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Interleukin-10 does not mediate the inhibitory effect of PDE-4 inhibitors and other cAMP-elevating drugs on lipopolysaccharide-induced tumors necrosis factor-α generation from human peripheral blood monocytes

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Abstract

Lipopolysaccharide (LPS)-induced liver injury in mice and LPS-induced tumor necrosis factor-α (TNF-α) generation by murine macrophages and hepatocytes are suppressed markedly by agents that elevate intracellular cAMP. Phosphodiesterase (PDE)-4 inhibitors, β2-adrenoceptor agonists, and E-series prostaglandins also attenuate the induction of the TNF-α gene in human monocytes in response to bacterial LPS. The mechanism of action of cAMP is unclear, but in the mouse, is believed to involve the generation of the anti-inflammatory cytokine, interleukin-10 (IL-10). In this article, we describe the results of studies designed to determine the extent to which IL-10 contributes to the suppression of TNF-α generation from LPS-stimulated human monocytes evoked by 8-bromo cyclic AMP (8-Br-cAMP), rolipram, salbutamol, and prostaglandin E2 (PGE2). LPS evoked a time- and concentration-dependent generation of TNF-α (t1/2=4.5 h; EC50=273 pg/mL), which was inhibited by exogenous human recombinant (h) IL-10 (IC50=124 pg/mL), and by rolipram (EC50=420 nM), 8-Br-cAMP (EC50=77 (μM), PGE2 (EC50=15 nM) and salbutamol (EC50 = 20 nM). In addition, 8-Br-cAMP, PGE2, and salbutamol (but not rolipram) augmented significantly LPS-induced IL-10 production (two-to fivefold) under identical experimental conditions. Pretreatment of monocytes with an anti-IL-10 monoclonal antibody (MAb) that abolished the inhibitory action of a maximally effective concentration of exogenous hrIL-10, failed to attenuate the inhibitory effect of rolipram, PGE2, salbutamol, and 8-Br-cAMP. Anti-IL-10 was similarly inactive when the number of monocytes seeded was increased from 0.5 to 4 × 106/mL or when measurements were made at 42 h post-LPS, a time when the concentration of IL-10 released was maximal. Collectively, these data suggest that in contrast to murine hepatocytes and macrophages, IL-10 does not mediate the inhibitory effect of cAMP-elevating drugs on TNF-α generation from human monocytes. Although the reason for this discrepancy is unclear, we suggest that the influence of cAMP on the transcriptional regulation of the TNF-α gene differs between species or when monocytes have differentiated into macrophages.

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Authors and Affiliations

  1. Thoracic Medicine, Imperial College School of Medicine at the National Heart and Lung Institute, SW3 6LY, London

    Paul M. Seldon, Peter J. Barnes & Mark A. Giembycz

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Seldon, P.M., Barnes, P.J. & Giembycz, M.A. Interleukin-10 does not mediate the inhibitory effect of PDE-4 inhibitors and other cAMP-elevating drugs on lipopolysaccharide-induced tumors necrosis factor-α generation from human peripheral blood monocytes. Cell Biochem Biophys 29, 179–201 (1998). https://doi.org/10.1007/BF02737835

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