Sparing interleukin-10 receptor expression by glucocorticoids is a prerequisite for the synergistic immunosuppressive effects of interleukin-10 and glucocorticoids.

Field: Biochemistry, Genetics and Molecular Biology (Life Sciences)

I read with great interest the article by Brunetti et al. describing the synergistic inhibitory effects of interleukin (IL)-10 and glucocorticoids (GCs) on T-cell activation (1). Although the authors provided further insight into how GCs and IL-10 synergize to suppress T-cell activation, the exact molecular mechanisms involved in this synergistic effect remain unclear. GCs are potent immunosuppressive hormones and are widely applied in the clinic for the treatment of inflammation, autoimmunity, and transplant rejection. Interestingly, GCs are not only immunosuppressive but also have a selective action on the immune response, preferentially suppressing the proinflammatory and T-helper (Th)1-inducing cytokine IL-12, whereas the anti-inflammatory and Th2-inducing cytokine IL-10 is not affected and can even be up-regulated (2). This selective effect by GCs now seems to occur in parallel with their effects on receptors for these cytokines. Expression of the IL-12 receptor is strongly suppressed by GCs (3), whereas expression of the IL-10 receptor is not suppressed and can even be enhanced (1,4). For example, I and Nagelkerken showed that expression of IL-10 receptors on monocytes is relatively resistant to GCs (4), which provides a mechanism for the observation that combination treatment with GCs and IL-10 leads to a differentiation of monocytes into potent Th2-inducing antigen presenting cells. Brunetti et al. stated in their article that GCs did not up-regulate the expression of the IL-10 receptor on T cells, and therefore the synergy between GC and IL-10 was not caused by induction of the IL-10 receptor (1). However, it has to be noted that under GC pressure, functional expression of the IL-10 receptor must remain to allow synergy between GCs and IL-10. The mechanism for the synergistic action of IL-10 and GCs on T-cell activation might be found at the level of transcription factors and coactivators involved in T-cell activation. Both IL-10 and GCs are potent suppressors of nuclear factor (NF)kB activation, one of the key transcription factors in T-cell activation (5,6). GCs can also suppress the action of other transcription factors important in T-cell activation such as activator protein-1 and NF of activated T cells. GCs use their negative actions through several mechanisms such as protein–protein interaction and up-regulation of IkB, an inactivator of NFkB (5). IL-10 does not act through protein–protein interaction but suppresses, for instance, the expression of the subunits of NFkB (6). It is therefore reasonable to hypothesize that by suppression of NFkB, IL-10 lowers the buffer capacity of NFkB for activated GC receptors. This means that more active GC receptors will be available to use their suppressive actions on other transcription factors like activator protein-1 and NF of activated T cells, leading to synergy. More detailed investigation of combination therapy with IL-10 and GCs on expression of transcription factors and coactivators important for T-cell activation should reveal the molecular mechanisms involved in the synergistic actions of IL-10 and GCs and may lead to the more rational development of effective combination therapy with IL-10 and GCs to prevent transplant rejection. Jeroen T. J. Visser