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CUTTING EDGE |
* Emory Vaccine Center, Atlanta, GA 30329;
Departments of Pathology and Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77550;
Department of Pathology, Emory University, Atlanta, GA 30322;
Department of Cell Biology, Harvard Medical School, Boston, MA 02115; and
¶ Department of Periodontology and Oral Biology, Boston University School of Dental Medicine, Boston, MA 02215
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Abstract |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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, and activate macrophages to produce mediators such as NO and TNF, which kill the intracellular pathogen. In contrast, helminth parasites nearly always induce Th2 cells, the cytokines of which (IL-4, IL-13, and IL-5) induce IgE- and eosinophil-mediated destruction of the pathogen (1). Although there is much known about the cytokines that induce Th1 or Th2 responses, the decision-making mechanisms that determine the type of immune response against a given pathogen are poorly understood. Emerging evidence suggests that the type of response is a complex function of several determinants, including the dendritic cell (DC)
3 subset, the nature of the microbial stimuli, the local microenvironment, and cytokines (2, 3, 4). Thus, although different DC subsets may have some intrinsic potential to preferentially induce Th1 or Th2 responses (5, 6, 7), DCs also display considerable functional plasticity in response to signals from microbes and the local microenvironments. For example, CpG DNA induces IL-12p70 in DCs and elicits Th1 responses (8), whereas schistosome egg Ags (SEA) (9), certain forms of Candida albicans (10), or Porphyromonas gingivalis LPS (11) fail to induce IL-12p70 and stimulate Th2-like responses. The nature of the pathogen-recognition receptors, which enable DCs to sense such diverse stimuli, are only beginning to be understood. Recent efforts have focused on the Toll-like receptors (TLRs), which have broad specificity for conserved molecular patterns shared by large groups of pathogens (12, 13, 14). The expression of different TLRs on DCs enable them to discriminate between different stimuli. For example, Escherichia coli LPS signals through TLR4, zymosan, and peptidoglycans from Staphylococcus aureus signal through TLR2, the CpG-rich bacterial DNA signal through TLR9, and the bacterial flagellin signal through TLR5 (12, 13, 14). It has been suggested that signaling through any of the TLRs instructs DCs to preferentially stimulate Th1 responses (12). Although P. gingivalis LPS, a putative TLR2 agonist (15), favors Th2 responses (11), it is not clear whether this is a characteristic of all TLR2 agonists or simply a peculiarity of P. gingivalis LPS. If indeed signaling via different TLRs instructs DCs to elicit distinct Th responses, then the intracellular signaling pathways, which mediate such different outcomes, are not known. Here, we demonstrate that signaling via distinct TLRs conditions human monocyte-derived DCs to bias toward different Th responses via differential modulation of distinct components of the MAP kinase signaling pathway. |
Materials and Methods |
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Highly pure E. coli LPS (Ec.LPS; Ref.11) and flagellin (16) were provided by Drs. T. Van Dyke and A. Gewirtz, respectively. SEA was purified by Dr. B. Doughty (17). Pam3Cys-Ser-Lys4 (Pam3cys) (14) was purchased from Dr. G. Jung (Institute of Organic Chemistry, University of Tubingen, Tubingen, Germany).
Isolation and culture of human monocyte-derived DCs
CD14+ monocytes were enriched from PBMC and cultured for 6 days with recombinant human GM-CSF at 100 ng/ml (PeproTech, Rocky Hills, NJ) plus recombinant human IL-4, at 20 ng/ml (PeproTech). At day 6, the cultures consisted uniformly of CD1a+CD14-HLA-DR+CD11c+ cells, which were negative for CD83. These immature DCs were pulsed with Ec.LPS (1 µg/ml), flagellin (0.5 µg/ml), Pam3cys (20 µg/ml), or SEA (100 µg/ml) for 48 h.
DC phenotype
This was determined by flow cytometry using a FACSCalibur (BD PharMingen, San Diego, CA). Briefly, gated CD1a+CD14-CD11c+HLA-DR+ DCs were analyzed for the expression of CD80, CD86, CD83, and CD40 (BD PharMingen).
Cytokine production by DCs
This was measured by ELISA (BD PharMingen). For inhibition studies, DCs were incubated with commercially available (Calbiochem, La Jolla, CA) inhibitors of p38 (SB203580 (18), extracellular signal-regulated kinase (ERK) 1/2 (U0126-a specific inhibitor of MAP/ERK kinases 1 and 2 (18)), or c-Jun N-terminal kinase (JNK) 1/2 SP600125 (19)) for 1 h before adding the stimuli.
