutations in the OSMR gene, encoding oncostatin M-specific receptor beta (OSMRbeta), in three families. OSMRbeta is a component of the oncostatin M (OSM) type II receptor and the interleukin (IL)-31 receptor, and cultured FPLCA keratinocytes showed reduced activation of Jak/STAT, MAPK, and PI3K/Akt pathways after OSM or IL-31 cytokine stimulation. The pathogenic amino acid substitutions are located within the extracellular fibronectin type III-like (FNIII) domains, regions critical for receptor dimerization and function. OSM and IL-31 signaling have been implicated in keratinocyte cell proliferation, differentiation, apoptosis, and inflammation, but our OSMR data in individuals with FPLCA represent the first human germline mutations in this cytokine receptor complex and provide new insight into mechanisms of skin itching.