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Journal of Virology, July 1999, p. 6177-6181, Vol. 73, No. 7
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
A Rhesus Macaque Rhadinovirus Related to Kaposi's
Sarcoma-Associated Herpesvirus/Human Herpesvirus 8 Encodes a
Functional Homologue of Interleukin-6
Johnan A. R.
Kaleeba,1,2
Eric P.
Bergquam,1 and
Scott
W.
Wong1,2,*
Division of Pathobiology and
Immunology,1 Oregon Regional Primate Research
Center, Beaverton, Oregon 97006,1 and
Department of Molecular Microbiology and
Immunology,2 Oregon Health Sciences
University, Portland, Oregon 97201
Received 8 February 1999/Accepted 12 April 1999
 |
ABSTRACT |
The rhesus rhadinovirus strain 17577 (RRV strain 17577) genome is
essentially colinear with human herpesvirus 8 (HHV8)/Kaposi's sarcoma-associated herpesvirus (KSHV) and encodes several analogous open reading frames (ORFs), including the homologue of cellular interleukin-6 (IL-6). To determine if the RRV IL-6-like ORF (RvIL-6) is
biologically functional, it was expressed either transiently in COS-1
cells or purified from bacteria as a glutathione
S-transferase (GST)-RvIL-6 fusion and analyzed by IL-6
bioassays. Utilizing the IL-6-dependent B9 cell line, we found
that both forms of RvIL-6 supported cell proliferation in a
dose-dependent manner. Moreover, antibodies specific to the IL-6
receptor (IL-6R) or the gp130 subunit were capable of
blocking the stimulatory effects of RvIL-6. Reciprocal titrations
of GST-RvIL-6 against human recombinant IL-6 produced a
more-than-additive stimulatory effect, suggesting that RvIL-6 does not
inhibit but may instead potentiate normal cellular IL-6 signaling
to B cells. These results demonstrate that RRV encodes an accessory
protein with IL-6-like activity.
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TEXT |
Rhesus macaques are naturally
infected with a herpesvirus, rhesus rhadinovirus (RRV), that is closely
related to human herpesvirus 8 (HHV8), also known as Kaposi's
sarcoma-associated herpesvirus (KSHV) (6). KSHV is the
etiological agent postulated to play a critical role in the development
of all forms of Kaposi's sarcoma (KS) and in specific
lymphoproliferative disorders such as primary effusion lymphoma and
multicentric Castleman's disease (5, 10, 13, 23). The RRV
strain 17577 genome has recently been sequenced, and analysis reveals
that it is essentially colinear with KSHV, possessing several of the
unique genes found in KSHV that distinguish it from other
herpesviruses, including viral interleukin 6 (vIL-6), viral macrophage
inflammatory proteins (vMIPs), and several viral interferon regulatory
factors (vIRFs) (20). Although a role for these viral
factors in KSHV-associated disease has not been clearly established,
several studies have shown that vIL-6 is functional in a number of
IL-6-dependent bioassays and may, as such, elicit biological responses
similar to those induced by cellular IL-6 (4, 14, 17).
The aim of this study was to investigate whether RRV vIL-6 (RvIL-6)
possesses IL-6-like activity. The RvIL-6 open reading frame encodes a
polypeptide of 207 amino acids, with overall amino acid sequence
identity of 17.8 and 12.7% (35.6 and 27.4% similarity) with the genes
encoded by rhesus macaque and KSHV, respectively (Fig.
1). It is also 19.6% identical (41.2%
similar) to human IL-6 (data not shown). Its classification as an
IL-6-like protein is illustrated by four conserved cysteines thought to
facilitate disulfide bridging among the IL-6 family of cytokines
(21). In human IL-6, the disulfide bond formed by the second
cysteine pair is critical for maintaining positional integrity of the
so-called site I that binds the IL-6R (3, 7, 21,
22). This same cysteine pair aligns with RvIL-6 Cys93 and Cys103,
which demarcate the topological equivalent of site I and also contains
a conserved Phe98, whose aromatic character has been shown to be
absolutely essential for human IL-6 interactions with its receptor
(22).
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FIG. 1.
Amino acid sequence alignment of RRV 17577-encoded
RvIL-6 with rhesus IL-6 and KSHV vIL-6. The relatedness of RvIL-6 to
rhesus IL-6 and KSHV vIL-6 was analyzed by using the CLUSTAL method
with the PAM 250 residue weight table and by a BLAST search of GenBank
sequences. The exact residue numbers for each of the three polypeptides
are shown to the left of each sequence. Gaps have been introduced to
account for the different lengths of the polypeptides and to generate
maximum alignment. Identical amino acid residues are boxed accordingly
for two or three sequences. The first N-terminal 21, 27, and 28 residues of RRV RvIL-6, rhesus IL-6, and KSHV vIL-6, respectively,
display characteristic features of a putative signal peptide sequence
with a hydrophobic core that is followed by a typical signal peptidase
cleavage site, as defined by the SignalP prediction (18).
