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Cutting Edge |
* Department of Experimental Dermatology, Schering AG, and
Institute of Medical Immunology, Medical School Charité, Humboldt University, Berlin, Germany
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResults and DiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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-helical proteins whose amino acid
sequences are up to 
30% identical to that of IL-10 and
comprise
definite positions for cysteine. Interestingly, the encoding genes are
located in the human genome in two clusters, one comprising the genes
for IL-10, IL-19, IL-20, and mda-7 on chromosome 1q31–32, and another
comprising the AK155 and IL-22-encoding genes located on human
chromosome 12q15 (3, 7). Like IL-10, all the receptors of
the novel molecules known so far belong to the cytokine receptor family
type 2 (8). They are mostly transmembrane glycoproteins
whose extracellular domains consist of 210 aa comprising two tandem
fibronectin type III domains and having several conserved amino acid
positions important for the secondary structure. In general, after
ligand binding two particular receptor chains, R1 and accessory R2, are
aggregated, forming the final functional receptor complex. Via their
heterogeneous intracellular domains they transduce the ligand binding
signal preferentially by Janus kinases-STAT pathways. Very recently, it
has been discovered that some of the human IL-10 homologs share single
receptor chains and even whole receptor complexes (9, 10, 11, 12).
Taking into account the clear relation between the novel IL-10 homologs
and IL-10, the entirety of these six molecules should be considered as
(IL-10) family members. In contrast to the extensively studied IL-10, the knowledge of the biology of the novel IL-10 homologs is still fragmentary. First functional data exist for IL-20, IL-22, and mda-7. Overexpression of IL-20 in transgenic mice induced neonatal lethality, psoriasis-like skin abnormalities, lack of adipose tissue, and elevated apoptosis of thymic lymphocytes (3). IL-22 was suggested to play a role in inflammatory processes through the observation that it induces acute phase reactant production in a hepatoma cell line and in vivo (9). Overexpression of mda-7 via adenoviral gene transfer induced growth inhibition in various tumor types (13). Interestingly, the mda-7 mouse counterpart, called FISP, was postulated to be a Th2-specific protein (14). No function is known for IL-19 and AK155 yet.
A first step in understanding the biological role of the novel molecules is the identification of their cellular sources and their target cell populations. So far, the knowledge about that is rather unsatisfying. The relation of these molecules to IL-10 suggests that they are also immunologically relevant; therefore, this study analyzed the gene expression of the IL-10-related molecules and their receptors in immune cells.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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PBMCs from healthy donors were isolated from venous blood as
previously described (15). Monocytes, NK cells, B cells, T
cells, and T cell subsets were prepared from PBMCs using depletion MACS
systems (Miltenyi Biotec, Bergisch Gladbach, Germany) obtaining
purities of at least 92% or, in case of double depletion, 85%. Cells
were cultured in endotoxin-tested medium
as described previously (15). Isolated cells (Figs. 1
and 2) were stimulated or not (controls) with
100 ng/ml LPS from Escherichia coli 0127 B8 (monocytes;
Sigma-Aldrich, Deisenhofen, Germany), 0.001% (w/v) heat-killed,
formalin-fixed Staphylococcus aureus cells (B cells;
PANSORBIN; Calbiochem-Novabiochem, Bad Soden, Germany), 10 ng/ml IL-2
and 10 ng/ml IL-12 (NK cells; R&D Systems,
Wiesbaden-Nordenstadt, Germany), or anti-CD3 mAb coated
on culture vessel (T cells and T cell subpopulations; 1
µg/cm2; Orthoclone; Cilag, Sulzbach, Germany)
for the indicated times. To study the effect of T cell costimulation
and functional polarization (Fig. 3), T
cells were cultured either in the presence of 5 µg/ml IgG1 and 5
µg/ml IgG2a (controls) or stimulated with anti-CD3 (Cilag) and
anti-CD28 mAbs (R&D Systems) coated on culture vessel (1
µg/cm2 each), in the presence of 5 µg/ml IgG1
and 5 µg/ml IgG2a, 10 ng/ml IL-12 and 5 µg/ml anti-IL-4 mAb, 10
ng/ml IL-4 and 5 µg/ml anti-IFN-
mAb (all from R&D Systems),
or 10 ng/ml IL-10 (PeproTech, Rock Hill, SC) and 10 ng/ml TGF-
1.2
(R&D Systems) for 6, 18, 42, and 66 h. Human EBV-transformed B
cells were provided by Dr. N. Babel (Charite, Berlin, Germany).
