INTERLEUKIN-10 STABILIZES INHIBITORY kB-α IN HUMAN MONOCYTES

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Abstract
Interleukin-10 (IL-10) protects animals from lethal endotoxemia. This beneficial effect is mediated, in part, by inhibition of inflammatory cytokine production, including tumor necrosis factor-α (TNF-α). Evidence suggests that IL-10 may inhibit activation of the transcription factor nuclear factor-kB (NF-kB) through an unknown mechanism. NF-kB activation in response to inflammatory signals is dependent upon degradation of its associated inhibitory peptide, inhibitory kB-α (IkB-α). We hypothesized that IL-10 prevents human monocyte NF-kB activation and resultant TNF-α production by stabilization of IkB-α. The purpose of this study was to determine the effect of IL-10 on lipopolysaccharide (LPS)-induced human monocyte TNF-α production, NF-kB activation, and IkB-α degradation. Monocytes were isolated from human donors. Cells were stimulated with endotoxin (LPS, 100 ng/mL) with and without human IL-10 (10 ng/mL). Following stimulation, TNF-α was measured in cell supernatants by ELISA, NF-kB activity by electrophoretic mobility shift assay, and IkB-α levels by Western blot. We observed that after LPS stimulation of human monocytes, TNF-α increased to 798 ± 67 pg/mL (p < .001 versus control). IL-10 attenuated LPS-stimulated TNF-α production (297 ± 54;p <.001 versus LPS alone). After LPS stimulation in human monocytes, IkB-α protein levels decreased, and NF-kB DNA binding increased. IL-10 pretreatment prevented LPS-induced decreases in IkB-α protein levels and attenuated NF-kB DNA binding. IL-10 appears to prevent activation of NF-kB by preserving IkB-α protein levels, leading to a reduction in TNF-α release.

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