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Cutting Edge: Role of Toll-Like Receptor 1 in Mediating Immune Response to Microbial Lipoproteins¹

Osamu Takeuchi^2,*,, Shintaro Sato^*,, Takao Horiuchi^*,, Katsuaki Hoshino^*,, Kiyoshi Takeda^*,, Zhongyun Dong, Robert L. Modlin and Shizuo Akira^3,*,

^* Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan; Solution Oriented Research for Science and Technology, Japan Science and Technology Corporation, Osaka, Japan; Department of Cancer Biology, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030; and Division of Dermatology, Department of Microbiology and Immunology and Molecular Biology Institute, University of California, Los Angeles, School of Medicine, Los Angeles, CA 90095

	Abstract

Top Abstract Introduction Materials and Methods Results and Discussion References

 
The Toll-like receptor (TLR) family acts as pattern recognition receptors for pathogen-specific molecular patterns (PAMPs). TLR2 is essential for the signaling of a variety of PAMPs, including bacterial lipoprotein/lipopeptides, peptidoglycan, and GPI anchors. TLR6 associates with TLR2 and recognizes diacylated mycoplasmal lipopeptide along with TLR2. We report here that TLR1 associates with TLR2 and recognizes the native mycobacterial 19-kDa lipoprotein along with TLR2. Macrophages from TLR1-deficient (TLR1^-/-) mice showed impaired proinflammatory cytokine production in response to the 19-kDa lipoprotein and a synthetic triacylated lipopeptide. In contrast, TLR1^-/- cells responded normally to diacylated lipopeptide. TLR1 interacts with TLR2 and coexpression of TLR1 and TLR2 enhanced the NF-B activation in response to a synthetic lipopeptide. Furthermore, lipoprotein analogs whose acylation was modified were preferentially recognized by TLR1. Taken together, TLR1 interacts with TLR2 to recognize the lipid configuration of the native mycobacterial lipoprotein as well as several triacylated lipopeptides.

	Introduction

Top Abstract Introduction Materials and Methods Results and Discussion References

 
The Toll-like receptor (TLR)⁴ family participates in innate immunity by detecting invading pathogens (1, 2, 3). So far, 10 members of the human TLR family have been discovered. Most of the known TLRs recognize discrete pathogen-associated molecular patterns (PAMPs) to trigger the activation of similar intracellular signaling pathways, leading to the nuclear translocation of a transcription factor, NF-B. The signaling ultimately culminates in the production of proinflammatory cytokines to evoke host defense responses and alert acquired immunity. Recent studies disclosed the ligands for various TLRs. TLR2 recognizes a variety of bacterial components, such as peptidoglycan (PGN), bacterial triacylated lipoproteins, mycoplasmal diacylated lipoprotein, and GPI anchors from Trypanosoma cruzi (4, 5, 6, 7, 8, 9, 10). TLR4 is essential for responses to LPS, a glycolipid specific to Gram-negative bacterial cell walls. TLR5 is reported to recognize flagellin, a protein component of bacterial flagella. Furthermore, nucleotides specific to pathogens and nucleotide analogs are also detected by TLRs: TLR3, TLR7, and TLR9 participate in the recognition of viral dsRNA, imidazoquinolines, and bacterial DNA with unmethylated CpG motif, respectively (1, 2, 3, 11).

There is evidence that TLRs can form heterodimers, which furthers defines their ligand specificity. Notably, TLR6 has a unique property to recognize a mycoplasmal lipoprotein cooperatively with TLR2 (12, 13). TLR6-deficient (TLR6^-/-) mice failed to produce proinflammatory cytokines in response to diacylated mycoplasmal lipopeptides, termed macrophage-activating lipopeptide 2 kDa (MALP-2), whereas they responded normally to a triacylated bacterial lipopeptide. TLR2^-/- macrophages did not respond to either of these lipopeptides (13). These observations indicate that TLR6 discriminates a subtle difference in the acylation of lipopeptides derived from microbial pathogens. Furthermore, these findings raised the possibility that TLR2 forms a heterodimer with a different TLR to recognize other PAMPs, in particular triacylated lipopeptides.

TLR1 shows high similarity with TLR6 (14). It was reported that overexpression of TLR1 inhibited the TLR2-mediated responses to phenol-soluble modulin secreted from Staphylococcus epidermidis (15). On the other hand, another report showed that TLR1 participates in the recognition of soluble factors released from Neisseria meningitides (16). However, the ligand of TLR1 in vivo is yet to be clarified. In the present study, we generated TLR1^-/- mice and analyzed the role of TLR1 in the recognition of bacterial lipopeptides.

	Materials and Methods

Top Abstract Introduction Materials and Methods Results and Discussion References

 
Generation of TLR1^-/- mice

A genomic clone containing mouse TLR1 was isolated from the 129Sv murine genomic library (Clontech Laboratories, Palo Alto, CA). A targeting vector was designed to replace a portion of an exon containing aa 575–795 of the mouse Tlr1 gene with a neo cassette flanked by 1.0 kb of the 5' genomic fragment and 10 kb of the 3' genomic arm. An HSV-tk cassette flanked the 3' genomic arm. A targeting vector was linearized with SalI and introduced into E14.1 embryonic stem (ES) cells. We screened 125 of G418- and gancyclovir-resistant clones for homologous recombination by PCR and confirmed by Southern blot analysis. Three ES clones were correctively targeted and were injected into C57BL/6 blastocysts. The chimeric mice were bred to C57BL/6 females to obtain F₁ offsprings. TLR1^-/- mice were obtained by intercrossing heterozygotes. TLR1^-/- mice and their wild-type littermates from these intercrosses were used for experiments.

Mice, bacteria, and reagents

TLR2^-/- mice were generated by gene targeting as described previously (7). The Mycobacterium bovis bacillus Calmette Guérin (BCG) was purchased from Kyowa (Tokyo, Japan). The native Mycobacterium tuberculosis 19-kDa lipoprotein was purified as described elsewhere (4). A synthetic N-palmitoyl-S-dipalmitoylglyceryl (Pam₃) Cys-Ser-(Lys)₄ (CSK₄) and MALP-2 were as described previously (5, 8). A synthetic lipoprotein analog, JBT3002, is as described previously (17). Other lipopeptides carrying different N-terminal acyl functions such as N-palmitoyl-S-dilaurylglyceryl (N-Pam-S-Lau₂) CSK₄, N-lauryl-S-dilaurylglyceryl (Lau₃) CSK₄, and N-myristyl-S-dimyristylglyceryl (Myr₃) CSK₄ were synthesized by the Peptide Institute (Osaka, Japan).

