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Regulation of plasminogen activator inhibitor mRNA levels in lipopolysaccharide-stimulated human monocytes. Correlation with production of the protein. 1992

B S Schwartz, and J D Bradshaw
Department of Medicine, University of Wisconsin, Madison 53706.

Peripheral blood monocytes are essential participants in processes that require pericellular plasminogen activation, a regulated proteolytic pathway that is greatly influenced by the relative concentrations of urokinase-type plasminogen activator (profibrinolytic) and plasminogen activator inhibitor type 2 (PAI-2) (anti-fibrinolytic). Monocyte synthesis of these molecules is inducible by bacterial lipopolysaccharide (LPS) although PAI-2 production is regulated over a much wider concentration range than is urokinase-type PA. The PAI-2 response of LPS-stimulated monocytes was investigated and found to be biphasic, with a peak of mRNA at 4-6 h after stimulation, a decrement in mRNA levels at 8-10 h, and a secondary increase at 16 h. The primary (early phase) response was studied in detail wherein PAI-2 protein production was found to depend on the levels of PAI-2 mRNA. The profiles of steady-state PAI-2 mRNA levels and PAI-2 protein production were parallel with respect to LPS concentration, time of exposure to LPS, and persistence of the response. PAI-2 mRNA accumulation was inducible by cycloheximide but prevented by actinomycin D. The increase in steady-state PAI-2 mRNA was mediated both by an increase in gene transcription and by stabilization of the mRNA once formed. Therefore, the initial phase of PAI-2 production by LPS-stimulated monocytes is determined by the amount of PAI-2 mRNA in these cells; levels of PAI-2 mRNA are controlled by several mechanisms, allowing for rapid variations in production of this molecule.

UI MeSH Term Description Entries
D008070 Lipopolysaccharides Lipid-containing polysaccharides which are endotoxins and important group-specific antigens. They are often derived from the cell wall of gram-negative bacteria and induce immunoglobulin secretion. The lipopolysaccharide molecule consists of three parts: LIPID A, core polysaccharide, and O-specific chains (O ANTIGENS). When derived from Escherichia coli, lipopolysaccharides serve as polyclonal B-cell mitogens commonly used in laboratory immunology. (From Dorland, 28th ed) Lipopolysaccharide,Lipoglycans
D009000 Monocytes Large, phagocytic mononuclear leukocytes produced in the vertebrate BONE MARROW and released into the BLOOD; contain a large, oval or somewhat indented nucleus surrounded by voluminous cytoplasm and numerous organelles. Monocyte
D003513 Cycloheximide Antibiotic substance isolated from streptomycin-producing strains of Streptomyces griseus. It acts by inhibiting elongation during protein synthesis. Actidione,Cicloheximide
D003609 Dactinomycin A compound composed of a two CYCLIC PEPTIDES attached to a phenoxazine that is derived from STREPTOMYCES parvullus. It binds to DNA and inhibits RNA synthesis (transcription), with chain elongation more sensitive than initiation, termination, or release. As a result of impaired mRNA production, protein synthesis also declines after dactinomycin therapy. (From AMA Drug Evaluations Annual, 1993, p2015) Actinomycin,Actinomycin D,Meractinomycin,Cosmegen,Cosmegen Lyovac,Lyovac-Cosmegen,Lyovac Cosmegen,Lyovac, Cosmegen,LyovacCosmegen
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D012333 RNA, Messenger RNA sequences that serve as templates for protein synthesis. Bacterial mRNAs are generally primary transcripts in that they do not require post-transcriptional processing. Eukaryotic mRNA is synthesized in the nucleus and must be exported to the cytoplasm for translation. Most eukaryotic mRNAs have a sequence of polyadenylic acid at the 3' end, referred to as the poly(A) tail. The function of this tail is not known for certain, but it may play a role in the export of mature mRNA from the nucleus as well as in helping stabilize some mRNA molecules by retarding their degradation in the cytoplasm. Messenger RNA,Messenger RNA, Polyadenylated,Poly(A) Tail,Poly(A)+ RNA,Poly(A)+ mRNA,RNA, Messenger, Polyadenylated,RNA, Polyadenylated,mRNA,mRNA, Non-Polyadenylated,mRNA, Polyadenylated,Non-Polyadenylated mRNA,Poly(A) RNA,Polyadenylated mRNA,Non Polyadenylated mRNA,Polyadenylated Messenger RNA,Polyadenylated RNA,RNA, Polyadenylated Messenger,mRNA, Non Polyadenylated
D014158 Transcription, Genetic The biosynthesis of RNA carried out on a template of DNA. The biosynthesis of DNA from an RNA template is called REVERSE TRANSCRIPTION. Genetic Transcription
D015152 Blotting, Northern Detection of RNA that has been electrophoretically separated and immobilized by blotting on nitrocellulose or other type of paper or nylon membrane followed by hybridization with labeled NUCLEIC ACID PROBES. Northern Blotting,Blot, Northern,Northern Blot,Blots, Northern,Blottings, Northern,Northern Blots,Northern Blottings
D015849 Plasminogen Inactivators Important modulators of the activity of plasminogen activators. The inhibitors belong to the serpin family of proteins and inhibit both the tissue-type and urokinase-type plasminogen activators. Plasminogen Activator Inhibitor,Plasminogen Activator Inhibitors,Endothelial Plasminogen Activator Inhibitors,Placental Plasminogen Activator Inhibitors,Plasminogen Activator Inhibitors, Endothelial,Plasminogen Activator Inhibitors, Placental,Activator Inhibitor, Plasminogen,Inactivators, Plasminogen,Inhibitor, Plasminogen Activator,Inhibitors, Plasminogen Activator

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