title: Thromboxane receptor signaling is required for fibronectin-induced matrix metalloproteinase 9 production by human and murine macrophages and is attenuated by the Arhgef1 molecule.
abstract: During an inflammatory response, resident and newly recruited tissue macrophages adhere to extracellular matrix and cell-bound integrin ligands. This interaction induces the expression of pro-inflammatory mediators that include matrix metalloproteinases (MMPs). Arhgef1 is an intracellular signaling molecule expressed by myeloid cells that normally attenuates murine macrophage MMP production in vivo and in vitro after cell culture on the extracellular matrix protein, fibronectin. In this study, we have extended the characterization of this fibronectin-induced Arhgef1-regulated signaling pathway in both human and murine myeloid cells. Our results show that MMP9 production by fibronectin-stimulated monocytes and macrophages depends on autocrine thromboxane receptor signaling and that under normal conditions, this signaling pathway is attenuated by Arhgef1. Finally, we show that the expression of ARHGEF1 by human peripheral blood monocytes varies between individuals and inversely correlates with fibronectin-mediated MMP9 production.
authors.affiliation: Integrated Department of Immunology, National Jewish Health and University of Colorado School of Medicine, Denver, Colorado 80206, USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Hartney
authors.forename: Claire E
authors.initials: CE
authors.lastname: Gustafson
authors.forename: Russell P
authors.initials: RP
authors.lastname: Bowler
authors.forename: Roberta
authors.initials: R
authors.lastname: Pelanda
authors.forename: Raul M
authors.initials: RM
authors.lastname: Torres
mesh_terms: D000818:Animals; D019898:Autocrine Communication / Q000502:physiology; D004790:Enzyme Induction / Q000502:physiology; D005353:Fibronectins / Q000378:metabolism*; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D006801:Humans; D016676:Macrophages, Alveolar / Q000166:cytology / Q000378:metabolism*; D017737:Macrophages, Peritoneal / Q000166:cytology / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis*; D051379:Mice; D017482:Receptors, Thromboxane / Q000378:metabolism*; D064067:Rho Guanine Nucleotide Exchange Factors; D015398:Signal Transduction / Q000502:physiology*
chemical_list: C577231:Arhgef1 protein, mouse; D005353:Fibronectins; D020662:Guanine Nucleotide Exchange Factors; D017482:Receptors, Thromboxane; D064067:Rho Guanine Nucleotide Exchange Factors; D020780:Matrix Metalloproteinase 9
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