Preparation of peritoneal macrophages and ELISA

Mice were injected i.p. with 2 ml of 4% thioglycolate (Difco, Detroit, MI). Three days later, peritoneal exudate cells were isolated from the peritoneal cavity. Then the cells were cultured for 2 h and adherent cells were used as peritoneal macrophages. Peritoneal macrophages (5 x 10⁴) were cultured in RPMI 1640 medium (Nacalai Tesque, Kyoto, Japan) supplemented with 10% FCS and were stimulated with indicated bacterial components for 24 h. Concentration of TNF- (Genzyme Techne, Minneapolis, MN) and IL-6 (R&D Systems, Minneapolis, MN) in culture supernatants were determined by ELISA.

Expression vectors

Human TLR1 tagged with hemagglutinin (HA) at the carboxyl terminus was generated by PCR and ligated into the expression plasmid pEF-BOS. pFLAG-TLR2 and pFLAG-TLR4 were as described previously (13).

Luciferase assay

Human embryonic kidney (HEK) 293 cells were transiently transfected with indicated vectors along with a pELAM luciferase reporter plasmid (18) and a pRL-TK (Promega, Madison, WI) for normalization of transfection efficiency by Lipofectamine 2000 (Invitrogen, San Diego, CA). Twenty-four hours after transfection, the cells were stimulated with 10 ng/ml Pam₃CSK₄ for 8 h. Then the cells were lysed and luciferase activity was measured using the dual-luciferase reporter assay system (Promega) according to the manufacturer’s instruction.

Immunoprecipitation and Western blotting

HEK293 cells were transiently transfected with 3 µg of Flag-tagged TLR2, TLR4, or 6 µg of HA-tagged TLR1 as indicated. After 36 h, the cells were lysed in the lysis buffer containing 1.0% Nonidet P-40, 150 mM NaCl, 20 mM Tris-HCl (pH 7.5), 5 mM EDTA, and a protease inhibitor mixture tablet, Complete (Roche Diagnostics, Indianapolis, IN). The lysates were precleared for 1 h with protein G-Sepharose and immunoprecipitated with 2 µg of anti-Flag M2 Ab or 2 µg of anti-HA 12CA5 Ab and protein G-Sepharose for 12 h. The beads were washed with the lysis buffer four times and immunoprecipitated proteins were eluted in SDS-PAGE sample buffer, separated on SDS-PAGE, and transferred onto polyvinylidene difluoride membrane. HA-tagged TLR1 was detected with anti-HA Ab (Roche Diagnostics) and HRP-labeled anti-mouse Ig Ab. Flag-tagged proteins were identified with HRP-conjugated anti-Flag M2 Ab. Then the Abs were detected by the ECL system (DuPont, Boston, MA)

	Results and Discussion

Top Abstract Introduction Materials and Methods Results and Discussion References

 
Generation of TLR1^-/- mice

To investigate the functional role of TLR1, the mouse Tlr1 gene was disrupted by homologous recombination in ES cells. A targeting vector was constructed for the deletion of a part of exon containing aa 575–795 of the mouse Tlr1 gene (Fig. 1A). This portion corresponds to a transmembrane and cytoplasmic region of TLR1. Chimeric males were crossed to C57BL/6 and F₁ heterozygous offspring were obtained. Intercrosses of these heterozygotes gave rise to homozygotes deficient in Tlr1. The targeted disruption of the Tlr1 gene was confirmed by Southern blotting of genomic DNA (Fig. 1B). Peritoneal macrophages from TLR1^-/- mice did not express TLR1 mRNA (Fig. 1C). In contrast, the expression of TLR2 mRNA in TLR1^-/- macrophages was normal compared with that in wild-type cells. TLR1^-/- mice grew healthy, fertile, and did not show any obvious abnormalities for up to 6 mo. Lymphocyte populations in thymocytes and splenocytes were not altered in TLR1^-/- mice (data not shown).

View larger version (37K): [in this window] [in a new window]   FIGURE 1. Establishment of TLR1-deficient mice. A, A mouse TLR1 genomic locus and the targeting vector. A filled box denotes a coding exon. Restriction enzymes: B, BamHI, E, EcoRI. B, Southern blot analysis of genomic DNA extracted from mouse tails digested with BamHI. DNA was electrophoresed, transferred to nylon membrane, and hybridized with the radiolabeled probe indicated in A. C, Northern blotting analysis of thioglycolate-elicited peritoneal macrophages. Total RNA (10 µg) was electrophoresed, transferred onto nylon membrane, and hybridized with a cDNA probe for TLR1. The same membrane was rehybridized with that for TLR2 and GAPDH.

To screen the components recognized by TLR1, we first examined the cytokine production from TLR1^-/- macrophages in response to a variety of PAMPs purified from bacteria. These include the native 19-kDa lipoprotein purified from M. tuberculosis, LPS from Salmonella minnesota Re595, and PGN from Staphylococcus aureus. Thioglycolate-elicited peritoneal macrophages from wild-type and TLR1^-/- mice were cultured in the presence of these PAMPs for 24 h, and the concentration of TNF- in culture supernatant was measured. In response to the 19-kDa lipoprotein, wild-type macrophages produced TNF- in a dose-dependent manner. In contrast, the production of TNF- from TLR1^-/- macrophages was markedly impaired for each concentration of lipoprotein tested (Fig. 2A). The production of IL-6 in response to the lipoprotein was also reduced in TLR1^-/- macrophages compared with that of wild-type cells (Fig. 2B). When stimulated with LPS and PGN, TLR1^-/- macrophages produced TNF- in a dose-dependent manner to almost the same extent as wild-type cells (Fig. 2, C and D). We next examined whether TLR1 is involved in the recognition of whole mycobacteria. Peritoneal macrophages were cultured with increasing amounts of live M. bovis BCG for 24 h, and the concentration of TNF- in culture supernatant was measured. As shown in Fig. 2E, the ability to produce TNF- in response to BCG was partially impaired in TLR1^-/- macrophages. These results indicate that TLR1 is involved in the recognition of the 19-kDa lipoprotein purified from mycobacteria as well as live mycobacteria.

