title: A receptor fusion protein for the inhibition of murine oncostatin M.
abstract: BACKGROUND
  Most cytokines signal through heteromeric receptor complexes consisting of two or more different receptor subunits. Fusion proteins of the extracellular parts of receptor subunits turned out to be promising cytokine inhibitors useful in anti-cytokine therapy and cytokine research.
  
  
  RESULTS
  We constructed receptor fusion proteins (RFP) consisting of the ligand binding domains of the murine oncostatin M (mOSM) receptor subunits mOSMR and mgp130 connected by a flexible linker as potential mOSM inhibitors. mgp130 is a shared cytokine receptor that is also used by other cytokines such as IL-6 and leukemia inhibitory factor (LIF). In this study we compare four types of mOSM-RFPs that contain either domains D1-D3 or domains D2-D3 of mgp130 and are arranged in two ways. Domain D1 of mgp130 turned out to be dispensable for mOSM-binding. However, the arrangement of the two receptor subunits is essential for the inhibitory activity. We found mOSM induced STAT3 phosphorylation to be suppressed only when the mOSMR fragment was fused in front of the mgp130 fragment.
  
  
  CONCLUSIONS
  mOSM-RFP consisting of D1-D4 of mOSMR and D2-D3 of mgp130 is a highly potent and specific inhibitor of mOSM. Since mOSM-RFP is encoded by a single gene it offers numerous possibilities for specific cytokine inhibition in gene delivery approaches based on viral vectors, transgenic animals and finally gene therapy.
authors.affiliation: Institute of Biochemistry and Molecular Biology, Medical School, RWTH Aachen University, Aachen, Germany.
authors.forename: Liv
authors.initials: L
authors.lastname: Brolund
authors.forename: Andrea
authors.initials: A
authors.lastname: Küster
authors.forename: Sabrina
authors.initials: S
authors.lastname: Korr
authors.forename: Michael
authors.initials: M
authors.lastname: Vogt
authors.forename: Gerhard
authors.initials: G
authors.lastname: Müller-Newen
mesh_terms: D000818:Animals; D000906:Antibodies / Q000378:metabolism; D015153:Blotting, Western; D003001:Cloning, Molecular; D005786:Gene Expression Regulation / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D053683:Oncostatin M / Q000037:antagonists & inhibitors*; D053681:Oncostatin M Receptor beta Subunit / Q000737:chemistry / Q000378:metabolism*; D017434:Protein Structure, Tertiary / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D019947:Receptors, Interleukin-6 / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D000906:Antibodies; D053681:Oncostatin M Receptor beta Subunit; C508349:Osmr protein, mouse; D012333:RNA, Messenger; D019947:Receptors, Interleukin-6; D011993:Recombinant Fusion Proteins; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D053683:Oncostatin M