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. 1999 Jul;73(7):6177–6181. doi: 10.1128/jvi.73.7.6177-6181.1999

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, Scott W Wong 1,2,*
PMCID: PMC112688  PMID: 10364379

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.

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).

FIG. 1.

FIG. 1

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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 α-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.

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.

FIG. 2.

FIG. 2

FIG. 2

FIG. 2

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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-β-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.

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).

FIG. 3.

FIG. 3

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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%.

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.

FIG. 4.

FIG. 4

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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.

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).

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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