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Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom
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Abstract |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, IL-2, and proinflammatory
cytokines (1, 2). IL-10 can be expressed by a wide range of cell types including T cells, B cells, monocytes, macrophages, and keratinocytes, and many tumor cells (1, 3, 4, 5, 6, 7, 8). Recently, we have shown that IL-10 transcription is regulated by the transcription factors Sp1 and Sp3 which are known to be constitutively and ubiquitously expressed (9). We have also shown that the low levels of IL-10 mRNA in resting T cell and macrophage cell lines as well as bone marrow dendritic cells could be up-regulated by activation (9). Weak PMA response elements were identified between –802 and –305 of the IL-10 promoter (9). However, the weak activity of the response elements could not account for the large increase in IL-10 mRNA accumulation upon PMA stimulation. We wondered whether IL-10 production is regulated by other transcriptional regulatory elements such as enhancers and/or posttranscriptional control mechanisms. The latter possibility had been implied by the finding that a T cell clone that was actively transcribing IL-10 did not yield detectable mature IL-10 mRNA (10). Consistent with this, we observed multiple copies of potential mRNA-destabilizing motifs AUUUA and AU-rich elements (ARE)3 (11) in the 3'-untranslated region (UTR) of mouse IL-10 mRNA (12).
Our own observations on posttranscriptional control of this gene began with the finding that although comparable promoter activity could be measured in resting and stimulated EL4 (T cell) and RAW 264 (macrophage) cell lines, the levels of IL-10 mRNA varied between the lines after activation (9). In this article, we have been able to show directly that the 3'-UTR of IL-10 mRNA is indeed destabilizing for IL-10 mRNA. We have identified the sequences concerned using transient and stable transfectants. The results of this and the IL-10 promoter analysis described in the accompanying paper (9) led us to conclude that many cell types might be constitutively transcribing IL-10 mRNA but that much of the regulation is determined posttranscriptionally. This might ensure that the immune system can react rapidly in moderating an inflammatory stimulus.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Luciferase reporter plasmids were constructed using the pGL3-Control Vector (Promega, Madison, WI) carrying a SV40 promoter/luciferase expression unit. Four fragments, AU1 (+727 to +818), AU2 (+807 to +936), AU3 (+1157 to +1239), and AU4 (+727 to +1239), containing the 3'-UTR sequences of IL-10 cDNA were amplified by PCR and cloned into an XbaI site (+1934) located between the luciferase gene and the poly(A) signal in the pGL3-Control Vector. The pGL3-Basic Vector was used as a negative control plasmid for a luciferase assay.
A fusion gene of mouse IL-10 (+11 to +609) (12) and the
human Ig (Ig) heavy chain constant region (+427 to +1132)
(13) was amplified and assembled by PCR. This fragment was
cloned downstream of the EF-1
promoter in the pMTF expression vector
carrying a neomycin resistance gene. The resulting plasmid (IL-10/Ig
"no-UTR") was used to construct plasmid IL-10/Ig "plus-UTR." A
fragment containing a 3'-UTR sequence (+610 to +1295) of IL-10 cDNA was
amplified and cloned downstream of the IL-10/Ig fragment in plasmid
IL-10/Ig no-UTR.
Cell culture and transfection
EL-4 and RAW 264 cells were cultured in IMDM with 5% FCS. For the luciferase reporter assay, 2 x 107 cells were electroporated with 10 µg luciferase reporter plasmids and 1 µg pRL-TK (Promega) as an internal control plasmid. Transfected cells were cultured in 10 ml IMDM-10% FCS. If required, PMA (50 ng/ml) or LPS (20 µg/ml) was added 6 h postelectroporation. Cells were harvested 48 h postelectroporation, and luciferase activities were analyzed by the Dual-Luciferase Reporter Assay System (Promega). These assays were repeated more than three times, and the activities were normalized to Renilla luciferase activities.
To generate stable transfectants, 2 x 106 EL-4 cells were electroporated with 20 µg of plasmids IL-10/Ig plus-UTR or no-UTR. Stable transfectants were selected by G418 (1 mg/ml).
Enzyme-linked immunosorbent assay
EL-4 transfectants were cultured with or without PMA (50 ng/ml) for 24 h. Culture supernatants were harvested and diluted (1/1 to 1/512). IL-10/Ig fusion protein in culture supernatants was analyzed by ELISA using anti-human IgG (The Jackson Laboratory, Bar Harbor, ME) as the capture Ab and biotin conjugated anti-mouse IL-10 (SXC10, PharMingen, San Diego, CA) as the detection Ab.
