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The Journal of Immunology, 2006, 177: 6584-6587.
Copyright © 2006 by The American Association of Immunologists, Inc.

CUTTING EDGE

Cutting Edge: Activation of Murine TLR8 by a Combination of Imidazoquinoline Immune Response Modifiers and PolyT Oligodeoxynucleotides

Keith K. B. Gorden, Xiaohong X. Qiu, Christine C. A. Binsfeld, John P. Vasilakos and Sefik S. Alkan1

Department of Pharmacology, 3M Pharmaceuticals, St. Paul, MN 55144


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results and Discussion
 Disclosures
 References
 
Synthetic immune response modifiers (IRM) such as imidazoquinolines can selectively activate human TLR7 or TLR8. Although these endosomal TLRs are close relatives, TLR7-deficient mice are unresponsive to TLR8 agonist IRMs. Similarly, natural ssRNA cannot activate murine TLR8, leading to the belief that murine TLR8 is nonfunctional. In this study, we transfected HEK293 cells with murine TLR8 and NF-{kappa}B reporter constructs and stimulated them with combinations of IRM and oligodeoxynucleotides (ODNs). When stimulated with TLR7 or TLR8 agonists alone, no NF-{kappa}B response was observed. However, a combination of polyT ODN plus the TLR8 agonist activated NF-{kappa}B, whereas polyT ODN plus the TLR7 agonist did not activate. Primary mouse cells responded to the IRM/polyT ODN by secreting TNF. Cells from TLR7–/– and TLR9–/– mice responded to the IRM/polyT ODN combination, whereas MyD88–/– cells did not respond. In conclusion, this study demonstrates for the first time that mouse TLR8 is functional.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results and Discussion
 Disclosures
 References
 
Toll-like receptors, as innate immune-sensing molecules, play a pivotal role in the protection of organisms against pathogens. It appears that all of the RNA- and DNA-sensing TLRs such as TLR3, TLR7, TLR8, and TLR9 are located within the endosomes (reviewed in Refs. 1, 2, 3). Recent findings shed considerable light on the relative role of these TLRs in the recognition of viral RNA (4, 5, 6) and in protection against viral infection (7, 8). It is now accepted that TLR3 senses dsRNA (polyinosinic acid/polycytidylic acid) (4), whereas evolutionarily related TLR7 and TLR8 recognize specific nucleic acid sequences in guanosine- and uridine-rich ssRNA (5, 6) and TLR9 senses unmethylated CpG motifs in DNA (9). However, some peculiarities remain concerning TLR7 and TLR8. Although TLR7 and TLR8 are close phylogenetic relatives, their natural ligand ssRNAs seem to stimulate human TLR7 and TLR8 and mouse TLR7 but not mouse TLR8. The same holds true for imidazoquinoline immune response modifiers (IRMs)2 (our unpublished observations) (10, 11).

Although the functional difference between synthetic agonists for human TLR7 and TLR8 have been described previously (12), the action of the "selective" compounds breaks down in the mouse where IRM agonists defined in the human system as "TLR7 or TLR8 selective" only activate the mouse innate immune system via TLR7 alone. In our studies, no small molecule IRM compounds have been found that can activate HEK293 cells expressing murine TLR8 whether the IRM is defined as TLR7 selective, TLR8 selective or TLR7/8 active in the human system (K. Gorden, X. Qiu, and S. S. Alkan, unpublished data).

The use of TLR7-deficient mice clearly shows that an IRM classified as TLR7/8 "mixed" activity (R848, also known as resiquimod) is active in mice only through mouse TLR7, as TLR7 –/– mouse did not respond to these IRMs (13). Failure in activation of mouse TLR8 by expected natural ssRNA sequences (6) or our synthetic ligands (10) have led to the conclusion that mouse TLR8 is nonfunctional.

