title: Inhibitory Mechanism of the Outer Membrane Growth of Chronic Subdural Hematomas.
abstract: We previously demonstrated that the inflammatory cytokine interleukin-6 (IL-6) activates the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling pathway in fibroblasts within the outer membranes of chronic subdural hematomas (CSDHs), and the activation of this pathway may induce CSDH outer membrane growth. The inhibitory system for this signal transduction pathway is unknown. CSDH fluids were obtained from 10 patients during trepanation surgery as the case group, and cerebrospinal fluid (CSF) samples were obtained from seven patients suffering from subarachnoid hemorrhage (SAH) on Day 1 as the control group. The concentrations of IL-6, soluble IL-6 receptor (sIL-6R), and soluble gp130 (sgp130) in CSDH fluid and CSF were measured using enzyme immunoassay kits. The co-localization of IL-6 and sgp130 in CSDH fluid was examined by immunoprecipitation. The expression levels of STAT3, JAK2, suppressor of cytokine signaling 3 (SOCS3), and protein inhibitor of activated Stat3 (PIAS3) in the outer membranes of CSDHs were examined by immunostaining. Soluble IL-6R and sgp130 concentrations in CSDH fluid were significantly higher than those in CSF after SAH. Sgp130 and IL-6 were co-immunoprecipitated from CSDH fluid. Immunostaining revealed STAT3, JAK2, SOCS3, and PIAS3 expression in fibroblasts located in the outer membranes of CSDHs. Soluble gp130 binds to IL-6/sIL-6R and acts as an antagonist of the JAK/STAT signaling pathway. SOCS3 also binds to JAK and inhibits its signaling pathway. In addition, PIAS3 regulates STAT3 activation. These factors might down-regulate the IL-6/JAK/STAT signaling pathway in fibroblasts within CSDH outer membranes. Therefore, these molecules may be novel therapeutic targets for the inhibition of CSDH growth.
authors.affiliation: 1 Department of Neurological Surgery, Aichi Medical University Aichi , Japan .
authors.forename: Koji
authors.initials: K
authors.lastname: Osuka
authors.affiliation: 2 High Technology Research Center, Pharmacology, Showa Pharmaceutical University , Tokyo, Japan .
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Watanabe
authors.affiliation: 3 Department of Anatomy II, Fujita Health University School of Medicine , Aichi, Japan .
authors.forename: Nobuteru
authors.initials: N
authors.lastname: Usuda
authors.affiliation: 1 Department of Neurological Surgery, Aichi Medical University Aichi , Japan .
authors.forename: Masahiro
authors.initials: M
authors.lastname: Aoyama
authors.affiliation: 1 Department of Neurological Surgery, Aichi Medical University Aichi , Japan .
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Iwami
authors.affiliation: 1 Department of Neurological Surgery, Aichi Medical University Aichi , Japan .
authors.forename: Mikinobu
authors.initials: M
authors.lastname: Takeuchi
authors.affiliation: 1 Department of Neurological Surgery, Aichi Medical University Aichi , Japan .
authors.forename: Takeya
authors.initials: T
authors.lastname: Watabe
authors.affiliation: 1 Department of Neurological Surgery, Aichi Medical University Aichi , Japan .
authors.forename: Masakazu
authors.initials: M
authors.lastname: Takayasu
mesh_terms: D000368:Aged; D050822:Cytokine Receptor gp130 / Q000378:metabolism*; D005260:Female; D020200:Hematoma, Subdural, Chronic / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D053612:Janus Kinases / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D019947:Receptors, Interleukin-6 / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism
chemical_list: D015850:Interleukin-6; D019947:Receptors, Interleukin-6; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D050822:Cytokine Receptor gp130; D053612:Janus Kinases
keywords: PIAS3; SOCS3; chronic subdural hematoma; soluble IL-6 receptor; soluble gp130