View larger version (28K): [in this window] [in a new window]   FIGURE 2. Impaired TNF- production in response to the mycobacterial 19-kDa lipoprotein in TLR1-deficient macrophages. A, C, D, and E, Peritoneal macrophages (1 x 105) prepared from wild-type and TLR1-/- mice were stimulated with increasing concentrations of 19-kDa lipoprotein purified from M. tuberculosis (A), live M. bovis BCG (C), S. Minnesota Re595 LPS (C), S. aureus PGN (D) and live M. bovis BCG (E) for 24 h. Then TNF- concentration in the culture supernatant was measured by ELISA. Data are shown as the mean ± SD of triplicate wells and are representative of three independent experiments. B, IL-6 concentration was measured in the culture supernatant of wild-type and TLR1-/- macrophages stimulated with 1 µg/ml 19-kDa lipoprotein and 100 ng/ml LPS. Data are shown as the mean ± SD of triplicate wells.

Lipoproteins are produced by a variety of pathogens including mycobacteria, Gram-negative bacteria, and Mycoplasma species (19). The N-terminal acylated lipopeptide region is responsible for the immunostimulatory activity of bacterial and mycoplasmal lipoproteins. Bacterial and mycoplasmal lipoproteins differ in the degree of acylation of N-terminal cysteine. Lipoproteins of bacteria are triacylated, whereas those of mycoplasma are diacylated (20). Synthetic lipoprotein analogs consisting of a palmitoyled version of N-acyl-S-diacyl cysteine and S-diacyl cysteine mimic the immunostimulatory activity of bacterial and mycoplasmal lipoprotein, respectively (21, 22).

We have previously shown that TLR2 is essential for both tri- and diacylated lipopeptide response and TLR6 specifically recognizes diacylated lipopeptide in conjunction with TLR2 (13). Cytokine production in response to the 19-kDa lipoprotein preparation was abrogated in TLR2^-/- macrophages (23). All of these results suggested that TLR1 also cooperates with TLR2 to recognize triacylated lipoprotein. To clarify the chemical structure recognized by TLR1, we stimulated peritoneal macrophages from wild-type and TLR1^-/- mice with the synthetic bacterial lipopeptide Pam₃CSK₄, and synthetic mycoplasmal diacylated MALP-2. TLR1^-/- macrophages showed significantly impaired TNF- production in response to Pam₃CSK₄ compared with wild-type cells, whereas TLR1^-/- cells responded normally to MALP-2 (Fig. 3, A and B). These results indicate that TLR1 is involved in the recognition of triacylated bacterial lipoprotein. In addition, TLR1 and TLR6 differentially recognize TLR2 ligands, distinguishing the degree of acylation of the lipopeptide.

View larger version (32K): [in this window] [in a new window]   FIGURE 3. Involvement of TLR1 in synthetic bacterial lipopeptide recognition. A and B, Peritoneal macrophages (1 x 105) from wild-type and TLR1-/- mice were cultured with increasing concentrations of Pam3CSK4 (A) and synthetic MALP-2 (B) for 24 h. Then the concentration of TNF- was measured. Data are shown as the mean ± SD of triplicate wells and are representative of three independent experiments. C, HEK293 cells were transiently cotransfected with control vector, TLR1, TLR2, and TLR6 expression vectors plus pELAM-luc reporter plasmid. After 24 h, the cells were stimulated with 10 ng/ml Pam3CSK4 for 8 h, and the cell lysates were assayed for luciferase activity. D, HEK293 cells were transiently transfected with the indicated combination of expression vectors for 4.0 µg/ml Flag-TLR2 or Flag-TLR4, and 6.0 µg/ml HA-TLR1. Total amount of plasmid DNA was kept constant with 10 µg by supplementing with empty vector. Thirty-six hours after transfection, the cells were lysed, immunoprecipitated with anti-Flag or anti-HA Ab (IP), and subsequently immunoblotted with anti-Flag or anti-HA Ab (WB) as indicated.

We then examined whether TLR2 and TLR1 interact in mammalian cells. HEK293 cells were cotransfected with Flag-tagged TLR2 or TLR4 and HA-tagged TLR1. Immunoprecipitation of HA-tagged TLR1 resulted in coprecipitation of Flag-tagged TLR2, but not of TLR4 (Fig. 3D). Reciprocally, HA-tagged TLR1 also coprecipitated with Flag-tagged TLR2. However, stimulation with Pam₃CSK₄ did not affect the extent of association between TLR1 and TLR2 (data not shown). These results suggest that TLR1 and TLR2 associate in a ligand-independent manner in HEK293 cells.

N-Pam-S-Lau₂ lipopeptides were preferentially recognized by TLR1

Although the response to Pam₃CSK₄ was significantly impaired in TLR1^-/- mice, we can still observe TLR1-independent cytokine production. Since TLR1 and TLR6 discriminate subtle differences in the lipid moiety of lipopeptides, we hypothesized that there are some other ligands recognized by TLR1 more preferentially and that the configuration of lipid moiety is critical for the involvement of TLR1.

To further screen the specific ligands recognized by TLR1, we synthesized lipopeptides bearing different combinations of fatty acids at their N terminus. These include Myr₃CSK₄, Lau₃CSK₄, N-Pam-S-Lau₂CSK₄, and a lipoprotein analog used for anticancer therapy, JBT3002 (17) As shown in Fig. 4, they differ in the length of fatty acids substituted on the N-terminal cysteine of the peptides. The lipid moiety of N-Pam-S-Lau₂CSK₄ and JBT3002 are the same. We stimulated macrophages from wild-type, TLR1^-/-, and TLR2^-/- mice with these compounds and measured TNF- production. All of these synthetic lipopeptides activated wild-type cells to produce TNF- in a dose-dependent manner (Fig. 4). Macrophages from TLR2^-/- mice did not produce any detectable TNF- in response to either of these lipopeptides. The ability of TLR1^-/- cells to produce TNF- was also impaired in response to Myr₃CSK₄ and Lau₃CSK₄ (Fig. 4, A and B). Interestingly, when stimulated with N-Pam-S-Lau₂CSK₄ and JBT3002, the production TNF- of was profoundly defective in TLR1^-/- cells, indicating that a subtle difference in lipid moiety of lipoprotein is critical for the TLR1 requirement (Fig. 4, C and D).