The four conserved cysteines (boxed and shaded) align with RvIL-6
residues 64, 70, 93, and 103, and the four putative domains (A1-2, B,
C, and D) that form the  -helical bundle structure typical of the
long-chain cytokine family (15) are marked by solid black
lines. Some conserved residues known to be critical for human IL-6
function are denoted as follows: *, residues that bind IL-6R
(3); ~, residues that facilitate human IL-6 interaction
with gp130 (7);  , this conserved proline introduces the
so-called bent effect that facilitates antiparallel helical
disorderedness characteristic of functional IL-6-like molecules
(21). The KSHV vIL-6 and rhesus IL-6 sequences were adapted
from references 14 and 26,
respectively.
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Recombinant RvIL-6 is capable of supporting B9 cell
growth.
To determine whether RvIL-6 might elicit growth
stimulatory effects on IL-6-responsive cells, we cloned RvIL-6 into two
different expression vectors. For expression in eukaryotic cells, we
cloned full-length RvIL-6 into pCMV, an expression vector utilizing the human cytomegalovirus immediate-early promoter (8), and
assayed supernatants from transfected COS-1 cells for IL-6-like
activity in a bioassay, using the IL-6-dependent B9 cell line
essentially as described previously (1, 3). As shown in Fig.
2A, RvIL-6-containing supernatant
stimulated B9 cell proliferation in a dose-dependent manner. Maximal
stimulation was threefold greater than that for control supernatant and
also equivalent to about 65 pg of human recombinant IL-6 (hrIL-6) (used
throughout the study as a positive control for B9 cell responsiveness
to growth stimulus)/ml.
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FIG. 2.
Assay for biological activity of recombinant RvIL-6. (A)
Serial dilutions of sterile-filtered culture supernatant from COS-1
cells transfected with either pCMV vector (white bar) or the
pCMV-RvIL-6 construct (grey bar) were assayed for their ability to
promote growth of the IL-6-dependent B9 cell line. A starting stock of
80 pg of hrIL-6 (black bar)/ml was diluted in parallel with
transfection supernatant and used as a positive control. (B) Sodium
dodecyl sulfate-12% polyacrylamide gel electrophoresis screening of
GST-RvIL-6 expressed and purified from bacteria. An individual clone
containing the pGEX.2T vector encoding GST alone, either uninduced
(lane 1) or induced with 0.1 mM
isopropyl- -D-thiogalactopyranoside (IPTG) (lane 2), and
lysates from a separate clone containing the pGEX.2T-RvIL-6 construct,
either uninduced (lane 3) or induced with 0.1 mM IPTG (lane 4). Lane 5 was loaded with the affinity-purified GST-RvIL-6 fraction eluted from
glutathione Sepharose 4B beads following matrix binding with bacterial
lysates containing GST-RvIL-6. Proteins were visualized by staining the
gel with Coomassie brilliant blue, and the positions of GST and
GST-RvIL-6 are indicated with asterisks. (C) Increasing concentrations
of purified GST (in micrograms per milliliter [open circles]),
GST-RvIL-6 (in micrograms per milliliter [closed circles]), hrIL-6
(in nanograms per milliliter [closed triangles]) or corresponding
volumes of starving media alone (open triangles) were assayed for IL-6
activity. IL-6 activity was determined by [3H]thymidine
incorporation. The data are presented as means of triplicate values of
counts per minute ± standard errors of the means. Analysis of
data variance was performed by using SuperAnova (Abacus Concepts, Inc.,
Berkeley, Calif.), and Tukey-Kramer was used for post hoc tests of
significance; the data are presented as means of triplicate values of
counts per minute ± standard errors of the means. **,
P < 0.01.
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To express the RvIL-6 in bacteria, the RvIL6 ORF, minus the signal
sequence (
18), was cloned into the prokaryotic expression
vector pGEX-2T (Pharmacia, Piscataway, N.J.) to create a glutathione
S-transferase-RvIL-6 (GST-RvIL-6) fusion that was purified
by
affinity over a glutathione Sepharose 4B matrix (Fig.
2B).
Bacterially
expressed fusions were sterile filtered and used directly
in the
bioassay. The GST-RvIL-6 fusion was also capable of stimulating
B9 cell growth in a dose-dependent manner, albeit less efficiently
than
hrIL-6, but at a rate statistically higher than purified
GST,
confirming the absence of bacterial lipopolysaccharide in
the
GST-RvIL-6 preparation that could otherwise have a stimulatory
effect
on B9 cells (Fig.
