title: IFN-alpha beta reconstitutes the deficiency in lipid A-activated AKR macrophages for nitric oxide synthase.
abstract: AKR mouse peritoneal macrophages (PM) were previously found to have a defect in their response to lipid A for nitric oxide (NO)-mediated tumor cytotoxicity, which was related to a lower level of C1q synthesis and reconstituted by exogenous IFN-gamma or C1q. We used AKR-PM as a model to further define the role of IFN-alpha beta in modulation of induction of macrophage nitric oxide synthase (NOS) in response to lipid A. Studies have revealed that AKR-PM produced a significantly lower level of IFN-alpha beta than responsive C3H-PM in response to lipid A. AKR-PM failed to increase NOS mRNA synthesis and NO generation when exposed to lipid A, although they had normal levels of TNF-alpha bioactivity and mRNA expression. This partial deficiency of AKR-PM to lipid A stimulation was reconstituted completely by exogenous IFN-alpha beta for both synthesis of NOS mRNA and release of NO. The failure of AKR-PM to produce NOS to lipid A stimulation appears to be related to reduced secretion of IFN-alpha beta and the resultant failure to express TNF-alpha type II receptor (TNF-RII) mRNA, which in turn decreases TNF-alpha binding to its receptor for autocrine induction of NOS. Insufficient synthesis and secretion of endogenous IFN-alpha beta may be the primary reason for AKR-PM refractoriness to induction of NOS in response to lipid A. furthermore, the close correlation between lack of IFN-alpha beta secretion and decreased TNF-RII mRNA synthesis may implicate a critical role for IFN-alpha beta in the upregulation of macrophage TNF-RII receptor expression for autocrine induction of NOS during lipid A stimulation.
authors.affiliation: Oklahoma Medical Research Foundation, Noble Center for Biomedical Research, Oklahoma City 73104, USA.
authors.forename: H
authors.initials: H
authors.lastname: Jiang
authors.forename: J A
authors.initials: JA
authors.lastname: Rummage
authors.forename: A
authors.initials: A
authors.lastname: Zhou
authors.forename: Z
authors.initials: Z
authors.lastname: Chen
authors.forename: M J
authors.initials: MJ
authors.lastname: Herriot
authors.forename: C A
authors.initials: CA
authors.lastname: Stewart
authors.forename: M
authors.initials: M
authors.lastname: Kolosov
authors.forename: R W
authors.initials: RW
authors.lastname: Leu
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001483:Base Sequence; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D005354:Fibrosarcoma; D016898:Interferon-alpha / Q000096:biosynthesis / Q000276:immunology / Q000494:pharmacology*; D016899:Interferon-beta / Q000096:biosynthesis / Q000276:immunology / Q000494:pharmacology*; D007939:Leukemia L1210; D008050:Lipid A / Q000494:pharmacology*; D008262:Macrophage Activation / Q000187:drug effects*; D017737:Macrophages, Peritoneal / Q000201:enzymology* / Q000276:immunology* / Q000378:metabolism; D008297:Male; D051379:Mice; D008806:Mice, Inbred AKR; D008809:Mice, Inbred C3H; D008969:Molecular Sequence Data; D009569:Nitric Oxide / Q000096:biosynthesis / Q000633:toxicity; D019001:Nitric Oxide Synthase / Q000096:biosynthesis / Q000172:deficiency*; D012333:RNA, Messenger / Q000096:biosynthesis; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics; D014407:Tumor Cells, Cultured
chemical_list: D000906:Antibodies; D016898:Interferon-alpha; D008050:Lipid A; D012333:RNA, Messenger; D018124:Receptors, Tumor Necrosis Factor; D009569:Nitric Oxide; D016899:Interferon-beta; D019001:Nitric Oxide Synthase