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NF-B Modulates TNF- Production by Alveolar Macrophages in Asymptomatic HIV-Seropositive Individuals¹

Jean-Marie Mathys^*, Suzanne M. Melanson^*, Deborah J. Schiffer-Alberts^*, John P. A. Ioannidis, Henry Koziel and Paul R. Skolnik^2,*

^* Department of Medicine, Division of Geographic Medicine and Infectious Diseases, Tupper Research Institute, Tufts University-New England Medical Center, Boston, MA 02111; HIV Research Branch, Division of AIDS, National Institutes of Health, Bethesda, MD 20892; and Division of Pulmonary and Critical Care Medicine, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215

Local TNF- 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-, but LPS stimulation of these cells significantly increased TNF- production. We tested whether NF-B affects TNF- production by AMs using N-tosyl-L-phenylalanine chloromethylketone (TPCK) or N-benzoyl-L-tyrosine ethyl ester (BTEE), which inhibit the degradation of IB, 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-B DNA binding induced by LPS treatment of AMs was inhibited by TPCK, BTEE, and D609. These agents also inhibited TNF- mRNA and TNF- protein production. After 24 h, the levels of TNF- mRNA reached equilibrium, as assessed by RT-PCR. The levels of NF-B mRNA remained constant under all conditions. The levels of IB- mRNA were similar after 30, 60, and 180 min, but the IB-ß mRNA concentration was initially low and increased over time under all conditions. IB- and IB-ß protein production was not affected by the chemical protease inhibitors. Our data show that TNF- production by LPS-stimulated AMs from asymptomatic HIV-seropositive and -seronegative individuals is regulated via the phospholipase C pathway and by NF-B DNA binding activity without obvious changes in IB- or IB-ß protein concentrations.

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