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*
Department of Immunology and Cell Biology, Mario Negri Institute, Milan, Italy;
Department of Pathology, University "La Sapienza" of Rome, Rome, Italy;
University of Maastricht, Maastricht, The Netherlands; and
§
Department of Biotechnology, University of Brescia, Brescia, Italy
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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TLR4 activates the MyD88 signaling pathway, initially identified for the IL-1R (15, 16). Indeed, LPS activates the MyD88/IRAK signaling cascade in monocytic and in endothelial cells (17). Available information suggests that a stereotyped signaling response is activated by different TLR family members.
Despite the assumption that TLR mediate innate immune response, no data are available regarding their expression pattern in immunocompetent cells. There are many members of the TLR family; six have been characterized (4, 5, 6, 18), and other partial cDNA sequences are deposited in the databases. Their number may reflect specialized functions, redundancy, and/or differential expression and roles in different cell types. The present study was designed to carefully characterize the pattern of expression of the first five TLR mRNAs. The results obtained demonstrate differential expression and regulation of TLR and suggest a novel classification of these molecules.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The cell culture medium routinely used was RPMI 1640 with 2 mM
glutamine and 10% FCS (complete medium). All reagents contained
<0.125 endotoxin units/ml of endotoxin as checked by
Limulus amebocyte lysate assay (Microbiological Associates,
Walkersville, MD). LPS (Escherichia coli 005:B5; Difco,
Detroit, MI) was used at 10 ng/ml. Human recombinant TNF-
(BASF/Knoll, Ludwigshafen, Germany) was used at 500 U/ml. Human
recombinant IL-1ß was a kind gift from Dr. J. E. Sims (Immunex,
Seattle, WA). Human recombinant IL-10 was from Shering Plough
(Kenilworth, NJ). Human recombinant IFN was purchased from Boehringer
Mannheim (Marburg, Germany). Lipoarabinomannans were a kind gift from
Dr. Belisle (Colorado State University, Fort Collins, CO).
Mannose-capped lipoarabinomannan is isolated from Mycobacterium
tuberculosis strain H37Rv. Noncapped
lipoarabinomannan (AraLAM) is isolated from a rapid growing
Mycobacterium spp. Phosphatidylinositol mannoside is
isolated from M. bovis strain bacillus
Calmette-Guérin. Actinomycin D and cycloheximide were purchased
from Sigma (St. Louis, MO).
Circulating human monocytes, polymorphonuclear cells (PMN), lymphocytes, and NK cells were separated from blood of normal donors (>95% pure as assessed by morphology) by Percoll (Pharmacia, Uppsala, Sweden) gradient centrifugation as described in detail elsewhere (19). Dendritic cells (DC) were obtained and maturated in vitro as described previously (20). Th1 and Th2 cells were a kind gift from Dr. D. D’Ambrosio (Roche Milano Ricerche, Italy). Large and small B lymphocytes were a kind gift from Dr. J. Golay (Mario Negri Institute). NK cells were kindly provided by Dr. Carla Paganin (Mario Negri Institute). After the appropriate treatment, cells were examined for TLR mRNA as detailed below.
Northern blot analysis
Total RNA was isolated by the guanidine isothiocyanate method
with minor modifications. Eight micrograms of total RNA was analyzed by
electrophoresis through 1% agarose/formaldehyde gels, followed by
Northern blot transfer to Gene Screen Plus membranes (New England
Nuclear, Boston, MA). The plasmids containing human TLR cDNAs were
labeled with [-32P]dCTP (3000 Ci/mmol;
Amersham, Buckingamshire, U.K.). Membranes were pretreated and
hybridized in 50% formamide (Merck, Rahway, NJ) with 10% dextran
sulfate (Sigma) and washed twice with 2x SSC (1x SSC, 0.15 M NaCl,
and 0.015 M sodium citrate) and 1% SDS (Merck) at 60°C for 30 min,
and finally washed twice with 0.1x SSC at room temperature for 30 min.
Membranes were exposed for 4–48 h at -80°C with intensifying
screens. RNA transfer to membranes was checked by UV irradiation, as
shown in each figure.