DC-T cell cultures
At day 6, immature DCs were pulsed with Ec.LPS (1 µg/ml), flagellin (0.5 µg/ml), Pam3cys (20 µg/ml), or SEA (100 µg/ml) for 48 h and then washed and cultured at graded doses, with 105 FACS-sorted, naive CD4+CD45RA+CD45RO- T cells. After 5 days, T cell proliferation was assessed by overnight [3H]thymidine labeling. The secretion of Th1 and Th2 cytokines was assessed by ELISA.
Evaluation of MAP kinase signaling
This was done with Western blotting or commercially available ELISA kits (BioSource International, Camarillo, CA). Briefly, on day 6, immature, human monocyte-derived DCs (2 x 106) were cultured for the indicated times, with various stimuli. ELISA were performed according to manufacturer’s instructions. For Western blotting, cellular extracts were prepared, as described in the BioSource ELISA Kit), and total protein (80–100 µg) was resolved on 10% SDS-PAGE gels and transferred to ImmunoBlot polyvinylidene difluoride membranes (Bio-Rad, Hercules, CA). Blotting was performed with anti-phospho-stress-activated protein kinase/JNK, p38, or ERK1/2 or anti-total stress-activated protein kinase/JNK, p38, or ERK1/2 Abs (New England Biolabs, Beverly, MA). Bands were visualized with secondary HRP-conjugated Ab and the SuperSignal West Pico Chemiluminescent Substrate (Pierce, Rockford, IL).
Flow cytometric evaluation of c-Fos and phospho-ERK expression in DCs
The expression of total c-Fos, phosphorylated c-Fos, or phospho-ERK in DCs was determined by FACS using Abs directed against the two different forms of c-Fos (20). On day 6, human monocyte-derived DCs were stimulated for 0.25, 1, and 4 h with various stimuli. Cells were then fixed in 2% paraformaldehyde (10% ultrapure EM grade; Polysciences, Warrington, PA) for 10 min at 37°C. After a washing, permeabilization was done with freshly prepared 90% ice cold methanol for 30 min on ice. Then the cells were washed twice in staining buffer (3% FCS in PBS), labeled with a 1/100 dilution of c-Fas Ab (Santa Cruz Biotechnology, Santa Cruz, CA) or Abs against phospho-c-Fos, or phospho-ERK (BD PharMingen) for 30 min on ice, then washed in staining buffer, and labeled using FITC-labeled goat anti-rabbit Ig (BD Biosciences). Flow cytometry was done on FACSCaliber.
Small interfering RNA (siRNA)
Five target sequences of 21 nucleotide c-fos siRNA were selected from the web site (http://www.ambion.com/techlib/misc/siRNA_finder.html) for silencing the gene. The transcription of siRNA and transfection in DCs was done according to instructions from Ambion (Austin, TX). Briefly, cells were transfected by 20 nM siRNA using a siPORT lipid transfection protocol; after 6–7 h of transfection, cells were stimulated for 40 h and cytokine secretion was assayed by ELISA (BD Biosciences).
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Results and Discussion |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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To study the direct effects of different TLR agonists on the functional responses of DCs, uncommitted, immature human monocyte-derived DCs were cultured in the presence of predetermined concentrations of highly purified Ec.LPS (Ec.LPS-TLR4 stimulus), the synthetic TLR2 agonist Pam3cys, and highly purified flagellin (TLR5 stimulus). In addition, we cultured DCs with SEA, a classic Th2 stimulus. Although the receptor through which SEA signals is not definitively known, SEA was used as a positive control to induce Th2 responses. As a negative control, DCs were cultured in the absence of any stimulus. As shown in Fig. 1a, all stimuli induced the maturation of DCs within 48 h, evidenced by the up-regulation of the costimulatory molecules, CD80 and CD86, although the induction of CD86 by Pam3cys and SEA was weaker than that by LPS and flagellin. CD80 induction by Pam3cys was also weaker. Most stimuli also induced the expression of the DC maturation marker, CD83. In the case of Pam3cys and SEA, the degree of maturation induced varied among different donors and was weaker than that induced by Ec.LPS or flagellin, as judged by the lower levels of CD83. Although all stimuli induced significant expression of the costimulatory molecules CD80 and CD86, both Pam3cys and SEA induced much lower levels of CD86.
