title: A long-acting tumor necrosis factor alpha-binding protein demonstrates activity in both in vitro and in vivo models of endometriosis.
abstract: Endometriosis is characterized by the presence of elevated proinflammatory cytokines such as tumor necrosis factor (TNF) alpha in the peritoneal cavity. Blocking interaction of TNFalpha with its receptor by the addition of excess TNFalpha-binding protein (TBP)-1 (a soluble form of TNF receptor-1) was effective in animal models of endometriosis. Recently, a novel, high-affinity inhibitor of TNFalpha, TNF-soluble high-affinity receptor complex (TNF-SHARC), was created by fusing TBP to both the alpha and beta subunits of inactive human chorionic gonadotropin. This dimeric protein was effective in inhibiting collagen-induced arthritis in mice. In the present study, the efficacy of TNF-SHARC in cellular and in vivo models of endometriosis was examined. TBP and TNF-SHARC dose-dependently inhibited TNFalpha-induced secretion of interleukin (IL)-6, IL-8, granulocyte macrophage-colony-stimulating factor, and monocyte chemoattractant protein-1 in immortalized human endometriotic cells. An in vivo mouse model of experimentally induced endometriosis using cycling C57BL/6 mice was established. Antide treatment (0.5 mg/kg), used as positive control, initiated 7 days after the establishment of the disease, reduced the weight of the lesions compared with control. TNF-SHARC at 3 mg/kg was not effective in inhibiting the disease, whereas at 9 mg/kg there was reduction in the lesion weight. In addition, antide and TNF-SHARC treatment in vivo increased in vitro natural killer cell activity compared with untreated animals. Thus, we provide evidence for supporting the development of TNF-SHARC as a therapeutic candidate for treating endometriosis in human.
authors.affiliation: Reproductive Health, EMD Serono Research Institute Inc, Rockland, Massachusetts 02370, USA.
authors.forename: Z Melis
authors.initials: ZM
authors.lastname: Altan
authors.forename: Deborah
authors.initials: D
authors.lastname: Denis
authors.forename: David
authors.initials: D
authors.lastname: Kagan
authors.forename: Eric M
authors.initials: EM
authors.lastname: Grund
authors.forename: Stephen S
authors.initials: SS
authors.lastname: Palmer
authors.forename: Selvaraj G
authors.initials: SG
authors.lastname: Nataraja
mesh_terms: D000818:Animals; D002460:Cell Line; D018997:Chorionic Gonadotropin, beta Subunit, Human / Q000235:genetics; D016207:Cytokines / Q000096:biosynthesis; D003602:Cytotoxicity, Immunologic; D004715:Endometriosis / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D004717:Endometrium / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005260:Female; D015292:Glycoprotein Hormones, alpha Subunit / Q000235:genetics; D006801:Humans; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000494:pharmacology / Q000627:therapeutic use*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000494:pharmacology
chemical_list: D018997:Chorionic Gonadotropin, beta Subunit, Human; D016207:Cytokines; D015292:Glycoprotein Hormones, alpha Subunit; D047888:Receptors, Tumor Necrosis Factor, Type I; D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha