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

ways involving members of the Janus tyrosine kinase (JAK) family and the signal
transducers and activators of transcription (STAT) [17]. IL-10 can activate also other
signaling pathways such as phosphatidylinositol 3-kinase in macrophages.
IL-10Ra is mainly found on immune cells. Its expression is generally low,varying between
100 and 800 molecules per cell ([18, 19] and R. Sabat, unpublished). As analyzed
so far, monocytes and macrophages exhibit the highest IL-10Ra expression
(R. Sabat, unpublished). The expression is adjustable, but only a few regulating factors
are known so far. In general, the activation of immune cells provokes down-regulation
of IL-10Ra expression [20]. In non-immune cells IL-10Ra expression has also
been observed [21±23]. Here, cellular activation mostly leads to induction of its expression.
In contrast to IL-10Ra, IL-10Rb is strongly expressed in most cells and tissues,
and does not seem to be regulated in its expression levels [24, 25].
8.2.3
IL-10 Homologs
In addition to various mammalian IL-10 homologous molecules (see below), four
viral IL-10 homologues are known. They are derived from Epstein±Barr virus (EBV),
equine Herpes type 2 virus, poxvirus Orf and cytomegalovirus (CMV) [26±29]. With
the exception of CMV IL-10, the similarity of the viral and cellular IL-10s with respect
to the amino acid sequence is very high. For instance, the amino acid sequence of the
EBV IL-10 (vIL-10) is 84% identical to that of hIL-10. This, apart from marginal differences
predominantly in the N-terminal part, results in very similar protein structures
[30]. The expression of vIL-10s appears during the lytic phase of virus infection.
vIL-10s are suggested to act via the same receptor as cellular IL-10. When compared
to hIL-10, however, an about 1000-fold lower efficiency is observed for many effects
[31]. This may be explained by a different affinity to IL-10Ra. Unfortunately, most
anti-hIL-10 antibodies and ELISA cannot discriminate between hIL-10 and vIL-10.
As well as the viral homologues, novel cellular molecules with homology to IL-
10 have been identified. These are combined now in the so-called IL-10 family comprising
IL-10, IL-19, IL-20, IL-22, AK155 and the melanoma differentiation associated
gene (MDA)-7 ([32±36, reviewed in [37]). Since the identification of these new
cytokines is very recent, knowledge of their biology is still limited. It is obvious so far
that the sequence homology is not reflected by a shared biological function. IL-20
and IL-22 are suggested to play different roles in inflammatory processes [33, 34].
MDA-7 has been shown to provoke irreversible growth arrest of tumors by induction
of apoptosis or differentiation [36]. The biological functions for IL-19 and AK155
have not been described yet [32, 35].
8.3
Biological Activitiesof IL-10
8.3 Biological Activities of IL-10
Numerous IL-10 effects have been demonstrated on a variety of cells in vitro
(Tab. 8.2). In vivo, immune cells, especially monocytes and macrophages, seem to re-
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