Analysis of RNA half-life
EL-4 transfectants generated using plasmids IL-10/Ig no-UTR or plus-UTR were cultured for 6 h with or without PMA (50 ng/ml). Actinomycin D was added (10 µg/ml), and cells were harvested at different time points (0, 0.5, 1, 1.5, 2, 3, and 4 h). RNA were isolated, and IL-10/Ig RNA was analyzed by Northern blot hybridization using a human Ig constant-region cDNA as a probe. As a control, HPRT mRNA was also analyzed. To measure the half-life of IL-10/Ig RNA, the intensity of IL-10/Ig and HPRT bands was analyzed by phosphorimaging (Molecular Dynamics, Sunnyvale, CA).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Potential mRNA destabilizing motifs AUUUA and related sequences
(AUUUUA, AUUUUUA) are located in the 3'-UTR of IL-10 mRNA. The relative
positions of these sequences are indicated in Fig. 1
A. We have classified these
AUUUA and related sequences into three potential regulatory regions by
both location and surrounding sequences. The first consists of three
nonclustered AUUUAs located between +741 and +806, and with surrounding
sequences that are not AU-rich (Fig. 1, A and B,
fragment AU1). The second consists of clustered AUUUAs located between
+827 and +895. Here, the surrounding sequences are of the typical
AU-rich type (Fig. 1, A and B, fragment AU2)
which are similar to those previously identified as mRNA-destabilizing
elements (11). The third is located near the 3'-end of
IL-10 mRNA (between +1183 and +1225). It contains nonclustered AUUUA
and AUUUUUA sequences with surrounding sequences that are not AU-rich
(Fig. 1, A and B, fragment AU3). To investigate
whether these sequences regulate stability of IL-10 mRNA, a luciferase
reporter assay was performed. Four fragments containing AUUUA and
related sequences (AU1, +727 to +818; AU2, +807 to +936; AU3, +1157 to
+1239 ; AU4, +727 to +1239) from the 3'-UTR of IL-10 cDNA (Fig. 1, A and B) were cloned between the luciferase cDNA
and the poly(A) additional signal in the pGL3-Control Vector carrying a
SV40 promoter/luciferase expression unit. Transcripts from the
resulting plasmids would therefore contain the luciferase-coding region
plus a part of the IL-10 mRNA 3'-UTR sequence. Luciferase activities in
transfected cells using these plasmids were compared with that using a
control plasmid (no insert), pGL3-Control Vector. If the inserted
fragments from the IL-10 3'-UTR contain RNA-destabilizing activity, the
luciferase activity generated will be less than that of the control
plasmid. In nonstimulated EL-4 cells, reporter activity fell by 
50%
when any of the AU1, AU2, or AU3 sequences in the 3'-UTR were used
(Fig. 1C) and by 80% with plasmid AU4, which carries the
longest 3'-UTR sequence (containing AU1, AU2, and AU3 sequences) (Fig. 1C). However, the results in PMA-stimulated EL-4 cells were
different. We observed a reduction of reporter activity with plasmids
AU1, AU3, and AU4, but not with plasmid AU2. This suggests that some
part of mRNA destabilizing activity may have been overridden by PMA
stimulation, whereas some still remained functional. Similar results
were obtained using macrophage cell line RAW 264 cells except that the
strong mRNA-destabilizing activity of fragment AU3 was sustained in
LPS-stimulated RAW 264 cells, implicating the region between +1157and
+1239 in this process. These results suggest that the stability of
IL-10 mRNA is regulated by heterogeneous mRNA-destabilizing elements
that may be dependent on cell type and nature of activation signals
located in the 3'-UTR of IL-10 mRNA.
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To further investigate IL-10 mRNA stability, we generated stable
EL-4 transfectants using IL-10 transgenes possessing or lacking the
3'-UTR sequence. To distinguish the transgene product from endogenous
IL-10, we used an IL-10/human Ig constant-region fusion protein gene
(IL-10/Ig), which was cloned into an expression vector carrying the
constitutive EF-1 promoter to ensure strong expression, and a
neomycin resistance gene for selection (Fig. 2A). The resulting plasmids
IL-10/Ig "no-UTR" (lacking the 3'-UTR of IL-10 cDNA) or IL-10/Ig
"plus-UTR" (possessing the 3'-UTR) were transfected into EL-4
cells, and clones of stable transfectants were selected. The ELISA
assay, which measured the Ig component of the IL-10/Ig construct, was
performed using culture supernatants diluted appropriately so as to
provide the most sensitive readout. We observed no difference in the
amount of IL-10/Ig protein that accumulated in the culture supernatants
of nonstimulated and PMA-stimulated "no-UTR" transfectants (Fig. 2B). However, the results with "plus-UTR" transfectants
were different. PMA stimulation raised the level of protein some 4- to
5-fold almost up to the level of the nonstimulated groups (Fig. 2B). To exclude positional effects of the transgenes, 24
independent transfectants were analyzed. EL-4 cells were transfected
with the test plasmids by electroporation and immediately inoculated at
limiting dilution into 96-well plates. Twenty-four transfectants were
randomly selected and subcultured. One set of subcultures was
stimulated with PMA for 24 h, whereas the other was not. Culture
supernatants from 48 clones were diluted 1/50 for the ELISA assay. The
reaction was stopped before the no-UTR group achieved saturation.
