Transcriptional control of cytokine release from monocytes of the newborn: effects of endogenous and exogenous interleukin-10 versus dexamethasone.
BACKGROUND
Monocytes play an important role in the fetal and neonatal inflammatory response syndrome. They are also the precursors of alveolar macrophages, microglial and Kupffer cells. Monocytes have pro-inflammatory (PI) and anti-inflammatory (AI) functions. Interleukin (IL)-10 is a potent AI cytokine released by monocytes.


OBJECTIVE
We determined the effects of endogenous and exogenous IL-10 versus equimolar levels of dexamethasone (DEX) on PI and AI cytokine release, as well as transcription factor DNA-binding activity, in endotoxin (lipopolysaccharide, LPS)-stimulated monocytes of the newborn.


METHODS
Monocytes were isolated into culture media from cord blood. ELISAs, electrophoretic mobility shift assays and Western blots were employed.


RESULTS
LPS-stimulated monocyte release of PI cytokines, tumor necrosis factor-alpha (TNF-alpha), IL-1beta and IL-8, over 18 h was significantly augmented by addition of an IL-10 monoclonal antibody. Exogenous IL-10 at 10(-8)M inhibited PI cytokine release by 89-97%, while DEX at an equimolar level had no effect. DNA-binding activities of the PI transcription factors nuclear factor-kappaB (NF-kappaB) and activator protein-1 (AP-1), and the AI transcription factor signal transducer and activator of transcription 3 (STAT3) were induced over 18 h. DEX at 10(-8)M had no effect on any transcription factor DNA binding, but exogenous IL-10 at 10(-8)M produced a 60% inhibition of AP-1 DNA binding and enhanced phosphorylation of nuclear STAT3 for 18 h.


CONCLUSIONS
At therapeutic levels of DEX, monocyte release of PI cytokine was insensitive to DEX in comparison to IL-10. IL-10 or its mechanism of action could lead to new therapy for inflammatory disorders in the perinatal period.
Chusid
Lina A
LA
Division of Neonatal-Perinatal Medicine, Schneider Children's Hospital, New Hyde Park, NY 11040, USA.
Pereira-Argenziano
Lucy
L
Miskolci
Veronika
V
Vancurova
Ivana
I
Davidson
Dennis
D
D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015153:Blotting, Western; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D024202:Electrophoretic Mobility Shift Assay; D004797:Enzyme-Linked Immunosorbent Assay; D005312:Fetal Blood / Q000166:cytology; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D007231:Infant, Newborn; D016753:Interleukin-10 / Q000276:immunology / Q000378:metabolism* / Q000494:pharmacology*; D053583:Interleukin-1beta / Q000378:metabolism; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D016676:Macrophages, Alveolar / Q000166:cytology; D009000:Monocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000911:Antibodies, Monoclonal; D005938:Glucocorticoids; C508609:IL10 protein, human; D053583:Interleukin-1beta; D016209:Interleukin-8; D008070:Lipopolysaccharides; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D003907:Dexamethasone