Plasmids
TLR1 and TLR3 plasmids were obtained from Immunex. TLR4 plasmid has been described previously (14). A partial TLR2 cDNA was obtained by RT-PCR and subcloned into pCRII vector (Invitrogen, San Diego, CA). A partial TLR5 cDNA containing plasmid was obtained by Research Genetics (Huntsville, AL; dbEST Image clone no. 277229 3').
In situ hybridization
TLR3 cDNA fragment (540 bp insert after EcoR V digestion) and control probes IL-1 were labeled with biotin-dCTP using random primers methods (Renaissance; NEN Life Science, Boston, MA). Five-micrometer cryostat sections from lymph nodes and monocyte-derived DC cytosmears were fixed with 4% buffered paraformaldehyde, dehydrated in ethanol, rehydrated in 1x PBS and 50 mM MgCl2, washed in 0.1 M Tris-HCl (pH 7.5) and 0.1 M glycine, and acetylated in 2x SSC, 0.1 M triethanolamine, and 0.5% acetic anhydride (pH 8), and dehydrated in ethanol. Dry sections were prehybridized for 1 h at 37°C with 60% formamide, 4x SSC, 500 mg/ml ssDNA, and hybridized overnight at 60°C with 20 pg/slide/probes, 4xSSC, 10 mM DTT, 5x Denhardt’s solution, 200 µg/ml salmon sperm DNA, and 10% w/v dextran sulfate. Unbound and aspecifically bound probes were removed by washes with 2x SSC for 20 min at room temperature and with 1% SSC and 0.01 SDS for 15 min at 60°C. The slides were then dried and sequentially incubated with streptavidin-FITC, mouse anti-FITC, biotinylated anti-mouse streptavidin-FITC, and finally with anti-FITC-HRP (Dako, Glostrup, Denmark). All of the incubations lasted for 30 min and were followed by a 10-min wash with cold TBS (150 mM NaCl2, 50 mM Tris-HCl (pH 7.5), and 0.01% Tween 20) on ice in the dark. After a final wash, the reactions were developed with 3-amino-9-ethylcarbazole, rinsed in water, and counterstained with hematoxylin. Nonspecific bound probe was controlled by previous digestion with 100 µg/ml ribonuclease A and 10 U/ml ribonuclease T (Sigma, Poole, U.K.). Our study was made on activated tumor draining lymph nodes.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Based on their sequence similarity, five human cDNAs have been identified and grouped into the same gene family, namely, the TLR family (4, 5, 6). Standard Northern blot analysis has been previously performed to detect specific transcripts for TLR1 to TLR5 in human tissues. In contrast, no data are currently available regarding the expression pattern of TLR mRNA in fresh human leukocyte populations (5).
We have systematically screened different human cell types to detect specific TLR transcripts. We separated fresh human monocytes, T lymphocytes, NK cells, and PMN from peripheral blood of healthy donors. B cells were prepared from tonsils and Th1 or Th2 cells are in vitro-derived lines from human lymphocytes. Mature DC were derived in vitro from monocyte precursors (see Materials and Methods).
To determine whether cells activation could somehow regulate TLR mRNA levels, the cells were also treated with different stimuli. Monocytes and PMN were activated by adding LPS to the cell culture medium; T lymphocytes were treated with PHA to trigger stimulation.
Total RNA was extracted from the cells and analyzed with Northern blot
to detect specific TLR transcripts. As shown in Fig. 1
, TLR1 mRNA is ubiquitously expressed.
In contrast, TLR2 to TLR5 show a restricted pattern of expression; in
particular TLR2, TLR4, and TLR5 are present in monocytes, PMN, and DC.
To note, TLR3 is exclusively expressed by DC, but absent in all of the
other leukocytes analyzed. Preliminary observations suggested that TLR4
mRNA expression can be up-regulated by LPS treatment of the cells.
(Fig. 1).
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TLR2 and TLR4 have been suggested to be involved in LPS signaling. LPS as well as other pro- and anti-inflammatory signals has been shown to regulate expression of signaling components of the IL-1R and the decoy receptor (21). It was therefore of interest to assess how LPS as well as other prototypic pro- and anti- inflammatory molecules affected expression of the myeloid-restricted TLR2 and TLR4 in monocytes.