In looking at the effects of the agonists of the TLR7, TLR8, and TLR9 subfamily on the activation of NF-{kappa}B-transfected HEK293 cells, we recently discovered that oligodeoxynucleotides (ODNs) could modulate IRM effects on human cells (19). For example, a combination of phosphothioate polyT ODN and TLR8 agonists significantly enhanced activation of human TLR8. Because the mouse TLR8 gene does not appear to be dysfunctional, we evaluated the effect of the same IRM/polyT ODN combination in various systems to determine whether murine TLR8 was functional. By using HEK293 cells transfected with murine TLR8- and primary TLR8-expressing mouse cells, we demonstrate that the murine TLR8 is indeed functional.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results and Discussion
 Disclosures
 References
 
Reagents and media

Small molecule imidazoquinoline TLR7, TLR8, and TLR7/8 agonists (3M-001, 3M-002, 3M-003, and imiquimod) were prepared by 3M Pharmaceuticals and described previously (12). All imidazoquinolines were prepared in DMSO (sterile cell culture grade; Sigma-Aldrich) at a concentration of 10 mM and stored in aliquots at 4°C. PolyT ODN was obtained from Invitrogen Life Technologies. Recombinant mouse TLR-7 (GenBank accession no. AF240467) and mouse TLR8 (GenBank accession no. AF246971) were obtained from Invivogen. The NF-{kappa}B-luciferase reporter construct was obtained from BD Clontech.

Transfection and reporter assay

Transient transfections were performed as previously described (12).

Preparation of primary mouse PBMC

Whole blood from mice collected by heart puncture bleeds into EDTA vacutainer tubes. PBMC are separated from whole blood by density gradient centrifugation using 1-Step (Accurate Chemical & Scientific). Blood is diluted 1/1 with Dulbecco’s PBS. The PBMC layer is collected and washed twice with Dulbecco’s PBS and resuspended at 4 x 106 cells/ml in RPMI 1640 (Celox; catalog no. CC260) with 10% heat-inactivated FBS and 1% penicillin-streptomycin (complete RPMI 1640) and 50 µM 2-ME. The PBMC suspension is added to 96-well, flat-bottom, sterile tissue culture plates containing an equal volume of complete RPMI 1640 medium containing the test compound.

Determination of secreted cytokines

Supernatants collected after overnight incubation with test compounds were analyzed for IL-12 p40 and TNF-{alpha} by ELISA (Biosource International).


   Results and Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
Disclosures
 References
 
To confirm our earlier findings, we transfected HEK293 cells with a plasmid expressing human TLR8 and an NF-{kappa}B luciferase reporter construct and the cells were then stimulated with a combination of IRMs (e.g., 10 µM 3M-003) and polyT ODN (titration). As shown in Fig. 1, 3M-003 activated the reporter 5-fold above background, which was enhanced in a dose-dependent manner by the addition of polyT ODN. From this result we concluded that certain ODNs could enhance the IRM-induced NF-{kappa}B activation in human TLR8-transfected HEK cells. Furthermore, the addition of the same ODNs had the opposite effect on TLR7; that is, the activation of NF-{kappa}B via TLR7 was inhibited in a manner that mirrored that enhancement of TLR8 activation. These activities are reviewed in depth elsewhere (19).


Figure 1
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  		FIGURE 1. PolyT ODN enhances 3M-003-induced NF-{kappa}B activation via human TLR8. HEK293 cells were transfected by FuGENE 6 with a plasmid expressing human TLR8 and an NF-{kappa}B-luciferase reporter construct. One day after transfection the cells were stimulated with 10 µM 3M-003 alone or in combination with a 13-mer polyT ODN at the indicated concentrations and incubated overnight before assaying for luciferase activity. One representative experiment of six is shown.

 
We then asked whether a similar combination could modulate the activities of IRMs in the mouse with regard to TLR7 and TLR8. For this we transfected HEK293 cells with murine TLR7 or TLR8 in combination with an NF-{kappa}B reporter construct and subsequently stimulated the cells with IRM and/or polyT ODN. When these cells were stimulated with imiquimod (human TLR7 agonist), 3M-002 (human TLR8 agonist), or 3M-003 (human TLR7/8 agonist) alone, no NF-{kappa}B response was observed in the murine TLR8-transfected cells. However, the addition of a polyT ODN titration to the TLR7/TLR8 or TLR8 agonists (as defined in the human system) showed dose-dependent activation of NF-{kappa}B in murine TLR8 transfected cells. In contrast, the TLR7 agonist and polyT ODN combination did not show NF-{kappa}B activation in the TLR8 transfected cells (Fig. 2A). The converse experiment with 3M-003 titrated against a fixed concentration of polyT ODN also showed NF{kappa}B activation (Fig. 2B). From this result we conclude that polyT ODN/IRM combination can activate NF-{kappa}B in mouse TLR8-transfected HEK293 cells. In murine TLR7-transfected cells, polyT ODN plus IRMs resulted in findings similar to those observed in the human TLR7-transfected cells with the exception of 3M-003 (Fig. 2C), which was seemingly unaffected by the ODN. 3M-003 proved to be a potent activator of NF-{kappa}B through murine TLR7 and was difficult to inhibit with the addition of polyT ODN at high IRM compound concentrations. The inhibitory effects of the polyT ODN was more clearly seen when 3M-003 was titrated against a fixed concentration of ODN as shown in Fig. 2D.