View larger version (28K): [in this window] [in a new window]   FIGURE 4. Differences in the lipoylation altered TLR1 responsibility. Peritoneal macrophages (1 x 105) from wild-type, TLR1-/-, and TLR2-/- mice were stimulated with increasing concentrations of Myr3CSK4 (A), Lau3CSK4 (B), N-Pam-S-Lau2CSK4 (C), and JBT3002 (D) for 24 h. Then the concentration of TNF- was measured. The results are shown as the mean ± SD of triplicate wells and are representative of three independent experiments.

	Acknowledgments

 
We thank E. Horita for excellent secretarial assistance and N. Okita for excellent technical assistance.

	Footnotes

 
¹ This work was supported by Special Coordination Funds of the Ministry of Education, Culture, Sports, Science and Technology, from the Japanese Government.

² Current address: Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, One Jimmy Fund Way, Boston, MA 02115.

³ Address correspondence and reprint requests to Dr. Shizuo Akira, Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan. E-mail address: sakira{at}biken.osaka-u.ac.jp

⁴ Abbreviations used in this paper: TLR, Toll-like receptor; PGN, peptidoglycan; PAMP, pathogen-associated molecular pattern; MALP-2, macrophage-activating lipopeptide 2 kDa; ES, embryonic stem; BCG, bacillus Calmette Guérin; HA, hemagglutinin; HEK, human embryonic kidney; Pam₃, N-palmitoyl-S-dipalmitoylglyceryl; N-Pam-5-Lau₂, N-palmitoyl-S-dilaurylglyceryl; Lau₃, N-lauryl-S-dilaurylglyceryl; Myr₃, N-myristyl-S-dimyristylglyceryl; CSK₄, Cys-Ser-(Lys)₄.

Received for publication March 25, 2002. Accepted for publication May 8, 2002.

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				P. E. Almeida, A. R. Silva, C. M. Maya-Monteiro, D. Torocsik, H. D'Avila, B. Dezso, K. G. Magalhaes, H. C. Castro-Faria-Neto, L. Nagy, and P. T. Bozza Mycobacterium bovis Bacillus Calmette-Guerin Infection Induces TLR2-Dependent Peroxisome Proliferator-Activated Receptor {gamma} Expression and Activation: Functions in Inflammation, Lipid Metabolism, and Pathogenesis J. Immunol., July 15, 2009; 183(2): 1337 - 1345. [Abstract] [Full Text] [PDF]

				A.-C. Raby, E. Le Bouder, C. Colmont, J. Davies, P. Richards, B. Coles, C. H. George, S. A. Jones, P. Brennan, N. Topley, et al. Soluble TLR2 Reduces Inflammation without Compromising Bacterial Clearance by Disrupting TLR2 Triggering J. Immunol., July 1, 2009; 183(1): 506 - 517. [Abstract] [Full Text] [PDF]

				Q.-L. Wu, I. N. Buhtoiarov, P. M. Sondel, A. L. Rakhmilevich, and E. A. Ranheim Tumoricidal Effects of Activated Macrophages in a Mouse Model of Chronic Lymphocytic Leukemia J. Immunol., June 1, 2009; 182(11): 6771 - 6778. [Abstract] [Full Text] [PDF]

				R. Covacu, L. Arvidsson, A. Andersson, M. Khademi, H. Erlandsson-Harris, R. A. Harris, M. A. Svensson, T. Olsson, and L. Brundin TLR Activation Induces TNF-{alpha} Production from Adult Neural Stem/Progenitor Cells J. Immunol., June 1, 2009; 182(11): 6889 - 6895. [Abstract] [Full Text] [PDF]

				K. Kurokawa, H. Lee, K.-B. Roh, M. Asanuma, Y. S. Kim, H. Nakayama, A. Shiratsuchi, Y. Choi, O. Takeuchi, H. J. Kang, et al. The Triacylated ATP Binding Cluster Transporter Substrate-binding Lipoprotein of Staphylococcus aureus Functions as a Native Ligand for Toll-like Receptor 2 J. Biol. Chem., March 27, 2009; 284(13): 8406 - 8411. [Abstract] [Full Text] [PDF]

				V. Cerovic, C. D. Jenkins, A. G. C. Barnes, S. W. F. Milling, G. G. MacPherson, and L. S. Klavinskis Hyporesponsiveness of Intestinal Dendritic Cells to TLR Stimulation Is Limited to TLR4 J. Immunol., February 15, 2009; 182(4): 2405 - 2415. [Abstract] [Full Text] [PDF]

				P. Blair, S. Rex, O. Vitseva, L. Beaulieu, K. Tanriverdi, S. Chakrabarti, C. Hayashi, C. A. Genco, M. Iafrati, and J. E. Freedman Stimulation of Toll-Like Receptor 2 in Human Platelets Induces a Thromboinflammatory Response Through Activation of Phosphoinositide 3-Kinase Circ. Res., February 13, 2009; 104(3): 346 - 354. [Abstract] [Full Text] [PDF]

				L. M. Gargano, J. C. Forrest, and S. H. Speck Signaling through Toll-Like Receptors Induces Murine Gammaherpesvirus 68 Reactivation In Vivo J. Virol., February 1, 2009; 83(3): 1474 - 1482. [Abstract] [Full Text] [PDF]

				S. A. Gomez, C. L. Arguelles, D. Guerrieri, N. L. Tateosian, N. O. Amiano, R. Slimovich, P. C. Maffia, E. Abbate, R. M. Musella, V. E. Garcia, et al. Secretory Leukocyte Protease Inhibitor: A Secreted Pattern Recognition Receptor for Mycobacteria Am. J. Respir. Crit. Care Med., February 1, 2009; 179(3): 247 - 253. [Abstract] [Full Text] [PDF]

				L. Sweet, W. Zhang, H. Torres-Fewell, A. Serianni, W. Boggess, and J. Schorey Mycobacterium avium Glycopeptidolipids Require Specific Acetylation and Methylation Patterns for Signaling through Toll-like Receptor 2 J. Biol. Chem., November 28, 2008; 283(48): 33221 - 33231. [Abstract] [Full Text] [PDF]

