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.
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Authors | Z Melis Altan, Deborah Denis, David Kagan, Eric M Grund, Stephen S Palmer, Selvaraj G Nataraja |
Journal | The Journal of pharmacology and experimental therapeutics
(J Pharmacol Exp Ther)
Vol. 334
Issue 2
Pg. 460-6
(Aug 2010)
ISSN: 1521-0103 [Electronic] United States |
PMID | 20435921
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Chorionic Gonadotropin, beta Subunit, Human
- Cytokines
- Glycoprotein Hormones, alpha Subunit
- Receptors, Tumor Necrosis Factor, Type I
- Recombinant Fusion Proteins
- Tumor Necrosis Factor-alpha
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Topics |
- Animals
- Cell Line
- Chorionic Gonadotropin, beta Subunit, Human
(genetics)
- Cytokines
(biosynthesis)
- Cytotoxicity, Immunologic
- Endometriosis
(drug therapy, immunology, pathology)
- Endometrium
(drug effects, metabolism, pathology)
- Female
- Glycoprotein Hormones, alpha Subunit
(genetics)
- Humans
- Killer Cells, Natural
(drug effects, immunology)
- Mice
- Mice, Inbred C57BL
- Receptors, Tumor Necrosis Factor, Type I
(genetics)
- Recombinant Fusion Proteins
(genetics, pharmacology, therapeutic use)
- Tumor Necrosis Factor-alpha
(antagonists & inhibitors, pharmacology)
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