NF-kappa B modulates TNF-alpha production by alveolar macrophages in asymptomatic HIV-seropositive individuals
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Mathys, J. M.
Melanson, S. M.
Schiffer-Alberts, D. J.
Ioannidis, J. P.
Koziel, H.
Skolnik, P. R.
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peer-reviewed
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J Immunol
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Local TNF-alpha production in different organs may affect HIV replication and pathogenesis. Alveolar macrophages (AMs) obtained by bronchoalveolar lavage from asymptomatic HIV-seropositive and HIV-seronegative individuals did not spontaneously release TNF-alpha, but LPS stimulation of these cells significantly increased TNF-alpha production. We tested whether NF-kappa B affects TNF-alpha production by AMs using N-tosyl-<cmd SC>l<cmd /SC> -phenylalanine chloromethylketone (TPCK) or N-benzoyl-<cmd SC>l<cmd /SC> -tyrosine ethyl ester (BTEE), which inhibit the degradation of I kappa B, or tricyclodecan-9-yl-xanthogenate-potassium (D609), which inhibits phospholipase C. Alveolar macrophages were exposed to LPS alone and with the chemical protease inhibitors TPCK, BTEE, and D609. NF-kappa B DNA binding induced by LPS treatment of AMs was inhibited by TPCK, BTEE, and D609. These agents also inhibited TNF-alpha mRNA and TNF-alpha protein production. After 24 h, the levels of TNF-alpha mRNA reached equilibrium, as assessed by RT-PCR. The levels of NF-kappa B mRNA remained constant under all conditions. The levels of I kappa B-alpha mRNA were similar after 30, 60, and 180 min, but the I kappa B-beta mRNA concentration was initially low and increased over time under all conditions. I kappa B-alpha and I kappa B-beta protein production was not affected by the chemical protease inhibitors. Our data show that TNF-alpha production by LPS-stimulated AMs from asymptomatic HIV-seropositive and -seronegative individuals is regulated via the phospholipase C pathway and by NF-kappa B DNA binding activity without obvious changes in I kappa B-alpha or I kappa B-beta protein concentrations.
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Adult, Cell Adhesion/genetics/immunology, DNA-Binding Proteins/metabolism, Female, HIV Seropositivity/*immunology, Humans, *I-kappa B Proteins, Macrophages, Alveolar/*immunology/*metabolism, Male, Middle Aged, NF-kappa B/genetics/metabolism/*physiology, Polymerase Chain Reaction, Primed In Situ Labeling, Prospective Studies, RNA, Messenger/antagonists & inhibitors/biosynthesis, Serine Proteinase Inhibitors/pharmacology, Signal Transduction/drug effects/immunology, Tosylphenylalanyl Chloromethyl Ketone/pharmacology, Tumor Necrosis Factor-alpha/antagonists & inhibitors/*biosynthesis/genetics, Type C Phospholipases/antagonists & inhibitors, Tyrosine/analogs & derivatives/pharmacology
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http://www.ncbi.nlm.nih.gov/pubmed/10640779
http://www.jimmunol.org/content/164/3/1588.full.pdf
http://www.jimmunol.org/content/164/3/1588.full.pdf
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en
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Πανεπιστήμιο Ιωαννίνων. Σχολή Επιστημών Υγείας. Τμήμα Ιατρικής