				T. Kiyokawa, S. Akashi-Takamura, T. Shibata, F. Matsumoto, C. Nishitani, Y. Kuroki, Y. Seto, and K. Miyake A single base mutation in the PRAT4A gene reveals differential interaction of PRAT4A with Toll-like receptors Int. Immunol., November 1, 2008; 20(11): 1407 - 1415. [Abstract] [Full Text] [PDF]

				M. R. Dasu, S. Devaraj, L. Zhao, D. H. Hwang, and I. Jialal High Glucose Induces Toll-Like Receptor Expression in Human Monocytes: Mechanism of Activation Diabetes, November 1, 2008; 57(11): 3090 - 3098. [Abstract] [Full Text] [PDF]

				A. L. F. Bernardino, T. A. Myers, X. Alvarez, A. Hasegawa, and M. T. Philipp Toll-Like Receptors: Insights into Their Possible Role in the Pathogenesis of Lyme Neuroborreliosis Infect. Immun., October 1, 2008; 76(10): 4385 - 4395. [Abstract] [Full Text] [PDF]

				M. Miettinen, V. Veckman, S. Latvala, T. Sareneva, S. Matikainen, and I. Julkunen Live Lactobacillus rhamnosus and Streptococcus pyogenes differentially regulate Toll-like receptor (TLR) gene expression in human primary macrophages J. Leukoc. Biol., October 1, 2008; 84(4): 1092 - 1100. [Abstract] [Full Text] [PDF]

				M. M. Wurfel, A. C. Gordon, T. D. Holden, F. Radella, J. Strout, O. Kajikawa, J. T. Ruzinski, G. Rona, R. A. Black, S. Stratton, et al. Toll-like Receptor 1 Polymorphisms Affect Innate Immune Responses and Outcomes in Sepsis Am. J. Respir. Crit. Care Med., October 1, 2008; 178(7): 710 - 720. [Abstract] [Full Text] [PDF]

				H. Wu, H. Wang, W. Xiong, S. Chen, H. Tang, and D. Han Expression Patterns and Functions of Toll-Like Receptors in Mouse Sertoli Cells Endocrinology, September 1, 2008; 149(9): 4402 - 4412. [Abstract] [Full Text] [PDF]

				M. Q. Nicol, J.-M. Mathys, A. Pereira, K. Ollington, M. H. Ieong, and P. R. Skolnik Human Immunodeficiency Virus Infection Alters Tumor Necrosis Factor Alpha Production via Toll-Like Receptor-Dependent Pathways in Alveolar Macrophages and U1 Cells J. Virol., August 15, 2008; 82(16): 7790 - 7798. [Abstract] [Full Text] [PDF]

				T. Shimizu, Y. Kida, and K. Kuwano A Triacylated Lipoprotein from Mycoplasma genitalium Activates NF-{kappa}B through Toll-Like Receptor 1 (TLR1) and TLR2 Infect. Immun., August 1, 2008; 76(8): 3672 - 3678. [Abstract] [Full Text] [PDF]

				N. J. Nilsen, S. Deininger, U. Nonstad, F. Skjeldal, H. Husebye, D. Rodionov, S. von Aulock, T. Hartung, E. Lien, O. Bakke, et al. Cellular trafficking of lipoteichoic acid and Toll-like receptor 2 in relation to signaling; role of CD14 and CD36 J. Leukoc. Biol., July 1, 2008; 84(1): 280 - 291. [Abstract] [Full Text] [PDF]

				J. Nigou, T. Vasselon, A. Ray, P. Constant, M. Gilleron, G. S. Besra, I. Sutcliffe, G. Tiraby, and G. Puzo Mannan Chain Length Controls Lipoglycans Signaling via and Binding to TLR2 J. Immunol., May 15, 2008; 180(10): 6696 - 6702. [Abstract] [Full Text] [PDF]

				T. Shimizu, Y. Kida, and K. Kuwano Ureaplasma parvum lipoproteins, including MB antigen, activate NF-{kappa}B through TLR1, TLR2 and TLR6 Microbiology, May 1, 2008; 154(5): 1318 - 1325. [Abstract] [Full Text] [PDF]

				D. L. Trott, E. M. Hellestad, M. Yang, and M. E. Cook Additions of Killed Whole Cell Bacteria Preparations to Freund Complete Adjuvant Alter Laying Hen Antibody Response to Soluble Protein Antigen Poult. Sci., May 1, 2008; 87(5): 912 - 917. [Abstract] [Full Text] [PDF]

				M. Peiser, J. Koeck, C. J. Kirschning, B. Wittig, and R. Wanner Human Langerhans cells selectively activated via Toll-like receptor 2 agonists acquire migratory and CD4+T cell stimulatory capacity J. Leukoc. Biol., May 1, 2008; 83(5): 1118 - 1127. [Abstract] [Full Text] [PDF]

				V. M. Abrahams, P. B. Aldo, S. P. Murphy, I. Visintin, K. Koga, G. Wilson, R. Romero, S. Sharma, and G. Mor TLR6 Modulates First Trimester Trophoblast Responses to Peptidoglycan J. Immunol., May 1, 2008; 180(9): 6035 - 6043. [Abstract] [Full Text] [PDF]

				P. Henneke, S. Dramsi, G. Mancuso, K. Chraibi, E. Pellegrini, C. Theilacker, J. Hubner, S. Santos-Sierra, G. Teti, D. T. Golenbock, et al. Lipoproteins Are Critical TLR2 Activating Toxins in Group B Streptococcal Sepsis J. Immunol., May 1, 2008; 180(9): 6149 - 6158. [Abstract] [Full Text] [PDF]

				L. S. de Paiva, A. Nobrega, G. O. De Melo, E. A. Hayashi, V. Carvalho, P. M. Rodrigues e Silva, M. Bellio, G. P. Teixeira, V. Rumjanek, S. S. Costa, et al. Selective blockade of lymphopoiesis induced by kalanchosine dimalate: inhibition of IL-7-dependent proliferation J. Leukoc. Biol., April 1, 2008; 83(4): 1038 - 1048. [Abstract] [Full Text] [PDF]

				K. Farhat, S. Riekenberg, H. Heine, J. Debarry, R. Lang, J. Mages, U. Buwitt-Beckmann, K. Roschmann, G. Jung, K.-H. Wiesmuller, et al. Heterodimerization of TLR2 with TLR1 or TLR6 expands the ligand spectrum but does not lead to differential signaling J. Leukoc. Biol., March 1, 2008; 83(3): 692 - 701. [Abstract] [Full Text] [PDF]