2C) (
19). Maximal GST-RvIL-6-mediated
cell
proliferation occurred with about 20 µg of protein/ml, equivalent
to
the effect of about 5 ng of hrIL-6/ml on the same cell line.
One
explanation for this 4,000-fold difference in bioactivity
could
be that GST-RvIL-6 is a weaker stimulator of B9 growth,
perhaps owing to the GST moiety (26 kDa) that could affect
interactions
between RvIL-6 (21 kDa) with its cognate receptor(s).
However,
our finding is similar to data from studies of KSHV vIL-6
function,
with different IL-6-dependent cell lines, in which other
researchers
have independently reported a consistently similar
magnitude of
difference in potency between recombinant vIL-6 and hrIL-6
(
4,
14,
17).
RvIL-6 utilizes the IL-6R/gp130 signaling pathway.
The data
above suggest that RvIL-6 may utilize the IL-6 signaling pathway
(24, 27) reported to be the possible mechanism for KSHV
vIL-6 function (4, 17). To determine whether IL-6R is
required for RvIL-6 function, we tested the effect of an anti-mouse IL-6R monoclonal antibody (clone D7715A7; Pharmingen, San Diego, Calif.) on GST-RvIL-6 stimulation of B9 cells. B9 cells, maintained in
the absence of hrIL-6, were incubated for 30 min with serial dilutions
of anti-IL-6R prior to the addition of GST-RvIL-6 or hrIL-6 and then
analyzed for cell proliferation. Anti-IL-6R antibody was able to dose
dependently block growth signals from both GST-RvIL-6 and hrIL-6 (Fig.
3A). The inhibitory effect of anti-IL-6R
was evident only when cells were pretreated with anti-IL-6R before the
addition of GST-RvIL-6 or hrIL-6 and not when added at the same time
(data not shown), implying that the antibody was specifically preventing the initial binding reactions between IL-6R and GST-RvIL-6 or hrIL-6. It is also evident from the data that at lower
concentrations of antibody, GST-RvIL-6 was slightly less sensitive than
hrIL-6, suggesting that the viral protein may require a higher
stoichiometric concentration of anti-IL-6R for effective neutralization
of its cognate sites on IL-6R. This result is strikingly similar to
previous reports of anti-human IL-6R inhibition of KSHV vIL-6 function on IL-6-responsive cell lines, relative to hrIL-6 (4, 17).
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FIG. 3.
Antibodies to both IL-6R and gp130 receptor subunits
inhibit GST-RvIL-6-mediated proliferation of B9 cells. B9 cells
maintained in the absence of IL-6 were seeded in a 96-well plate
containing increasing concentrations of either anti-IL-6R (A) or
anti-gp130 (B). After 30 min. of preincubation at room temperature,
constant GST-RvIL-6 (10 µg/ml, for both panels A and B [closed
circles]) or hrIL-6 (10 ng/ml for panel A and 5 ng/ml for panel B
[closed triangles]) was added, and cell proliferation was analyzed.
Data points represent the means of triplicate values of counts per
minute ± standard errors of the means. The insets for each graph
represent the calculated percent neutralization, defined as (counts per
minute with antibody/maximum counts per minute without antibody) × 100%.
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To determine whether gp130 can also serve as the transducer of RvIL-6
signals, B9 cells were pretreated with serial dilutions
of monoclonal
anti-human gp130 (generously provided by Beth Habecker,
Oregon Health
Sciences University). After 30 min, constant GST-RvIL-6
(10 µg/ml) or
hrIL-6 (5 ng/ml) was added, and cell proliferation
was analyzed. As
shown in Fig.
3B, anti-gp130 antibody dose dependently
inhibited both
GST-RvIL-6 and hrIL-6 growth signals. Unlike the
result with
anti-IL-6R, anti-gp130 had a comparable inhibitory
effect on both
GST-RvIL-6 and hrIL-6, with 50% inhibition of both
signals occurring
at about 700 to 800 ng of antibody/ml (Fig.
3B, inset). This result
suggests that RvIL-6 is capable of signaling
through the shared gp130
subunit.
The finding that RvIL-6 is capable of initiating a signal through IL-6R
and gp130 implies that RvIL-6 can either compete with
host IL-6 for the
receptor system in an inhibitory fashion or
that it may function to
enhance the underlying IL-6 response.
We examined this issue by
adding increasing amounts of GST-RvIL-6
to B9 cells in the
presence of 2.5 ng of hrIL-6/ml, a concentration
that is within the
linear range of proliferation to this stimulus.
