Transcriptional Control of Cytokine Release from Monocytes of the Newborn: Effects of Endogenous and Exogenous Interleukin-10 versus Dexamethasone

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Abstract
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-α (TNF-α), IL-1β and IL-8, over 18 h was significantly augmented by addition of an IL-10 monoclonal antibody. Exogenous IL-10 at 10–8M 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-ĸB (NF-ĸB) 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 10–8M had no effect on any transcription factor DNA binding, but exogenous IL-10 at 10–8M produced a 60% inhibition of AP-1 DNA binding and enhanced phosphorylation of nuclear STAT3 for 18 h. Conclusion: 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.

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