The human pancreatic adenocarcinoma cell line BxPC-3 and the human
hepatocyte carcinoma cell line Hep G2 were purchased from European
Cell Culture Collection (Salisbury, U.K.). The human keratinocyte cell
line, HaCaT, was provided by Dr. N. E. Fusenig (Deutsches
Krebsforschungs-Zentrum, Heidelberg, Germany).
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Assessment of composition of isolated cell populations and confirmation of cellular activation were performed by flow cytometry as previously described (15), with the additional use of the following fluorescence-labeled mAb clones: 13B8.2 (anti-CD4) and B9.11 (anti-CD8) from Coulter Immunotech (Hamburg, Germany) and HI100 (anti-CD45RA) and UCHL1 (anti-CD45RO) from BD PharMingen (Hamburg, Germany).
TNF- quantification
TNF- concentration in monocyte culture supernatant was
measured as previously described (15).
Gene expression analysis
Total cellular RNA from isolated blood cells and different cell
lines was prepared as described previously (15). Total RNA
from human tissues was obtained from Clontech Laboratories (Heidelberg,
Germany). mRNA was reverse transcribed and analyzed by TaqMan PCR as
described previously (15). Primers and
6-carboxyfluorescein (FAM)/6-carboxytetramethylrhodamine (TAMRA)
double-labeled probes for analyzing IL-10 family members and
their receptors as listed in Table I.
Additionally, the expression of IFN-, IL-4, and TGF- was analyzed
to check initiated T cell polarization. Because preceding experiments
demonstrated amplification efficiencies in our system of nearly 1 for
all panels, specific gene expression was calculated relative to that of
the housekeeping gene hypoxanthine phosphoribosyl-transferase-1. The
detection limit for accurate quantification was at 0.001-fold
expression of hypoxanthine phosphoribosyl-transferase-1.
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Results and Discussion |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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production in the monocyte culture and elevated expression of
different activation markers, e.g., CD69, on the lymphocyte populations
(Fig. 1
A). Gene expression of the IL-10 family members was
analyzed by real-time RT-PCR. IL-10 is known to be produced by various
cell types, e.g., activated monocytes, NK cells, B cells, and T cells
(for review see Ref. 1). As shown in Fig. 1B,
IL-10 mRNA could also be detected in resting monocytes, B cells, and T
cells. Among the analyzed cells, monocytes appear to be the strongest
producers of IL-10, and activation-induced IL-10 mRNA was detected at
2–18 h, peaking at 6 h. In T cells IL-10 expression increased
during stimulation time, and in NK cells it was detected at low levels
only after 18 h of stimulation. In contrast to IL-10, little is
known about the cellular expression of the novel IL-10-related
molecules. Using Northern blot analysis, Gallagher et al.
(2) recently described IL-19 expression in PBMCs and
monocytes becoming apparent after 4 h of LPS stimulation. Our
results complement these data, showing clear IL-19 levels already in
unstimulated monocytes and an activation-induced expression kinetically
very similar to IL-10. Moreover, we can demonstrate the complete
absence of IL-19 expression in resting as well as in activated NK and T
cells. Very low and irregular expression of IL-19 was also detected in
B cells. Although we cannot absolutely exclude the IL-19 presence in
these cells due to contamination by monocytes, B cells in principle
appear to be able to produce IL-19. In line with the fact that
EBV-transformed B cell cDNA served as source for first cloning of IL-19
(2), our studies revealed clear IL-19 mRNA expression in
such cells (data not shown). The cellular sources of IL-20 are not
known so far. In this work we show that it is produced by monocytes
early after stimulation (2 h) and is rapidly down-regulated afterward.
This kinetics suggest that IL-20 might be an early proinflammatory
cytokine. Interestingly, no other cell population analyzed in this
study expressed this molecule. mda-7 was first discovered as a gene
induced during terminal differentiation of human melanoma cells in
response to IFN- and the protein kinase C activator mezerein
(6). In this work we show that it is also clearly
expressed in monocytes and up-regulated in these cells after
stimulation at all time points. Slight and delayed mda-7 expression was
also seen in our study in activated T cells. IL-22 was originally
identified in the murine system as a molecule differentially expressed
in IL-9-treated murine T lymphoma cells, and its mRNA expression was
also reported in various organs in the mouse after LPS injection
(4, 9). In this study we show that IL-22 expression is
specific for activated T cells and, at lower levels, NK cells in which
it increases with time. A similar expression pattern was detected for
AK155 expression. Until now, only one publication about AK155 exists
describing the expression in virus-transformed T cells as detected by
Northern blot assay and, using more sensitive RT-PCR, also in normal T
cells and PBMC. Taken together, in contrast to IL-10 being expressed in
monocytes, NK cells, B cells, and T cells, the production of the novel
IL-10 homologs is restricted to special populations where it is
up-regulated after cellular activation. Regarding the expression
pattern, three groups may be distinguished: those that are
preferentially expressed in monocytes (IL-19, IL-20), those that are
restricted to (activated) T cells and NK cells (IL-22, AK155), and,
finally, the mda-7, which is expressed in monocytes and T cells.
