Two inhibitors of pro-inflammatory cytokine release, interleukin-10 and interleukin-4, have contrasting effects on release of soluble p75 tumor necrosis factor receptor by cultured monocytes
✍ Scribed by David A. Joyce; Deena P. Gibbons; Patricia Green; James H. Steer; Marc Feldmann; Fionula M. Brennan
- Publisher
- John Wiley and Sons
- Year
- 1994
- Tongue
- English
- Weight
- 826 KB
- Volume
- 24
- Category
- Article
- ISSN
- 0014-2980
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✦ Synopsis
Two inhibitors of pro-inflammatory cytokine
-release, interleukin-10 and interleukin-4, have contrasting effects on release of soluble p75 tumor necrosis factor receptor by cultured monocytes *
The biological activity of the pro-inflammatory cytokine, tumor necrosis factor (TNF)-a depends on the level of TNF-a itself, the expression of the p55 and p75 cell surface receptors for TNF on target cells and the concentrations of the natural inhibitors of TNF-a, the soluble p55 and p75 TNF receptors (TNF-R).
Interleukin (1L)-10 and IL-4 are known to inhibit TNF-a production by monocytes. We, therefore, investigated the effects of IL-10 and IL-4 on the cell surface expression and release of TNF-R by human monocytes to determine whether these cytokines also indirectly modulated the biological activity of TNF-a. Exposure to IL-10 (1-10 U/ml) for 24 or 48 h increased soluble p75 TNF-R expression and concomitantly reduced surface expression of p75 TNF-R.
Further, IL-la-stimulated production of TNF-a was diminished by IL-10 and only a small proportion of this TNF-a was bioactive, consistent with increased production of inhibitory soluble TNF-R. IL-10 also induced down-regulation of surface p55 TNF-R on monocytes, and increased release of soluble p55 TNF-R. However, the expression of soluble p55 TNF-R was much lower than soluble p75 TNF-R, indicating that it contributed less importantly to neutralization of TNF-a under these conditions. Like IL-10, IL-4 supressed the release of TNF-a by monocytes. In contrast to IL-10, however, IL-4 (0.1-10 ng/ml) supressed the release of soluble p75 TNF-R from monocytes in a dose-dependent manner.
Release of soluble p55 TNF-R was also supressed by IL-4. IL-10, therefore, reduces the pro-inflammatory potential of TNF in three ways: by down-regulating surface TNF-R expression whilst increasing production of soluble TNF-R and inhibiting the release of TNF-a itself.This suggests that IL-10 may be useful in the treatment of diseases where overexpression of TNF-a occurs.