				A. Pegu, S. Qin, B. A. Fallert Junecko, R. E. Nisato, M. S. Pepper, and T. A. Reinhart Human Lymphatic Endothelial Cells Express Multiple Functional TLRs J. Immunol., March 1, 2008; 180(5): 3399 - 3405. [Abstract] [Full Text] [PDF]

				S. Thakran, H. Li, C. L. Lavine, M. A. Miller, J. E. Bina, X. R. Bina, and F. Re Identification of Francisella tularensis Lipoproteins That Stimulate the Toll-like Receptor (TLR) 2/TLR1 Heterodimer J. Biol. Chem., February 15, 2008; 283(7): 3751 - 3760. [Abstract] [Full Text] [PDF]

				D. Yang, Q. Chen, S. B. Su, P. Zhang, K. Kurosaka, R. R. Caspi, S. M. Michalek, H. F. Rosenberg, N. Zhang, and J. J. Oppenheim Eosinophil-derived neurotoxin acts as an alarmin to activate the TLR2-MyD88 signal pathway in dendritic cells and enhances Th2 immune responses J. Exp. Med., January 21, 2008; 205(1): 79 - 90. [Abstract] [Full Text] [PDF]

				S. Bas, L. Neff, M. Vuillet, U. Spenato, T. Seya, M. Matsumoto, and C. Gabay The Proinflammatory Cytokine Response to Chlamydia trachomatis Elementary Bodies in Human Macrophages Is Partly Mediated by a Lipoprotein, the Macrophage Infectivity Potentiator, through TLR2/TLR1/TLR6 and CD14 J. Immunol., January 15, 2008; 180(2): 1158 - 1168. [Abstract] [Full Text] [PDF]

				T. Shimizu, Y. Kida, and K. Kuwano Mycoplasma pneumoniae-Derived Lipopeptides Induce Acute Inflammatory Responses in the Lungs of Mice Infect. Immun., January 1, 2008; 76(1): 270 - 277. [Abstract] [Full Text] [PDF]

				J. Ruby, K. Rehani, and M. Martin Treponema denticola Activates Mitogen-Activated Protein Kinase Signal Pathways through Toll-Like Receptor 2 Infect. Immun., December 1, 2007; 75(12): 5763 - 5768. [Abstract] [Full Text] [PDF]

				Q. Zhou and S. Amar Identification of Signaling Pathways in Macrophage Exposed to Porphyromonas gingivalis or to Its Purified Cell Wall Components J. Immunol., December 1, 2007; 179(11): 7777 - 7790. [Abstract] [Full Text] [PDF]

				T. R. Murphy, H. J. Legere III, and H. R. Katz Activation of Protein Kinase D1 in Mast Cells in Response to Innate, Adaptive, and Growth Factor Signals J. Immunol., December 1, 2007; 179(11): 7876 - 7882. [Abstract] [Full Text] [PDF]

				K. Takahashi, T. Shibata, S. Akashi-Takamura, T. Kiyokawa, Y. Wakabayashi, N. Tanimura, T. Kobayashi, F. Matsumoto, R. Fukui, T. Kouro, et al. A protein associated with Toll-like receptor (TLR) 4 (PRAT4A) is required for TLR-dependent immune responses J. Exp. Med., November 26, 2007; 204(12): 2963 - 2976. [Abstract] [Full Text] [PDF]

				A. J. Tonks, E. Dudley, N. G. Porter, J. Parton, J. Brazier, E. L. Smith, and A. Tonks A 5.8-kDa component of manuka honey stimulates immune cells via TLR4 J. Leukoc. Biol., November 1, 2007; 82(5): 1147 - 1155. [Abstract] [Full Text] [PDF]

				J. Geisel, F. Kahl, M. Muller, H. Wagner, C. J. Kirschning, I. B. Autenrieth, and J.-S. Frick IL-6 and Maturation Govern TLR2 and TLR4 Induced TLR Agonist Tolerance and Cross-Tolerance in Dendritic Cells J. Immunol., November 1, 2007; 179(9): 5811 - 5818. [Abstract] [Full Text] [PDF]

				H. Chen, M. J. Cowan, J. D. Hasday, S. N. Vogel, and A. E. Medvedev Tobacco Smoking Inhibits Expression of Proinflammatory Cytokines and Activation of IL-1R-Associated Kinase, p38, and NF-{kappa}B in Alveolar Macrophages Stimulated with TLR2 and TLR4 Agonists J. Immunol., November 1, 2007; 179(9): 6097 - 6106. [Abstract] [Full Text] [PDF]

				S. Bhatnagar, K. Shinagawa, F. J. Castellino, and J. S. Schorey Exosomes released from macrophages infected with intracellular pathogens stimulate a proinflammatory response in vitro and in vivo Blood, November 1, 2007; 110(9): 3234 - 3244. [Abstract] [Full Text] [PDF]

				Y.-C. Chen, E. Giovannucci, P. Kraft, R. Lazarus, and D. J. Hunter Association between Toll-Like Receptor Gene Cluster (TLR6, TLR1, and TLR10) and Prostate Cancer Cancer Epidemiol. Biomarkers Prev., October 1, 2007; 16(10): 1982 - 1989. [Abstract] [Full Text] [PDF]

				S. Thibault, M. R. Tardif, C. Barat, and M. J. Tremblay TLR2 Signaling Renders Quiescent Naive and Memory CD4+ T Cells More Susceptible to Productive Infection with X4 and R5 HIV-Type 1 J. Immunol., October 1, 2007; 179(7): 4357 - 4366. [Abstract] [Full Text] [PDF]

				S. Young Goo, Y. S. Han, W. H. Kim, K.-H. Lee, and S.-J. Park Vibrio vulnificus IlpA-induced Cytokine Production Is Mediated by Toll-like Receptor 2 J. Biol. Chem., September 21, 2007; 282(38): 27647 - 27658. [Abstract] [Full Text] [PDF]

				D. Vallois, C. H. Grimm, P. Avner, C. Boitard, and U. C. Rogner The Type 1 Diabetes Locus Idd6 Controls TLR1 Expression J. Immunol., September 15, 2007; 179(6): 3896 - 3903. [Abstract] [Full Text] [PDF]

