title: Inhibitors of C1q biosynthesis suppress activation of murine macrophages for both antibody-independent and antibody-dependent tumor cytotoxicity.
abstract: The inhibitors of C1q biosynthesis and secretion, 3,4-dehydro-DL-proline (DHP) and 2,2'-dipyridyl, were previously shown to suppress murine macrophage FcR-dependent phagocytosis and cytolysis of IgG-opsonized RBC targets. Inasmuch as non-antibody macrophage activators also bind C1q to initiate C1 activation, we determined the effects of these same inhibitors of C1q biosynthesis on activation of macrophages for antibody-independent, nonspecific tumor cytotoxicity by lipid A and a variety of other non-antibody activators. Preexposure of mouse inflammatory peritoneal macrophages to either DHP (0.5 to 2.5 mM) or 2,2'-dipyridyl (0.1 to 0.3 mM) for 24 h produced a dose-related suppression of their response to activation by lipid A to mediate tumor cytotoxicity of L1210 mouse leukemia targets. Inhibition of C1q secretion by DHP-treated macrophages was confirmed both by a complement hemolytic assay and by autoradiographic analysis of [35S]methionine-labeled culture supernatants. DHP-treated macrophages were inhibited in their response to direct activation and triggering of IFN-gamma-primed macrophages by lipid A, Poly I:C, and cobra venom factor for tumor cytotoxicity. DHP inhibited macrophage activation for antibody-dependent cellular cytotoxicity of L1210 tumor targets mediated by antitumor target IgG. The addition of exogenous purified C1q (2 micrograms/ml) to macrophages after DHP treatment, reconstituted their response to activation for both antibody-independent and antibody-dependent tumor cytotoxicity. Our results indicate that C1q synthesis and secretion by effector macrophages is a prerequisite for the initiation of their activation by both immune complex and by non-antibody agents that also bind C1q. It now appears that macrophage-derived C1q may act as an auxiliary amplification signal for autocrine-like modulation of the initiation of macrophage activation by both the antibody-dependent and independent pathways.
authors.affiliation: Biomedical Division, Samuel Roberts Noble Foundation, Inc., Ardmore, OK 73402.
authors.forename: R W
authors.initials: RW
authors.lastname: Leu
authors.forename: A Q
authors.initials: AQ
authors.lastname: Zhou
authors.forename: B J
authors.initials: BJ
authors.lastname: Shannon
authors.forename: M J
authors.initials: MJ
authors.lastname: Herriott
mesh_terms: D015082:2,2'-Dipyridyl / Q000494:pharmacology*; D000818:Animals; D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects*; D015922:Complement C1q / Q000494:pharmacology / Q000502:physiology*; D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D066298:In Vitro Techniques; D007371:Interferon-gamma / Q000494:pharmacology; D008050:Lipid A / Q000494:pharmacology; D008262:Macrophage Activation / Q000187:drug effects*; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D009374:Neoplasms, Experimental / Q000276:immunology; D011392:Proline / Q000031:analogs & derivatives* / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology*; D012636:Secretory Rate / Q000187:drug effects
chemical_list: D008050:Lipid A; D011725:Pyridines; C002195:3,4-dehydroproline; D015082:2,2'-Dipyridyl; D015922:Complement C1q; D007371:Interferon-gamma; D011392:Proline