Figure 2
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  		FIGURE 2. PolyT ODN modulates NF-{kappa}B activation induced by synthetic TLR7/8 agonist via murine TLR7 and TLR8. HEK293 cells were transfected by FuGENE 6 with a plasmid expressing murine TLR8 (A and B) or murine TLR7 (C and D) and an NF-{kappa}B-luciferase reporter construct. One day after transfection the cells were stimulated with either the combination of a 13-mer polyT ODN titration and IRM compounds 3M-001, 3M-002, 3M-003, and imiquimod at a fixed concentration of 10 µM, (A and C) or the imidazoquinoline compound 3M-003 (TLR7/TLR8) titration alone or in combination with a 13-mer polyT ODN at a concentration of 3 µM (B and D). The cells were incubated overnight before assaying for luciferase activity. One representative experiment of four is shown.

 
We then tested whether mouse TLR8 activation observed in transfected HEK293 cells would also apply to mouse primary cells. Previously, we described TLR selectivity on the basis of human TLR7 and TLR8 activation using both HEK293 and primary human cells. Thus, the compound 3M-001 selectively activated TLR7 and was a potent inducer of IFN-{alpha} from human PBMC. In contrast, the compounds 3M-002 and 3M-003 activated TLR8 and induced TNF-{alpha} and IL-12 in human PBMC (12). However, the conundrum seen in murine TLR7-transfected cells was the fact that mouse TLR7 was activated by both of these so-called TLR7- and TLR8-selective IRMs (as defined in the human system) and that the TNF-{alpha} and IFN-{alpha} are both products of TLR7 activation in the mouse (13). Thus, to determine whether murine TLR8 is functional in primary mouse cells, we titrated ODNs against TLR7-selective (imiquimod), TLR8-selective (3M-002), and TLR7/TLR8 agonist (3M-003) IRMs using mouse PBMC and assayed for TNF-{alpha} production (Fig. 3A). As in the human system, the amount of TNF-{alpha} induced by the TLR7-selective IRM (imiquimod) was inhibited by polyT ODN in a dose-dependent manner, whereas the TLR7/TLR8 (3M-003) and the TLR8 compound (3M-002) were unaffected by the addition of ODN. We theorized that the inhibition of TLR7-related cytokine production by ODN with the IRM compounds 3M-002 and 3M-003 might be overcome by the activation of mouse TLR8 in combination with polyT ODN observed in the HEK293 system.


Figure 3
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  		FIGURE 3. Combination of polyT ODN and synthetic TLR7/TLR8 or TLR8 agonist induces TNF-{alpha} in wild-type and TLR7-deficient murine PBMC. PBMC from wild-type (A) mice or TLR7 –/– (B) mice were isolated and stimulated with the imidazoquinoline compounds at 10 µM alone or in combination with a 13-mer polyT ODN at the indicated concentrations and incubated overnight. Supernatants were collected and assayed for TNF-{alpha} by ELISA. One representative experiment of three is shown.

 
To see whether the combination of IRM and ODN was activating the mouse PBMC independently of TLR7, we repeated the experiment shown in Fig. 3A with PBMC from TLR7–/– mice. As can be seen in Fig. 3B, TLR7–/– cells produced TNF-{alpha} when stimulated with IRM/polyT ODN mixture. This result shows that the combination of IRM and ODN activates the mouse innate immune system independently of TLR7 and shows a similar response to activation of NF-{kappa}B in murine TLR8-transfected HEK293 cells. To further clarify the mode of action of the IRM/ODN combination, PBMC from TLR9 –/– and MyD88 –/– mice were stimulated with LPS, CpG, and 3M-003 with and without polyT ODN. The results shown in Fig. 4 eliminate the possibility of the IRM ODN combination activating TNF-{alpha} in a TLR9-dependent manner and shows that the activation of TNF-{alpha} by IRM/polyT ODN is dependent on a functional MyD88 gene, as with human TLR8. We conclude from this finding that the murine form of TLR8 is active in primary cells and has some similarities to the human TLR8 in its response to small molecule synthetic agonists.


