A recombinant lipoprotein containing an unsaturated fatty acid activates NF-κB through the TLR2 signaling pathway and induces a differential gene profile from a synthetic lipopeptide

Leng, Chih Hsiang; Chen, Hsin–Wei; Chang, Li Sheng; Liu, Hsueh Hung; Liu, Hsin‐Yu; Sher, Yuh Pyng; Chang, Yu Yin; Lien, Shu Pei; Huang, Tzu Yi; Chen, Mei Yu; Chou, Ai Hsiang; Chong, Pele; Liu, Shih‐Jen

doi:10.1016/j.molimm.2010.04.012

Cited by 44 publications

(40 citation statements)

References 34 publications

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“…This suggests that the protein moiety of rlip-TbpB also plays a role, by providing Thelper (Th) epitopes or another additive signal. This hypothesis is in line with a recent paper (40), showing that a lipidated protein (recombinant lipidated DEN3 construct) had a better stimulating effect in vitro on mouse spleen cells than a synthetic peptidic agonist (Pam3), inducing, in particular, a different gene expression profile. A simple mixture of a synthetic TLR2 agonist (Pam2CSK4) with the nonlipidated protein is not active as an adjuvant for LOS, suggesting that a covalent link between the protein and the lipid moiety is required.…”

Section: Discussionsupporting

confidence: 88%

Improvement of Immunogenicity of Meningococcal Lipooligosaccharide by Coformulation with Lipidated Transferrin-Binding Protein B in Liposomes: Implications for Vaccine Development

Mistretta¹,

Guy²,

Bérard³

et al. 2012

Clin. Vaccine Immunol.

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ABSTRACTAmong various meningococcal antigens, lipooligosaccharide (LOS) and recombinant lipidated transferrin-binding protein B (rlip-TbpB) are considered to be putative vaccine candidates against group BNeisseria meningitidis. In the present work, we report the development of a new liposome-based vaccine formulation containing both rlip-TbpB and L8 LOS. The endotoxic activity of the liposomal LOS was evaluatedin vitrousing theLimulusAmebocyte Lysate assay and compared to the endotoxic activity of free LOS. Above a 250:1 lipid/LOS molar ratio, liposomes were shown to effectively detoxify the LOS as the endotoxic activity of the LOS was reduced by more than 99%. Immunogenicity studies in rabbits showed that the presence of rlip-TbpB dramatically increased the immunogenicity of the LOS. While the formulation raised a strong anti-TbpB response, it elicited a higher anti-LOS IgG level than the liposomal LOS alone. Sera from rabbits immunized with rlip-TbpB/liposomal LOS displayed increased ability to recognize LOS on live bacteria expressing the L8 immunotype and increased anti-LOS-specific bactericidal activity compared to sera from rabbits immunized with liposomal LOS alone. Measurement of interleukin-8 (IL-8) produced by HEK293 cells transfected with Toll-like receptor (TLR) after stimulation with rlip-TbpB showed that the protein is a TLR2 agonist, which is in accordance with the structure of its lipid. Furthermore, anin vivostudy demonstrated that the lipid moiety is not only required for its adjuvant effect but also has to be linked to the protein. Overall, the rlip-TbpB/LOS liposomal formulation was demonstrated to induce an effective anti-LOS response due to the adjuvant effect of rlip-TbpB on LOS.

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Section: Discussionsupporting

confidence: 88%

Improvement of Immunogenicity of Meningococcal Lipooligosaccharide by Coformulation with Lipidated Transferrin-Binding Protein B in Liposomes: Implications for Vaccine Development

Mistretta¹,

Guy²,

Bérard³

et al. 2012

Clin. Vaccine Immunol.

