title: IL-6 trans-signaling is another pathway to upregulate Osteopontin.
abstract: Osteopontin (OPN) is a pro-fibrotic molecule upregulated by pro-inflammatory cytokines. Interleukin (IL)-6 functions downstream of IL-1β and has unique signal pathways: classic- or trans-signaling via membrane-bound IL-6R or soluble IL-6R (sIL-6R). We investigated the effect of IL-6 trans-signaling on the upregulation of OPN.
  
  
  
  We used THP-1 cells and THP-1 macrophages differentiated from THP-1 cells using phorbol 12-myristate 13-acetate (PMA). After IL-1β stimulation, expression of OPN, IL-6, sIL-6R, and a disintegrin and metalloproteinase 17 (ADAM17) was examined by ELISA and quantitative PCR. The effects of anti-human IL-6 neutralizing antibody, soluble gp130 (sgp130, IL-6 trans-signaling-specific inhibitor), TAPI-1 (ADAM inhibitor) and siRNA against IL-6R or ADAM17 on OPN expression were evaluated.
  
  
  
  IL-1β increased OPN and induced IL-6 in THP-1 macrophages. Anti-IL-6 neutralizing antibody and siRNA against IL-6R inhibited OPN upregulation induced by IL-1β. TAPI-1 significantly inhibited the increase in sIL-6R induced by IL-1β. Treatment with sgp130 attenuated OPN elevation by IL-1β, whereas sgp130 did not change OPN levels in THP-1 macrophages without IL-1β stimulation. ADAM17 was expressed in THP-1 macrophages and THP-1 cells and IL-1β stimulation significantly increased ADAM17 expression, regardless of PMA treatment. TAPI-1 and siRNA against ADAM17 significantly inhibited OPN increased by IL-1β.
  
  
  
  IL-6 and sIL-6R induced by IL-1β may trigger IL-6 trans-signaling, contributing to the upregulation of OPN in THP-1 macrophages. Macrophages may be used as a source of IL-6 and sIL-6R and evoke IL-6 trans-signaling.
authors.affiliation: Department of Laboratory Medicine, Shinshu University Hospital, Matsumoto, Japan.
authors.forename: Takaaki
authors.initials: T
authors.lastname: Uchibori
authors.affiliation: Department of Laboratory Medicine, Shinshu University Hospital, Matsumoto, Japan. Electronic address: kmatsuda@shinshu-u.ac.jp.
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Matsuda
authors.affiliation: Department of Laboratory Medicine, Shinshu University Hospital, Matsumoto, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Shimodaira
authors.affiliation: Department of Laboratory Medicine, Shinshu University Hospital, Matsumoto, Japan.
authors.forename: Mitsutoshi
authors.initials: M
authors.lastname: Sugano
authors.affiliation: Department of Laboratory Medicine, Shinshu University Hospital, Matsumoto, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Uehara
authors.affiliation: Department of Laboratory Medicine, Shinshu University Hospital, Matsumoto, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Honda
mesh_terms: D000072198:ADAM17 Protein / Q000037:antagonists & inhibitors / Q000276:immunology; D006801:Humans; D053583:Interleukin-1beta / Q000276:immunology; D015850:Interleukin-6 / Q000276:immunology*; D008264:Macrophages / Q000276:immunology*; D053495:Osteopontin / Q000276:immunology*; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D000074084:THP-1 Cells; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology*
chemical_list: C508585:IL1B protein, human; C508600:IL6 protein, human; D053583:Interleukin-1beta; D015850:Interleukin-6; C506895:SPP1 protein, human; D053495:Osteopontin; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human
keywords: ADAM17; Fibrosis; IL-1β; IL-6 trans-signaling; Osteopontin