				H. MacLeod and L. M. Wetzler T Cell Activation by TLRs: A Role for TLRs in the Adaptive Immune Response Sci. Signal., September 4, 2007; 2007(402): pe48 - pe48. [Abstract] [Full Text] [PDF]

				C. M. Fremond, D. Togbe, E. Doz, S. Rose, V. Vasseur, I. Maillet, M. Jacobs, B. Ryffel, and V. F. J. Quesniaux IL-1 Receptor-Mediated Signal Is an Essential Component of MyD88-Dependent Innate Response to Mycobacterium tuberculosis Infection J. Immunol., July 15, 2007; 179(2): 1178 - 1189. [Abstract] [Full Text] [PDF]

				J. R. Dye, A. Palvanov, B. Guo, and T. L. Rothstein B Cell Receptor Cross-Talk: Exposure to Lipopolysaccharide Induces an Alternate Pathway for B Cell Receptor-Induced ERK Phosphorylation and NF-{kappa}B Activation J. Immunol., July 1, 2007; 179(1): 229 - 235. [Abstract] [Full Text] [PDF]

				C. M. Johnson, E. A. Lyle, K. O. Omueti, V. A. Stepensky, O. Yegin, E. Alpsoy, L. Hamann, R. R. Schumann, and R. I. Tapping Cutting Edge: A Common Polymorphism Impairs Cell Surface Trafficking and Functional Responses of TLR1 but Protects against Leprosy J. Immunol., June 15, 2007; 178(12): 7520 - 7524. [Abstract] [Full Text] [PDF]

				J. A Mitchell, M. J Paul-Clark, G. W Clarke, S. K McMaster, and N. Cartwright Critical role of toll-like receptors and nucleotide oligomerisation domain in the regulation of health and disease J. Endocrinol., June 1, 2007; 193(3): 323 - 330. [Abstract] [Full Text] [PDF]

				T. Imanishi, H. Hara, S. Suzuki, N. Suzuki, S. Akira, and T. Saito Cutting Edge: TLR2 Directly Triggers Th1 Effector Functions J. Immunol., June 1, 2007; 178(11): 6715 - 6719. [Abstract] [Full Text] [PDF]

				A. M. Keestra, M. R. de Zoete, R. A. M. H. van Aubel, and J. P. M. van Putten The Central Leucine-Rich Repeat Region of Chicken TLR16 Dictates Unique Ligand Specificity and Species-Specific Interaction with TLR2 J. Immunol., June 1, 2007; 178(11): 7110 - 7119. [Abstract] [Full Text] [PDF]

				K. O. Omueti, D. J. Mazur, K. S. Thompson, E. A. Lyle, and R. I. Tapping The Polymorphism P315L of Human Toll-Like Receptor 1 Impairs Innate Immune Sensing of Microbial Cell Wall Components J. Immunol., May 15, 2007; 178(10): 6387 - 6394. [Abstract] [Full Text] [PDF]

				O. Hoffmann, J. S. Braun, D. Becker, A. Halle, D. Freyer, E. Dagand, S. Lehnardt, and J. R. Weber TLR2 Mediates Neuroinflammation and Neuronal Damage J. Immunol., May 15, 2007; 178(10): 6476 - 6481. [Abstract] [Full Text] [PDF]

				T. Into, J.-i. Dohkan, M. Inomata, M. Nakashima, K.-i. Shibata, and K. Matsushita Synthesis and Characterization of a Dipalmitoylated Lipopeptide Derived from Paralogous Lipoproteins of Mycoplasma pneumoniae Infect. Immun., May 1, 2007; 75(5): 2253 - 2259. [Abstract] [Full Text] [PDF]

				D. Togbe, L. Schofield, G. E. Grau, B. Schnyder, V. Boissay, S. Charron, S. Rose, B. Beutler, V. F.J. Quesniaux, and B. Ryffel Murine Cerebral Malaria Development Is Independent of Toll-Like Receptor Signaling Am. J. Pathol., May 1, 2007; 170(5): 1640 - 1648. [Abstract] [Full Text] [PDF]

				M. Hashimoto, M. Furuyashiki, R. Kaseya, Y. Fukada, M. Akimaru, K. Aoyama, T. Okuno, T. Tamura, T. Kirikae, F. Kirikae, et al. Evidence of Immunostimulating Lipoprotein Existing in the Natural Lipoteichoic Acid Fraction Infect. Immun., April 1, 2007; 75(4): 1926 - 1932. [Abstract] [Full Text] [PDF]

				Y. Asai, Y. Makimura, and T. Ogawa Toll-like receptor 2-mediated dendritic cell activation by a Porphyromonas gingivalis synthetic lipopeptide J. Med. Microbiol., April 1, 2007; 56(4): 459 - 465. [Abstract] [Full Text] [PDF]

				T. Kielian, N. K. Phulwani, N. Esen, M. Md. Syed, A. C. Haney, K. McCastlain, and J. Johnson MyD88-Dependent Signals Are Essential for the Host Immune Response in Experimental Brain Abscess J. Immunol., April 1, 2007; 178(7): 4528 - 4537. [Abstract] [Full Text] [PDF]

				K. R. Alugupalli, S. Akira, E. Lien, and J. M. Leong MyD88- and Bruton's Tyrosine Kinase-Mediated Signals Are Essential for T Cell-Independent Pathogen-Specific IgM Responses J. Immunol., March 15, 2007; 178(6): 3740 - 3749. [Abstract] [Full Text] [PDF]

				S. Liang, M. Wang, R. I. Tapping, V. Stepensky, H. F. Nawar, M. Triantafilou, K. Triantafilou, T. D. Connell, and G. Hajishengallis Ganglioside GD1a Is an Essential Coreceptor for Toll-like Receptor 2 Signaling in Response to the B subunit of Type IIb Enterotoxin J. Biol. Chem., March 9, 2007; 282(10): 7532 - 7542. [Abstract] [Full Text] [PDF]

				S. Hamm, A. Heit, M. Koffler, K. M. Huster, S. Akira, D. H. Busch, H. Wagner, and S. Bauer Immunostimulatory RNA is a potent inducer of antigen-specific cytotoxic and humoral immune response in vivo Int. Immunol., March 1, 2007; 19(3): 297 - 304. [Abstract] [Full Text] [PDF]