We found that the
corresponding stimulation index is consistently
and increasingly higher
with each additional concentration of
GST-RvIL-6 (Fig.
4). Moreover, reciprocal addition of
increasing
amounts of hrIL-6 in conjunction with constant GST-RvIL-6
also
caused a more-than-additive stimulatory effect (data not shown),
suggesting that there may indeed be a synergistic integration
of
signals simultaneously delivered by both hrIL-6 and GST-RvIL-6.
These
findings are significant, because they suggest that RvIL-6
may directly
utilize the IL-6 receptor system without inhibiting
the normal cellular
IL-6 response.
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FIG. 4.
GST-RvIL-6 does not inhibit hrIL-6-mediated growth of B9
cells. B9 cells maintained in the absence of IL-6 were incubated with
increasing concentrations of GST-RvIL-6 alone (closed circles) or in
the presence of a constant amount of hrIL-6 (2.5 ng/ml [closed
squares]) and assayed for proliferation. The data are presented as
means of triplicate values of counts per minute ± standard errors of
the means. The horizontal dotted line indicates the average level of
proliferation normally obtained with 2.5 ng of hrIL-6/ml.
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The discovery that RvIL-6 is functional and capable of triggering the
IL-6R/gp130 pathway is intriguing, especially since
the protein has
such limited homology with cellular IL-6. In contrast,
vIL-10 encoded
by Epstein-Barr virus BCRFI displays 70% sequence
similarity with its
cellular counterpart (
12) and also exhibits
some of the
known functions of IL-10 (
16). It is therefore conceivable
that only a limited number of conserved residues may be necessary
for
IL-6-like function, as has been found by mutational analysis
of
human IL-6 (
21). As such, RvIL-6 may represent an
ancestral
host gene pirated by RRV 17577 as a common theme among
pathogenic
herpesviruses (
2).
The poor inhibitory effects of anti-IL-6R on RvIL-6 activity, relative
to hrIL-6, indicate that differences in IL-6R interactions
exist
between the viral protein and hrIL-6. Interestingly, KSHV
vIL-6 was
recently shown to stimulate STAT3-containing DNA binding
activity in
IL-6R-deficient cells, suggesting that KSHV vIL-6
may not require the
IL-6R subunit (
11). We contend that this
finding is not
contradictory to what we have observed with RvIL-6,
since it is still
possible that RvIL-6 and KSHV vIL-6 have binding
activities for IL-6R
when this subunit is available on the target
cell. The apparent
conservation of critical IL-6R-binding residues
in both RvIL-6 and KSHV
vIL-6 (Fig.
1) strongly supports this
view. We predict that RvIL-6 may
also bind and homodimerize gp130
in the absence of IL-6R, resulting in
induction of DNA binding
activity as observed for vIL-6. However, the
signal generated
from such an interaction would be qualitatively weaker
than the
one triggered in the presence of both gp130 and IL-6R. This
concept
is beyond the intended scope of this report but could be
evaluated
in IL-6R
versus IL-6R
+ cells upon exposure to
either RvIL-6 or vIL-6.
In the context of infection, RvIL-6 could be involved in pathogenesis
by modulating some aspect of viral interaction with
the immune
system, especially since it may enhance, rather than
inhibit,
host IL-6 signaling. RvIL-6 could exert a stimulatory
effect on
circulating lymphocytes and/or promote cell survival
via the
IL-6-inducible interferon regulatory factor (IRF) (
25)
that
can antagonize the interferon-mediated clearance of virus-infected
cells. In accordance with this notion, it is interesting that
RRV
strain 17577 has eight copies of a homologue of cellular IRF
(
20) which could function like the oncogenic KSHV v-IRF (K9)
(
9).
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ACKNOWLEDGMENTS |
This work was supported by Public Health Service grants CA75922
(S.W.W.) and RR00163 (S.W.W.). J.A.R. Kaleeba is an N.L. Tartar Trust
Research Fellow.
We thank Michael K. Axthelm, Ann B. Hill, Jay Nelson, David Parker,
Robert P. Searles, and Lisa I. Strelow for helpful discussions and Lori
Boshears for assistance with preparation of the manuscript.
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FOOTNOTES |
*
Corresponding author. Mailing address: Oregon Regional
Primate Research Center, Division of Pathobiology and Immunology, 505 N.W. 185th Ave., Beaverton, OR 97006. Phone: (503) 690-5534. Fax: (503)
690-5524. E-mail: wongs{at}ohsu.edu.
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Journal of Virology, July 1999, p. 6177-6181, Vol. 73, No. 7
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
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