Figure 4
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  		FIGURE 4. Induction of TNF-{alpha} by combination of polyT ODN and synthetic TLR7/TLR8 agonist in murine PBMC is MyD88 dependent. PBMC from TLR9–/–, TLR7–/–, or MyD88 –/– mice were isolated and stimulated with LPS (0.1 µg/ml), CpG1668 (3 µM), 3M-003 (10 µM), and the combination of 3M-003 (10 µM) and 13-mer polyT ODN (3 µM) and incubated overnight. Supernatants were collected and assayed for TNF-{alpha} by ELISA. One representative experiment of three is shown.

 
Even though the mechanism for the combination of ODN and imidazoquinoline enhancement of NF-{kappa}B induction in the TLR8-transfected HEK293 system needs further clarification, our results indicate that murine TLR8 is functional at least in regard to imidazoquinoline-induced NF{kappa}B activation and TNF-{alpha} production. These results further suggest that the natural agonist for mouse and human TLR8 might be similar, because the same IRM/ODN combination that enhanced human TLR8 (19) activated murine TLR8 in the HEK293 system and in primary mouse cells. However, the failure to observe a functional murine TLR8 response without enhancement of ODN suggests that the activation of mouse TLR8 may require additional factors or adaptors. This could be at the level of ligand-receptor interaction, such as the involvement or modification of additional cofactors or intracellular trafficking of the ligand-TLR8 complex. Recent reports have described the ability of exogenous ODN to traffic to specific endosomal compartments that can be modulated by the addition of 1,2-dioleoyloxy-3-(trimethylammonium)propane (14). Also, the interaction between IRMs and ODN (19) could allow for the enhanced retention or optimal trafficking of IRMs in an intracellular compartment that is preferred by both human and murine TLR8.

It is well accepted that the sequestration of TLR8 as well as TLR7 in the endosomes helps to avoid contact with cytoplasmic RNAs and to access only viral RNAs. However, this safeguard mechanism might not be enough for self/nonself RNA discrimination and additional mechanisms such as RNA modification might be needed (15, 16, 17).

A recent study with imidazoquinoline compounds shows the necessity of cryopyrin/Nalp3 (18) for generating mature IL-1β and IL-18 production, which was previously thought to be solely dependent on the TLR7-MyD88 pathway. Data generated with Cias1–/– mice showed that the production of IL-1β and IL-18 in response to the stimulation by the TLR7 agonist imiquimod (R837) and the TLR7/TLR8 agonist resiquimod (R848) was abrogated in the absence of a functional cryopyrin gene; however, the TNF-{alpha} response that we used as a marker for TLR8 activation was unaffected (18). The cryopyrin-dependent IL-1β/IL-18 response was also independent of MyD88, where we have demonstrated that the activation by IRM/ODN is through MyD88. The authors (18) also showed that the IL-1β response to bacterial RNA was dependent on this mechanism, bringing up a recurrent theme between the overlap of activities of small molecule IRMs and nucleic acid moieties from pathogenic organisms. Finally, because small interfering RNAs, which can be recognized by TLR7 and TLR8, are being considered for therapeutic agents (reviewed in Ref. 17), the exact mechanism of RNA recognition by TLR7 and TLR8 deserves further investigation. It is our hope that the ability to use the mouse as an animal model for TLR8 activation as described here will help to facilitate such important research.


   Acknowledgments
 
We thank Drs. R. L. Miller and K. Lipson for critical reading the manuscript and helpful suggestions. The technical assistance of L. Neys, B. Nace, J. Oesterich, and S. Gibson is greatly appreciated.


   Disclosures
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
 Disclosures
References
 
The authors have no financial conflict of interest.


   Footnotes
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 Address correspondence and reprint requests to Dr. Sefik S. Alkan, 3M Pharmaceuticals, 3M Center, 270-2S-06, St. Paul, MN 55144. E-mail address: ssalkan{at}mmm.com Back

2 Abbreviations used in this paper: IRM, immune response modifier; ODN, oligodeoxynucleotide. Back

Received for publication June 22, 2006. Accepted for publication September 18, 2006.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
 Disclosures
 References
 

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