Untreated monocytes express appreciable levels of TLR4 and TLR2
transcripts in the absence of deliberate stimulation. Treatment with
bacterial LPS for 3 h, significantly augmented in a dose-dependent
manner TLR4 mRNA. As low as 0.1 ng/ml LPS was sufficient to increase
TLR4 expression (Fig. 2A). In
contrast, up to 100 ng/ml failed to regulate TLR2 expression (Fig. 3). Induction of augmented expression of
TLR4 was blocked by the transcription inhibitor actinomycin D and by
the protein synthesis inhibitor cycloheximide, supporting that LPS acts
at different levels of regulation (Fig. 2A). On the other
hand, LPS treatment of the cells induced TLR2 mRNA levels in PMN but
not in monocytes (six different donors; Fig. 1
and data not shown).
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B, AraLAM from
Mycobacterium significantly augmented TLR4 transcript
levels. Furthermore, proinflammatory cytokines such as IL-1ß,
TNF-, and IFN-
, all induced TLR4 transcription. Qualitatively
similar data were obtained for monocytes and PMN (Fig. 2B and data not shown, respectively). We next analyzed
whether anti-inflammatory cytokines could revert this effect. Fresh
human monocytes were incubated with IL-10 or LPS or simultaneously with
both stimuli. As evident from Fig. 3, as low as 20 ng/ml IL-10
completely blocked LPS-activated TLR4 induction. In contrast, the
levels of TLR2 transcript in monocytes remained unchanged in response
to LPS and/or IL-10. All in all, these observations suggest that TLR4 (in monocytes and PMN) and TLR2 (in PMN) can be regulated at sites of infection or inflammation either directly by bacterial components or indirectly by primary cytokines. In contrast, the anti-inflammatory cytokine IL-10 inhibits the effect of LPS on TLR4, but not TLR2 transcripts.
TLR3 is exclusively expresses by DC
DC are a heterogeneous system of leukocytes highly specialized in the priming of T cell-dependent immune responses. The hallmark of DC is the ability to capture pathogens and Ags of various origin, to process and present antigenic peptides, and to migrate through tissues to reach secondary lymphoid organs, where the stimulation of naive T cells takes place. Upon exposure to immune or inflammatory signals, DC undergo functional maturation and re-enter the circulatory system to home to the T cell areas of lymphoid organs. Given their central role in the switching from innate to acquired immune responses, we analyzed the expression pattern of TLRs in mature human DC vs precursor monocytes.
After culture in the presence of GM-CSF, IL-4, or IL-13 for 7 days,
precursor monocytes differentiate into DC. Upon an additional exposure
to inflammatory signals (such as TNF-, IL-1ß, or LPS), they
undergo functional maturation (20). As shown in Figs. 1 and 4, differentiated DC express
detectable levels of all of the TLR analyzed. Importantly, TLR3 was
exclusively expressed by DC but absent in precursor monocytes.
Moreover, the expression of TLR3 dramatically increased during
differentiation of the cells in vitro. Finally, when DC were treated
with inflammatory signals to fully mature them, TLR3 expression
significantly decreased while TLR4 expression augmented (Fig. 4B); this may represent a regulatory mechanism after DC have
encountered pathogens.
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, A and B,
monocyte-derived DC were hybridized for TLR3 and by way of comparison
for IL-1ß. It was found that >95% of the cells had a strong
cytoplasmic signal for both mRNAs. The study was extended to sections
of human tissues. Langerhans type cells were mostly negative for TLR3
(data not shown). However, in the T cell-dependent areas of lymph
nodes, several interdigitating reticulum cells with DC characteristics
were positive (Fig. 5, C and D).