Significant amounts of IL-10/Ig protein was detected in almost all
culture supernatants of the "no-UTR" transfectants (22 of 24
nonstimulated and 24 of 24 PMA-stimulated cells) (Fig. 3). On the other hand, IL-10/Ig protein
was detected only in the culture supernatants of all PMA-stimulated
"plus-UTR" transfectants, but not from the nonstimulated
counterparts (Fig. 3). These results suggest that IL-10 production was
negatively regulated by the 3'-UTR of IL-10 mRNA in nonstimulated EL-4
cells, although PMA stimulation is capable of partially overriding the
effect.
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We have shown that IL-10 production is regulated through
posttranscriptional mechanisms. We estimated the extent of IL-10 mRNA
stability in nonstimulated and PMA-stimulated EL-4 cells by measuring
the half-life of IL-10/Ig mRNA. EL-4 transfectants were cultured with
or without PMA for 6 h and then treated with actinomycin D to
block transcription. RNAs were isolated at different time points and
analyzed by Northern blot hybridization using human Ig and mouse HPRT
cDNAs as probes (Fig. 4). The
"no-UTR" RNA was quite stable in both nonstimulated and
PMA-stimulated EL-4 cells (half-life, >12 h) (Fig. 4); in contrast,
the half-life of IL-10/Ig "plus-UTR" RNA was 1 h in
nonstimulated cells increasing to 3 h in the PMA-stimulated
transfectants. Within the 6 h PMA-stimulated groups, the
"no-UTR" RNA was more stable than "plus-UTR" RNA, suggesting
that some mRNA destabilizing signals in the 3'-UTR of IL-10 mRNA were
still active.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We have classified AUUUA motifs and the related sequences into three
potential regulatory regions by both location and surrounding
sequences. These regions identified in the mouse IL-10 mRNA sequence
(12) are also conserved in the human sequence
(14). AUUUA motifs between +807 and +936 (Fig. 1
, A and B, fragment AU2) of the 3'-UTR are present
in AU-rich sequences. mRNA-destabilizing activity in this particular
region was not observed in PMA-stimulated EL-4 cells and LPS-stimulated
RAW 264 cells. However, mRNA-destabilizing activity remained in the
other two regions (AU1 and AU3) in both cells. Particularly, strong
mRNA-destabilizing activity in the fragment AU3 was observed in
LPS-stimulated RAW 264 cells. Stabilization of IL-10 mRNA may be
dependent on cell type and/or stimuli. We have also confirmed these
data with stable transfectants.
Regulatory region AU2 in the 3'-UTR of IL-10 mRNA contains clustered
AUUUA and related sequences, i.e., long AREs (Fig. 1B,
fragment AU2) which is similar to other mRNA-destabilizing sequences
observed in 3'-UTR of many cytokine genes and oncogenes. Recently,
several proteins binding to AREs (15, 16, 17, 18, 19) and proteasomes
recognizing AREs (20) have been identified, suggesting
that these proteins and proteasomes might be involved in mRNA
destabilization. IL-10 mRNA stability might be regulated by these
factors and proteasomes through region AU2. mRNA-destabilizing activity
in AU2 seems only to function in nonstimulated EL-4 cells. In contrast,
in stimulated EL-4 cells, mRNA stability was no different to the
control. This suggests that any putative destabilizing factor(s) may
not be expressed and/or be unstable in stimulated cells. Alternatively,
it may be that AU2 contains a PMA-responsive element that mediates mRNA
stabilization. This may be overridden by the destabilization activities
of AU1 and AU3 in full length sequence. In nonstimulated RAW 264 cells,
the luciferase activity produced by the AU2 plasmid was only slightly
less than that of the control plasmid. Because this reduction of
luciferase activity is not large, we cannot conclude the presence of
mRNA-destabilizing activity. However, in LPS-stimulated RAW 264 cells,
we did not observe any reduction in luciferase activity with the AU2
plasmid. This suggests that destabilizing activity was lacking in
stimulated cells. Because RAW 264 is a macrophage cell line, RAW 264
cells might have been partially stimulated (through "danger") by
DNA transfection. Under these circumstances, RNA-destabilizing activity
might have been partially inhibited.
