title: Tissue inhibitor of matrix metalloproteinase-1 overexpression in M1 myeloblasts impairs IL-6-induced differentiation.
abstract: The balance between matrix metalloproteinase (MMP) and tissue inhibitor of matrix metalloproteinase (TIMP) is important for extracellular matrix interactions of hematopoietic cells. MMP-independent growth modulating activity for TIMP-1 on B lymphocytes and erythroid progenitors has also been described, but a role for TIMP-1 in myelomonocytic differentiation has not been previously reported. In this study, we demonstrate that TIMP-1 overexpression impairs differentiation of the myeloblastic M1 cell line following interleukin (IL)-6 stimulation. We generated retroviral vectors coexpressing human TIMP-1 and the green fluorescent protein (GFP) and stably transduced murine M1 myeloid cells. TIMP-1 expressing cells showed a large reduction in IL-6-induced macrophage differentiation in vitro that was reversible with a specific monoclonal antibody. The differentiation delay in M1/TIMP-1 cells was also specifically reversible by pharmacologic phosphatidylinositol-3 kinase (PI3-K) inhibition. Additionally, overexpression of a TIMP-1/GFP fusion protein also impaired M1 differentiation and this protein was localized to the cell surface, consistent with an autocrine receptor-mediated mechanism. Surprisingly, TIMP-1 transduced cells had a selective advantage for growth in IL-6, indicating that functional effects on growth and differentiation of M1 cells were primarily through an autocrine mechanism. Intrinsic TIMP-1 expression in myeloid leukemia cells might thus impact upon survival or differentiation.
authors.affiliation: Hematopoiesis Department, American Red Cross, Jerome H Holland Laboratory for the Biomedical Sciences, Rockville, MD 20855, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Haviernik
authors.forename: Carisa
authors.initials: C
authors.lastname: Lahoda
authors.forename: Heath L
authors.initials: HL
authors.lastname: Bradley
authors.forename: Teresa S
authors.initials: TS
authors.lastname: Hawley
authors.forename: Ali
authors.initials: A
authors.lastname: Ramezani
authors.forename: Robert G
authors.initials: RG
authors.lastname: Hawley
authors.forename: Maryalice
authors.initials: M
authors.lastname: Stetler-Stevenson
authors.forename: William G
authors.initials: WG
authors.lastname: Stetler-Stevenson
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Bunting
mesh_terms: D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism*; D002454:Cell Differentiation / Q000502:physiology*; D004789:Enzyme Activation; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D015850:Interleukin-6 / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D012190:Retroviridae / Q000235:genetics; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics*
chemical_list: D015850:Interleukin-6; D019715:Tissue Inhibitor of Metalloproteinase-1; D019869:Phosphatidylinositol 3-Kinases