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

156 8 Interleukin-10 in Cancer Immunity
Tab. 8.1 Cellular sources of IL-10 in vitro
Cell population Reference
T cells 2
Monocytes 42
Macrophages 43
B cells 136
NK cells 137
Eosinophils 138
Mast cells 139
Keratinocytes 140
of two structural domains that are oriented in a V-shaped form where each domain
is composed of four a helices from one monomer and two a helices from the other.
Such a topology was first observed for the interferon (IFN)-g homodimer [8].
Numerous, different cell populations express IL-10 after activation in vitro (Tab. 8.1).
With respect to the in vivo situation, the immune cells are most likely to be the major
producers of this cytokine. Among them, the relevance of an individual cell population
for IL-10 production varies depending on the concrete immunological situation.
For instance, in the case of tissue-invading pathogens, IL-10 is produced particularly
by the resident macrophages and mast cells as a counter-regulation of the initial inflammatory
response [9]. In contrast, IL-10 production by regulatory T cells seems to
be especially important for the maintenance of peripheral immunological tolerance
[10]. Once secreted in the plasma, the half-life of hIL-10 amounts to several hours [11].
8.2.2
IL-10R
IL-10's pleiotropic activities are mediated by a specific cell surface receptor complex.
The IL-10R is composed of two different chains, IL-10Ra and IL-10Rb [12, 13]. Both
chains belong to the class II cytokine receptor family (CRF2). Further members of
this receptor family are the receptor subunits for IFN-a/b, IFN-g, IL-20, IL-22 and
the membrane tether for coagulation factor VIIa. CRF2 members are usually transmembrane
glycoproteins, whose extracellular domains typically consist of about 210
amino acids forming two tandem fibronectin type III domains and have several conserved
amino acid positions that are important for the secondary structure. In contrast,
their intracellular domains vary in length and do not demonstrate striking sequence
homology (reviewed in [14]). Binding of IL-10 to its receptor complex consists
of two steps: IL-10 first binds to IL-10Ra. The IL-10/IL-10Ra interaction very
probably changes the cytokine conformation allowing the association of the IL-10/
IL-10Ra complex with the IL-10Rb. IL-10Rb alone is unable to bind IL-10 [13]. The
molecular basis of the interaction between human IL-10 and IL-10Ra has been characterized
in detail [6, 7, 15]. Recently, an IL-10 epitope becoming available after its
conformational change has been proposed to represent the binding site for IL-10Rb
[7, 16]. Activation via the IL-10R complex has been shown to mobilize signaling path-