Differential regulation of tumor necrosis factor-alpha in human alveolar macrophages and peripheral blood monocytes: a cellular and molecular analysis.
Human tumor necrosis factor-alpha (TNF), a mononuclear phagocyte (MO)-derived peptide, is increasingly being recognized for its pleomorphic immunologic effects. A number of studies have demonstrated that LPS can induce TNF synthesis, but data examining the production and regulation of TNF in human MO populations are lacking. In this study, we present data demonstrating that alveolar macrophages (AMO) and peripheral blood monocytes (PBM) obtained from 10 normal volunteers display a significant difference in both the production of TNF and their susceptibility to TNF regulation by prostaglandin E2 (PGE2) and dexamethasone (Dex). Adherent populations of PBM and AMO were incubated for 18 h in the presence of either LPS (10 micrograms/ml) alone, PGE2 for 1 h prior to LPS challenge, Dex for 1 h prior to LPS challenge, or control media alone. Cell-free supernatants were examined for TNF bioactivity and cellular TNF mRNA was assessed via in situ hybridization and Northern blot analysis. PGE2 and Dex treatment of PBM suppressed LPS-induced TNF production by 78% and 72%, respectively, while AMO-TNF production was suppressed by only 22% and 33%. The accumulation of TNF mRNA in PBM was reduced 63% by PGE2 and 45% by Dex, as assessed by laser densitometry. Similar studies demonstrated that TNF mRNA accumulation in AMO was reduced 12% and 13% by PGE2 and Dex, respectively. A 1,000-fold increase in PGE2 levels was necessary to induce 50% suppression of the maximal response to AMO as compared to PBM. These data support the notion that human MO derived from different compartments or stages of differentiation exhibit differential responsiveness to immunomodulators.
Strieter
R M
RM
Department of Internal Medicine, University of Michigan Medical School, Ann Arbor 48109-0360.
Remick
D G
DG
Lynch
J P
JP
Genord
M
M
Raiford
C
C
Spengler
R
R
Kunkel
S L
SL
D000328:Adult; D001483:Base Sequence; D015152:Blotting, Northern; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology; D015232:Dinoprostone / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007700:Kinetics; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008969:Molecular Sequence Data; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism*; D009693:Nucleic Acid Hybridization; D015345:Oligonucleotide Probes; D009928:Organ Specificity; D012313:RNA / Q000235:genetics / Q000302:isolation & purification; D012333:RNA, Messenger / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics* / Q000302:isolation & purification
D015345:Oligonucleotide Probes; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D012313:RNA; D003907:Dexamethasone; D015232:Dinoprostone