Cancer Immune Therapy Edited by G. Stuhler and P. Walden ...

160 8 Interleukin-10 in Cancer Immunity
sensitive towards this cytokine. This is due to the down-regulation of IL-10Ra upon
T cell activation [20]. The interaction between CD28 and IL-10Ra seems to be essential
for the influence of IL-10 on these cells [61]. The presence of IL-10 during the activation
of CD4 + T cells results in the development of a regulatory phenotype of these
cells [62±65]. It is characterized by weak proliferation and a specific cytokine profile
after repeated stimulation. Typical for these cells is also their capacity to transfer this
phenotype to other T cells with the same antigen specificity. This transfer may not be
dependent on soluble mediators, but on cell surface molecules [66]. Whether the influence
of IL-10 on CD4 + T cells or on APC in vivo is the most important in the generation
of such regulatory cells remains to be clarified. In vitro, both pathways have
been demonstrated. IL-10 does not exert potent direct inhibitory effects on CD8 + T
cells. It can even activate CD8 + T cells under certain conditions [67, 68].
8.3.3
Effectson Natural Killer (NK) Cells
The effect of IL-10 on NK cells is mainly stimulatory. IL-10 favors the cytotoxic activity
of these cells. It increases the IL-2-induced production of cytokines such as IFN-g,
GM-CSF and TNF-a. Furthermore, it amplifies the IL-2-induced proliferation of the
CD56 bright NK cell subpopulation [18]. Moreover, IL-10 augments the ability of IL-18
to stimulate NK cells [69].
8.3.4
Effectson other Immune Cells
IL-10 has various, but weak stimulatory effects on B cells. It prevents apoptosis and enhances
the proliferation and differentiation towards plasma cells [70, 71]. It also plays
a role in Ig switching. In combination with IL-4 it induces IgG4 but inhibits IgE production;
in combination with TGF-b, IL-10 induces IgA1 and IgA2 secretion [72, 73].
Very similar to monocytes and macrophages, IL-10 in granulocytes inhibits the production
of pro-inflammatory (TNF-a and IL-1b) and induces the production of antiinflammatory
(IL-1RA) mediators. Moreover, it inhibits the release of various chemokines
by neutrophils [74, 75]. The synthesis of cyclooxygenase-2 as well as the production
of prostaglandin E2 is also inhibited by IL-10 [76]. Another effect of IL-10 is
the inhibition of lipopolysaccharide (LPS)-induced synthesis of pro-inflammatory
mediators in eosinophils and mast cells [77, 78]. In combination with IL-3 and IL-4,
however, IL-10 favors the growth of mast cells [79].
8.3.5
IL-10'sRole in the Immune System
Most generally, the immune system can either be divided into the specific and the
unspecific or into the humoral and the cellular system. The role of IL-10 particularly
concerns the inhibition of the unspecific humoral immunity due to its effects on
monocytes, macrophages and also granulocytes. IL-10 exerts inhibitory effects on