				V. Y. Toshchakov, M. J. Fenton, and S. N. Vogel Cutting Edge: Differential Inhibition of TLR Signaling Pathways by Cell-Permeable Peptides Representing BB Loops of TLRs J. Immunol., March 1, 2007; 178(5): 2655 - 2660. [Abstract] [Full Text] [PDF]

				M. Wiens, M. Korzhev, S. Perovic-Ottstadt, B. Luthringer, D. Brandt, S. Klein, and W. E. G. Muller Toll-Like Receptors Are Part of the Innate Immune Defense System of Sponges (Demospongiae: Porifera) Mol. Biol. Evol., March 1, 2007; 24(3): 792 - 804. [Abstract] [Full Text] [PDF]

				M. Pevsner-Fischer, V. Morad, M. Cohen-Sfady, L. Rousso-Noori, A. Zanin-Zhorov, S. Cohen, I. R. Cohen, and D. Zipori Toll-like receptors and their ligands control mesenchymal stem cell functions Blood, February 15, 2007; 109(4): 1422 - 1432. [Abstract] [Full Text] [PDF]

				N. Satta, S. Dunoyer-Geindre, G. Reber, R. J. Fish, F. Boehlen, E. K. O. Kruithof, and P. de Moerloose The role of TLR2 in the inflammatory activation of mouse fibroblasts by human antiphospholipid antibodies Blood, February 15, 2007; 109(4): 1507 - 1514. [Abstract] [Full Text] [PDF]

				M.-F. Tsan and Baochong Gao Review: Pathogen-associated molecular pattern contamination as putative endogenous ligands of Toll-like receptors Innate Immunity, February 1, 2007; 13(1): 6 - 14. [Abstract] [PDF]

				R. Aflatoonian, E. Tuckerman, S.L. Elliott, C. Bruce, A. Aflatoonian, T.C. Li, and A. Fazeli Menstrual cycle-dependent changes of Toll-like receptors in endometrium Hum. Reprod., February 1, 2007; 22(2): 586 - 593. [Abstract] [Full Text] [PDF]

				D. van Duin, S. Mohanty, V. Thomas, S. Ginter, R. R. Montgomery, E. Fikrig, H. G. Allore, R. Medzhitov, and A. C. Shaw Age-Associated Defect in Human TLR-1/2 Function J. Immunol., January 15, 2007; 178(2): 970 - 975. [Abstract] [Full Text] [PDF]

				A. Bagchi, E. A. Herrup, H. S. Warren, J. Trigilio, H.-S. Shin, C. Valentine, and J. Hellman MyD88-Dependent and MyD88-Independent Pathways in Synergy, Priming, and Tolerance between TLR Agonists J. Immunol., January 15, 2007; 178(2): 1164 - 1171. [Abstract] [Full Text] [PDF]

				C. Erridge, C. M. Spickett, and D. J. Webb Non-enterobacterial endotoxins stimulate human coronary artery but not venous endothelial cell activation via Toll-like receptor 2 Cardiovasc Res, January 1, 2007; 73(1): 181 - 189. [Abstract] [Full Text] [PDF]

				J. Wang, Y. Shao, T. A. Bennett, R. A. Shankar, P. D. Wightman, and L. G. Reddy The Functional Effects of Physical Interactions among Toll-like Receptors 7, 8, and 9 J. Biol. Chem., December 8, 2006; 281(49): 37427 - 37434. [Abstract] [Full Text] [PDF]

				D. D. Bolz, R. S. Sundsbak, Y. Ma, S. Akira, J. H. Weis, T. G. Schwan, and J. J. Weis Dual Role of MyD88 in Rapid Clearance of Relapsing Fever Borrelia spp. Infect. Immun., December 1, 2006; 74(12): 6750 - 6760. [Abstract] [Full Text] [PDF]

				V. Flacher, M. Bouschbacher, E. Verronese, C. Massacrier, V. Sisirak, O. Berthier-Vergnes, B. de Saint-Vis, C. Caux, C. Dezutter-Dambuyant, S. Lebecque, et al. Human Langerhans Cells Express a Specific TLR Profile and Differentially Respond to Viruses and Gram-Positive Bacteria J. Immunol., December 1, 2006; 177(11): 7959 - 7967. [Abstract] [Full Text] [PDF]

				Y. F. Lau, G. Deliyannis, W. Zeng, A. Mansell, D. C. Jackson, and L. E. Brown Lipid-containing mimetics of natural triggers of innate immunity as CTL-inducing influenza vaccines Int. Immunol., December 1, 2006; 18(12): 1801 - 1813. [Abstract] [Full Text] [PDF]

				M. Triantafilou, F. G. J. Gamper, R. M. Haston, M. A. Mouratis, S. Morath, T. Hartung, and K. Triantafilou Membrane Sorting of Toll-like Receptor (TLR)-2/6 and TLR2/1 Heterodimers at the Cell Surface Determines Heterotypic Associations with CD36 and Intracellular Targeting J. Biol. Chem., October 13, 2006; 281(41): 31002 - 31011. [Abstract] [Full Text] [PDF]

				H. Li, S. Nookala, X. R. Bina, J. E. Bina, and F. Re Innate immune response to Francisella tularensis is mediated by TLR2 and caspase-1 activation J. Leukoc. Biol., October 1, 2006; 80(4): 766 - 773. [Abstract] [Full Text] [PDF]

				M. Hashimoto, K. Tawaratsumida, H. Kariya, A. Kiyohara, Y. Suda, F. Krikae, T. Kirikae, and F. Gotz Not Lipoteichoic Acid but Lipoproteins Appear to Be the Dominant Immunobiologically Active Compounds in Staphylococcus aureus. J. Immunol., September 1, 2006; 177(5): 3162 - 3169. [Abstract] [Full Text] [PDF]

				K. Miyake Invited review: Roles for accessory molecules in microbial recognition by Toll-like receptors Innate Immunity, August 1, 2006; 12(4): 195 - 204. [Abstract] [PDF]

				A. Punturieri, P. Copper, T. Polak, P. J. Christensen, and J. L. Curtis Conserved Nontypeable Haemophilus influenzae-Derived TLR2-Binding Lipopeptides Synergize with IFN-beta to Increase Cytokine Production by Resident Murine and Human Alveolar Macrophages J. Immunol., July 1, 2006; 177(1): 673 - 680. [Abstract] [Full Text] [PDF]

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