As already demonstrated, T cells are producers of IL-22, mda-7, and
AK155 after TCR engagement, as mimicked by anti-CD3 mAb exposure.
When asking for the contribution of the CD4+ and
the CD8+ subpopulations to this production we
found that CD4+ cells expressed larger amounts of
IL-22 and AK155, and marginally more mda-7 than did
CD8+ (data not shown). Among
CD4+ cells, naive and memory subsets can be
distinguished by the presence of CD45RA and CD45RO expression,
respectively. As shown in Fig. 2, IL-22 was preferentially produced by
activated memory cells. mda-7 was expressed in both activated naive and
memory cells, although the kinetics of expression in these subsets were
different. AK155 was exclusively expressed in activated memory
cells.
We further asked whether costimulation would modulate anti-CD3
mAb-induced production of IL-22, mda-7, and AK155. Cells were cultured
on anti-CD3 mAb/anti-CD28 mAb-coated vessels for 6 and 18
h as above, and additionally for 42 and 66 h (Fig. 3A).
The impact of costimulation on the expression of IL-22, mda-7, and
AK155 correlated with the contribution of
CD4+CD45RA+ T cells to the
production of these molecules. Compared with anti-CD3 mAb
stimulation alone, costimulation clearly increased the extent of IL-22
(19-fold at 6 h and no modulation at 18 h) and mda-7
(6-fold at 6 h and 8-fold at 18 h) mRNA. AK155
expression did not clearly increase upon costimulation (<2-fold at
6 h and no difference at 18 h).
Among T cells, one can differentiate between distinct subsets based on
their cytokine profile and their functional activities. Type 1 (T1) T
cells produce IFN- and TNF- and mediate the cellular immunity.
Type 2 (T2) T cells secrete IL-4, IL-5, and IL-13, which in turn
regulate the humoral immunity. It has been shown that IL-12 drives
polarization toward T1 in a STAT4-dependent manner, and IL-4
STAT6-dependently drives polarization toward T2. Furthermore, the
presence of IL-10 and/or TGF- upon T cell stimulation has been shown
to generate a phenotype of regulatory T cells able to counterregulate
the activity of T cells (1). We asked whether polarization
of T cells toward such subsets would modulate their expression of IL-10
homologs. T cells were activated as in Fig. 3A but in the
presence of IL-12/neutralizing anti-IL-4 mAb, IL-4/neutralizing
anti-IFN- mAb, IL-10/TGF-, or isotypic control mAbs. Fig. 3B shows the specific expressions relative to those of
nonpolarized T cells. Again, no expression of IL-19 and IL-20 was
detected under any conditions tested in these experiments (data not
shown). Initiation of T1 polarization enhances the expression of IL-22
and, to a lesser extent, of AK155 at later time points (42 and 66
h). The presence of T2 milieu led to slight reduction of IL-22
expression at 42 and 66 h. Initiation of polarization toward the
regulatory phenotype induced massive and slight reduction of IL-22 and
AK155 expression, respectively. Therefore, IL-22 and AK155 may
represent typical T1 mediators. The murine counterpart of mda-7 has
been detected in CD4-positive T2 and also nonpolarized cells in an
IL-4-dependent manner (14). Our data show that the
expression of mda-7 in the human system seems to be distinctly
regulated. At an early time point (6 h) it was down-regulated in cells
under T1 milieu and slightly up-regulated in cells under T2 milieu. At
66 h, exposure to T1 milieu increased this
production. A distinct regulation of mda-7 in the human system is
also underlined by the observation of absent mda-7 expression in
LPS-stimulated murine macrophage-like RAW 264.7 cells
(14), which is not in line with our data obtained with
human monocytes (Fig. 1B). Taken together, the novel members
of the IL-10 family are essentially produced by blood immune cells. In
contrast, our preliminary studies demonstrated only minor expression of
these molecules among a wide range of human tissues (data not shown).
