title: Phagocytosis mediated by Yersinia invasin induces collagenase-1 expression in rabbit synovial fibroblasts through a proinflammatory cascade.
abstract: We show that the interaction of the Yersinia surface protein, invasin, with rabbit synovial fibroblasts mediates bead phagocytosis and induces expression of interleukin 1alpha (IL-1alpha), tumor necrosis factor-alpha (TNF-alpha) and MMP-1/collagenase-1 (CL-1). Presentation of invasin as a ligand on the surface of 4.5 microm beads induced phagocytosis and increased CL-1 expression 20-fold after 24 hours. By contrast, presentation of invasin as a spreading substrate did not induce CL-1 expression. CL-1 induction following phagocytosis of invasin-coated beads was mediated by a mechanism dependent on high-affinity binding to beta1 integrins and the function of the small GTPase RhoA. Expression of a function-perturbing mutant, RhoAN19, abrogated bead-induced CL-1 expression. RhoA activation coupled bead phagocytosis with signal transduction because expression of constitutively active mutant RhoV14 was sufficient to trigger CL-1 expression. The signal-transduction cascade elicited by bead phagocytosis triggered NFkappaB activation, stimulating a proinflammatory cellular response with transient increases in TNF-alpha production that peaked at 2 hours and induction of IL-1alpha that was sustained for at least 10 hours. Inhibition of IL-1alpha function by blocking antibodies or IL-1 receptor antagonist showed that IL-1alpha is the autocrine intermediary for subsequent CL-1 induction.
authors.affiliation: Department of Anatomy, University of California, San Francisco, CA 94143-0452, USA.
authors.forename: E
authors.initials: E
authors.lastname: Werner
authors.forename: F
authors.initials: F
authors.lastname: Kheradmand
authors.forename: R R
authors.initials: RR
authors.lastname: Isberg
authors.forename: Z
authors.initials: Z
authors.lastname: Werb
mesh_terms: D018829:Adhesins, Bacterial; D000818:Animals; D001426:Bacterial Proteins / Q000737:chemistry / Q000378:metabolism*; D017364:Collagenases / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D019012:Integrin beta1 / Q000378:metabolism; D007375:Interleukin-1 / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D010587:Phagocytosis / Q000502:physiology*; D011817:Rabbits; D015398:Signal Transduction / Q000502:physiology; D013583:Synovial Membrane / Q000166:cytology / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015007:Yersinia / Q000737:chemistry; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: D018829:Adhesins, Bacterial; D001426:Bacterial Proteins; D019012:Integrin beta1; D007375:Interleukin-1; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; C053476:invasin, Yersinia; D017364:Collagenases; C417249:collagenase 1; D020742:rhoA GTP-Binding Protein