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E)
(22). |
Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We separated fresh human monocytes, NK cells, PMN, B cells, T lymphocytes, Th1 or Th2 lymphocytes, and monocyte-derived DC. Total RNA was extracted from the cells and analyzed by Northern blot to detect specific TLR transcripts. To note, TLR1, TLR2, and TLR4 probes allowed a signal detection on the filter only after a few hours of autoradiography. On the other hand, TLR3 and TLR5 probes required at least an overnight exposure of the filter to evidence a specific transcript, suggesting that distinct TLR transcripts may be produced at different levels; however, the levels of receptor expression will also depend on the stability of the protein so that availability of specific Abs will permit a definitive quantitative analysis of TLR expression in different cell types.
The results presented here show that the first characterized five TLR family members show differential expression and regulation of their specific transcripts in human leukocyte populations. TLR1 is expressed in all subsets examined. No significant regulation of its expression was observed, except for the down-regulation of specific transcripts in T cells after exposure to PHA. TLR2, TLR4, and TLR5 were only present in myelomonocytic cells and are undetectable in lymphoid subsets, resting or activated. In one of six different donors, TLR5 messenger was barely detectable in NK cells.
When regulation was examined, TLR4 was found to be increased by bacterial products and primary proinflammatory cytokines. Exposure to bacterial products, such as LPS or lipoarabinomannan, or to proinflammatory cytokines, increased TLR4 expression in monocytes and PMN, whereas IL-10 blocked this effect. In contrast, TLR2 was unaffected by these pro- and anti-inflammatory signals in monocytes but it was augmented in PMN. All in all, these observations suggest that TLR4 (in monocytes and PMN) and TLR2 (in PMN) expression can be regulated at sites of infection or inflammation, either directly by bacterial components or indirectly by primary cytokines. It should be noted that TLR4 is a component of the receptor complex for Gram-negative bacteria (13); on the other hand, TLR2 may be more specifically involved in the signaling receptor for Gram-positive bacteria (13, 14). Intriguingly, our data show that the levels of expression of TLR4 and TLR2 are differentially regulated in monocytes, supporting the hypothesis that eventual responsiveness of the cells to distinct bacterial components may be modulated by external stimuli. The present findings with LPS and TLR4 confirm and extend our own preliminary data (16). It has been previously reported that TLR4 expression is inhibited by LPS in a mouse cell line (7). It is unclear whether this divergence reflects species or cell differences. Given the structural and functional relation of TLR with IL-1 receptors, it is of interest that pro- and anti-inflammatory signals have been shown to have reciprocal and divergent effects on signaling components of the IL-1 receptor complex and on the decoy receptor (21).
TLR3 transcripts were selectively expressed in human DC both in vitro and in vivo. As assessed by in situ hybridization, most Langherans cells in the skin did not express TLR3; on the other hand, TLR3 expressing DC were clearly detectable in the T cell areas of lymph nodes. DC are heterogeneous in terms of ontogeny, marker phenotype, and function (23). In particular, the monocyte-derived DC used for the present in vitro studies clearly differ from Langherans cells in many respects, including lack of Bribeck granules, chemokine receptor expression, and expression of the mannose receptor (23, 24). The expression of TLR3 in DC of different origin and function will need to be investigated in detail.
Interestingly, in vitro experiments showed that TLR3 expression was inhibited upon exposure to LPS or proinflammatory cytokines that induce functional maturation. Therefore, DC are unique in that they express TLR3 and have the whole repertoire of five characterized TLRs. This full repertoire may reflect the unique role of DC in sensing pathogens and causing transition from innate to specific immunity.
Collectively, these data suggest that it may be useful to classify TLR based on their mRNA expression pattern as ubiquitous (TLR1), restricted, (TLR2, TLR4, and TLR5), and specific (TLR3) molecules.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Marta Muzio, Department of Immunology and Cell Biology, Mario Negri Institute, via Eritrea 62, Milan, I-20157, Italy.
3 Abbreviations used in this paper: LBP, LPS-binding protein; TLR, Toll-like receptor; DC, dendritic cell; PMN, polymorphonuclear leukocyte.
Received for publication December 29, 1999. Accepted for publication March 10, 2000.
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B and JNK/SAPK activation upstream of TRAF6. J. Exp. Med. 187:2097.B through interleukin-1 signaling mediators in cultured human dermal en-dothelial cells and human mononuclear phagocytes. J. Biol. Chem. 274:7611.This article has been cited by other articles:
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