Regarding the structural features and expression patterns, mda-7 and
AK155 resemble the other members of the IL-10 family, thus advocating
the renaming of these molecules into IL-24 and IL-26, respectively.
We then asked for the targets of IL-10 family members among immune
cells. For this purpose, we analyzed the expression of receptor chains
known to function as subunits in its receptor complexes, by
quantitative real-time PCR. Three R1 type chains for IL-10 and related
molecules, IL-10R1, IL-20R1, and IL-22R1, and two R2 type chains,
IL-10R2 and IL-20R2, are known so far. R1 chains can associate with R2
chains to form functional receptors as follows: IL-10R1/IL-10R2 mediate
effects of IL-10; IL-20R1/IL-20R2 mediate effects of IL-19, IL-20, and
mda-7; IL-22R1/IL-10R2 mediate effects of IL-22; and IL-22R1/IL-20R2
mediate effects of IL-20 and mda-7. Whether IL-10R1/IL-20R2 or
IL-20R1/IL-10R2 can form functional receptors is unknown so far. No
receptor has been identified for AK155 so far, but it may be assumed
that it is within the same receptor family. As demonstrated in Fig. 4, IL-10R1 and IL-10R2 were highly
expressed by monocytes, NK cells, B cells, and T cells. Among them,
monocytes show the strongest expression of these receptors, suggesting
highest sensitivity of these cells toward IL-10. All cell populations
also express IL-20R2, though at lower levels. Monocytes, NK cells, and
T cells do not express any of the known partner chains of IL-20R2
(neither IL-20R1 nor IL-22R1). Therefore, the isolated expression of
IL-20R2 suggests that it may associate with the IL-10R1 or a still
unknown R1 chain to confer sensitivity toward another ligand (e.g.,
AK155). In B cells, expression of IL-22R1 was additionally detected at
levels near the detection limit of the used method. Our further data
suggest that no additional chain is expressed in the analyzed cell
populations upon stimulation for 6 h as described in Fig. 1 or in
T cells after 42 h under polarizing conditions as described in
Fig. 3 (data not shown). The absent detection of IL-22R1 expression in
T cells does not support IL-22 effects on these cells
(10). All in all, these data demonstrate a minimal
expression of known receptors for the novel IL-10 homologs in immune
cells. This suggests that there exist major targets in cells other than
these cells. In fact, the analysis of different human tissues and their
representative cell populations revealed high specific expressions of
different receptors in these samples (Fig. 4).
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Acknowledgments |
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Footnotes |
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2 Abbreviations used in this paper: mda, melanoma differentiation-associated gene; T1, type 1; T2, type 2; FAM, 6-carboxyfluorescein; TAMRA, 6-carboxytetramethylrhodamine.
Received for publication January 15, 2002. Accepted for publication April 5, 2002.
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) is a common chain of both the IL-10 and IL-22 (IL-10-related T cell-derived inducible factor, IL-TIF) receptor complexes. J. Biol. Chem. 276:2725.This article has been cited by other articles:
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K. Wolk, S. Kunz, N. E. A. Crompton, H.-D. Volk, and R. Sabat Multiple Mechanisms of Reduced Major Histocompatibility Complex Class II Expression in Endotoxin Tolerance J. Biol. Chem., May 9, 2003; 278(20): 18030 - 18036. [Abstract] [Full Text] [PDF]
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J. H. Von der Thusen, J. Kuiper, T. J. C. Van Berkel, and E. A. L. Biessen Interleukins in Atherosclerosis: Molecular Pathways and Therapeutic Potential Pharmacol. Rev., March 1, 2003; 55(1): 133 - 166. [Abstract] [Full Text] [PDF]
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C. Chang, E. Magracheva, S. Kozlov, S. Fong, G. Tobin, S. Kotenko, A. Wlodawer, and A. Zdanov Crystal Structure of Interleukin-19 Defines a New Subfamily of Helical Cytokines J. Biol. Chem., January 24, 2003; 278(5): 3308 - 3313. [Abstract] [Full Text] [PDF]
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J. Parrish-Novak, W. Xu, T. Brender, L. Yao, C. Jones, J. West, C. Brandt, L. Jelinek, K. Madden, P. A. McKernan, et al. Interleukins 19, 20, and 24 Signal through Two Distinct Receptor Complexes. DIFFERENCES IN RECEPTOR-LIGAND INTERACTIONS MEDIATE UNIQUE BIOLOGICAL FUNCTIONS J. Biol. Chem., November 27, 2002; 277(49): 47517 - 47523. [Abstract] [Full Text] [PDF]
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