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“…A similar observation was made using Pam2EQL as a model. Moreover, the engagement of TLR2 led to the activation of multiple signaling pathways in DCs, including JNK, p38, ERK, MyD88, and NF-kB signaling (32,33). Our data showed that the upregulation of Rab7 is dependent on MyD88 pathway (Fig.…”

Section: Discussionmentioning

confidence: 53%

“…4B, 4C). Previous studies showed TLR2 activation resulted in downstream MAPK signaling, such as JNK, p38, and ERK signaling (32,33). To further investigate the signaling pathways of TLR2 that regulate Rab7 expression, MAPK signaling inhibitors were used to treat BMDCs.…”

Section: Tlr2 Facilitates Pam2idg Endocytosis By Bmdcs and Is Requirementioning

confidence: 99%

Molecular Mechanisms of TLR2-Mediated Antigen Cross-Presentation in Dendritic Cells

Shen

Song

Chen

et al. 2014

The Journal of Immunology

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Cross-presentation is a key function of dendritic cells (DCs), which present exogenous Ags on MHC class I molecules to prime CTL responses. The effects of TLR triggering on the cross-presentation of exogenous Ags by DCs remain unclear. In this study, we used synthetic dipalmitoylated peptides and TLR2 agonist–conjugated peptides as models to elucidate the mechanisms of TLR2-mediated cross-presentation. We observed that the internalization of dipalmitoylated peptides by bone marrow–derived DCs was facilitated by TLR2 via clathrin-mediated endocytosis. The administration of these dipalmitoylated peptide-pulsed bone marrow–derived DCs eliminated established tumors through TLR2 signaling. We further demonstrated that the induction of Ag-specific CTL responses and tumor regression by dipalmitoylated peptides was TAP independent. In addition, presentation of dipalmitoylated peptides by MHC class I molecules was blocked in the presence of an endosomal acidification inhibitor (chloroquine) or a lysosomal degradation inhibitor (Z-FL-COCHO). The endocytosed dipalmitoylated peptide also passed rapidly from early endosome Ag-1–positive endosomes to RAS-related GTP-binding protein 7 (Rab7)–associated late endosomes compared with their nonlipidated counterparts. Furthermore, we found that dipalmitoylated peptide–upregulated Rab7 expression correlated with Ag presentation via the TLR2/MyD88 pathway. Both JNK and ERK signaling pathways are required for upregulation of Rab7. In summary, our data suggest that TLR2-mediated cross-presentation occurs through the upregulation of Rab7 and a TAP-independent pathway that prime CTL responses.

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“…These results are different from those obtained from rAg473 which can induced DC maturation in TLR2 À/À mice, and support that rAg473 may assume various supramolecular structures which may affect the TLR dependence. Further studies (Chen et al, 2009;Leng et al, 2010) indicated that rlipo-D1E3 induced significant production of TNF-α, IL-6, and IL-12p40 from the BMDCs of wild-type and TLR4-deficient mice but not from the BMDCs of TLR2 À/À mice (p < 0.01). rlipo-D1E3 immunized wild-type and TLR4-deficient mice produced equivalent IgG titers of anti-rE3 antibodies, but anti-rE3 antibody titers were decreased when TLR2 À/À mice were immunized.…”

Section: Recombinant Chimeric Lipoproteins Can Activate Bmdcsmentioning

confidence: 98%

“…After incubation for 24 h, the supernatants were harvested and analyzed for TNF-α, IL-6, and IL12p40 by ELISA. The figure is adapted from Leng et al (2010) with permission from the publisher, Elsevier.…”

Section: Recombinant Chimeric Lipoproteins Can Activate Bmdcsmentioning

confidence: 99%

Recombinant Lipoproteins as Novel Vaccines with Intrinsic Adjuvant

Chong

Huang

Leng

et al. 2015

Peptide and Protein Vaccines

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A recombinant lipoprotein containing an unsaturated fatty acid activates NF-κB through the TLR2 signaling pathway and induces a differential gene profile from a synthetic lipopeptide

Cited by 44 publications

References 34 publications

Improvement of Immunogenicity of Meningococcal Lipooligosaccharide by Coformulation with Lipidated Transferrin-Binding Protein B in Liposomes: Implications for Vaccine Development

Improvement of Immunogenicity of Meningococcal Lipooligosaccharide by Coformulation with Lipidated Transferrin-Binding Protein B in Liposomes: Implications for Vaccine Development

Molecular Mechanisms of TLR2-Mediated Antigen Cross-Presentation in Dendritic Cells

Recombinant Lipoproteins as Novel Vaccines with Intrinsic Adjuvant

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