Although regulatory region AU1 and AU3 contain AUUUA and AUUUUUA sequences, these sequences are not clustered, and the surrounding sequences are not AU rich. Therefore, these regions are not similar to typical AREs previously identified as mRNA-destabilizing sequences. Lagnado et al. (21) also proposed that a minimal mRNA destabilizing sequence is not AUUUA but may be UUAUUUA(U/A)(U/A). The IL-10 3'-UTR contains similar sequences, AUAUUUAUU and CUAUUUAUU in fragment AU1 and the identical sequence UUAUUUAUA in fragment AU3. These sequences might function as mRNA-destabilizing sequences. A protein binding to the short AU-rich sequence UUAUUUAUU has also been identified (19). Such a factor may regulate IL-10 mRNA stability through the region AU1 and AU3.
Comparison of the luciferase activities produced using AU1 and AU3
plasmids with that using control plasmid in PMA-stimulated EL-4 cells
resulted in a small reduction of luciferase activity (Fig. 1, AU1
and AU3 in EL-4/PMA) (given the inherent variability of the luciferase
assay, we could not conclude that these reductions were significant).
However, the same plasmids in nonstimulated EL-4 cells produced large
reductions in luciferase activity. We conclude that the putative
RNA-destabilizing factors binding to AU1 and AU3 may express poorly in
PMA-stimulated cells but also that these factors may be more stable
than those binding to AU2, resulting in the outcome of no apparent
destabilizing activity on AU2 and partial destabilizing activity on AU1
and AU3. We need additional experiments to resolve this issue (e.g.,
identification and characterization of factors binding to AU1, AU2,
and AU3).
mRNA-destabilizing activity in the longest fragment (AU4) is stronger than the others. We speculate that this might be caused by gathering of destabilizing activity in each fragment. However, it is possible that these regions might cooperate with each other to regulate RNA stability.
In LPS-stimulated RAW 264 cells, similar RNA-destabilizing activities in fragments AU3 and AU4 (fragment AU4 contains the sequence in fragment AU3) were detected. IL-10 mRNA in LPS-stimulated RAW 264 cells seems to be destabilized mainly through the sequence in fragment AU3. The likelihood is, then, that the different RNA destabilizing elements described here might depend on distinct destabilizing signals. The corollary is that cells capable of producing high levels of IL-10 (Tr1 cells, Th2 cells, and certain tumors) may fail to destabilize mRNA.
The results of this and previous (9) papers lead us to the "regulatory" model of IL-10 expression. Transcription of IL-10 is ubiquitously and constitutively regulated by Sp1 and Sp3. In nonstimulated cells, the constitutively expressed IL-10 mRNA is kept at low levels through mRNA-destabilizing signals. Upon activation, IL-10 transcription is up-regulated through PMA response elements located in IL-10 promoter, and then IL-10 mRNA levels are further increased through RNA stabilization controlled by regulatory regions located in the 3'-UTR. Variable expression levels of IL-10 may be determined by the heterogeneity of mRNA-destabilizing signals.
This combination of ubiquitous transcriptional and posttranscriptional mechanisms for IL-10 expression might be critical to the role of this cytokine. Low concentrations of IL-10 might maintain the background tone of the immune system, thus controlling proinflammatory cytokine expression. When appropriate activation signals arise, IL-10 production could be rapidly up-regulated at sites of inflammation to limit proinflammatory cytokine cascades and restore immune homeostasis via negative feedback.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Masahide Tone, Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford, OX1 3RE, U.K.
3 Abbreviations used in this paper: ARE, AU-rich element; UTR, untranslated region.
Received for publication December 21, 1999. Accepted for publication April 5, 2000.
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mRNA. J. Biol. Chem. 273:13781. messenger RNA. FEBS Lett. 5:157.
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M. Tone, M. J. Powell, Y. Tone, S. A. J. Thompson, and H. Waldmann IL-10 Gene Expression Is Controlled by the Transcription Factors Sp1 and Sp3 J. Immunol., July 1, 2000; 165(1): 286 - 291. [Abstract] [Full Text] [PDF]
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), 6-h PMA-stimulated IL-10/Ig no-UTR (
), nonstimulated IL-10/Ig
plus-UTR (•), and 6 h PMA-stimulated IL-10/Ig plus-UTR (
)
transfectants were assessed by phosphorimaging.