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1000 pg/ml of IL-12p70, but Pam3cys and SEA induced little or no IL-12p70 (Fig. 1b). As indicated, the absolute amounts of cytokine secreted varied significantly from donor to donor, but the relative levels of the cytokines induced by the different stimuli were consistent. IL-10, a regulatory cytokine that is known to dampen both Th1 and Th2 responses in humans (6), was induced by Ec.LPS, flagellin, and Pam3cys, and at lower levels by SEA (Fig. 1b). The proinflammatory cytokine TNF-
was strongly induced by Ec.LPS and flagellin but was induced at weaker levels by Pam3cys and SEA. Taken together, these data suggest that the different stimuli induce cytokine profiles distinct from those of DCs. In particular, Pam3cys and SEA induce little or no IL-12p70, relative to the TLR4 and TLR5 ligands. This impaired IL-12 induction was not a dose-related phenomenon, because even very high doses of Pam3cys and SEA, which induced high levels of CD83 on DCs (data not shown), did not induce IL-12p70. Ec.LPS and flagellin induce Th1 responses, but Pam3cys and SEA bias the response toward the Th2 pathway
Given these differences in cytokine secretion, we wondered whether DCs stimulated with the various stimuli induce different types of Th responses. DCs cultured for 48 h with the various stimuli were washed and cultured, at graded doses, with naive, allogeneic, CD4+CD45RA+CD45RO- T cells. After 5 days, the cultures were pulsed with [3H]thymidine) for 12 h to measure the proliferation of T cells. As seen in Fig. 2a, in all cases, DCs induced efficient proliferation of T cells. The Th cytokines secreted in culture was determined by cytokine ELISA (Fig. 2b). DCs cultured in the absence of any stimuli induced <1000 pg/ml of the Th1 cytokine IFN-, and 300–400 pg/ml of the Th2 cytokines IL-5 and IL-13, this profile being consistent with a Th0 response. However, DCs stimulated with Ec.LPS or flagellin induced 4000 pg/ml IFN- and much lower levels of IL-5 and IL-13, a typical Th1 profile, this being consistent with the high levels of IL-12p70 induced by these stimuli (Fig. 1a). In contrast, DCs stimulated with Pam3cys or SEA biased the response toward the Th2 pathway. In particular, SEA induced a Th2 response, with <300 pg/ml IFN- (less than uncommitted DCs), but 800 pg/ml IL-5, and 800 pg/ml IL-13. Pam3cys induced 2000 pg/ml IFN- and high levels of IL-5 (600 pg/ml) and IL-13 (600 pg/ml). Interestingly, IL-4 could not be detected in any of the cultures, even with SEA, a classic Th2 stimulus, and even after restimulation of the T cells with anti-CD3 + anti-CD28, or PMA + ionomycin (data not shown). This is consistent with numerous other studies with human DCs (2, 3, 4, 7), in which classical Th2 responses have always been difficult to obtain in vitro. Nevertheless, these data suggest that TLR4 and TLR5 ligands induce uncommitted DCs to adopt a Th1-inducing mode, but Pam3cys and SEA induce DCs that skew the response toward the Th2 end of the spectrum. This is underscored by the ratios of IFN- to IL-5 or IFN- to IL-13, which reflect the Th1/Th2 balance (Fig. 2c). Although Ec.LPS and flagellin favor Th1 responses, Pam3cys and SEA clearly tilt the balance toward Th2 responses (Fig. 2b). This was not a dose-related phenomenon, because even very high doses of Pam3cys and SEA, which induced high levels of CD83 on DCs (data not shown), did not induce Th1 responses.
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secretion was diminished, when a neutralizing Ab against IL-12 was used (data not shown). Taken together, the present data suggest that TLR4 and TLR5 ligands induce Th1 responses via IL-12p70, but TLR2 ligands or SEA induce Th2/Th0 responses, possibly via a default mechanism that fails to induce IL-12p70. Pam3cys and SEA induce enhanced ERK signaling
To gain insights into the potential intracellular signaling mechanisms that may mediate the different DC responses, we focused on the MAP kinase signaling pathway, one of the most ancient signal transduction pathways in mammalian cells (21). MAP kinases consist of three major groups, p38 MAP kinases, the ERK1/2, and JNK1/2 (21). Previous reports indicate a critical role for MAP kinases in regulating Th1/Th2 balance in T cells (21), and emerging evidence suggests a role for these proteins in regulating cytokine production from APCs (18). We therefore sought to determine the phosphorylation of p38, ERK1/2, and JNK1/2 in DCs stimulated with various stimuli. As shown in Fig. 3a, there were differences in the magnitude and duration of phosphorylation of the MAP kinases induced by the different stimuli. Ec.LPS, flagellin, and Pam3cys induced enhanced phosphorylation of p38 MAP kinase, relative to unstimulated DCs, although there were some subtle differences in the duration of phosphorylation. Ec.LPS, and flagellin induced enhanced duration of p38 phosphorylation, whereas Pam3cys did not (Fig. 3a). SEA was a very weak inducer of p38. In the case of ERK1/2 phosphorylation, however, Pam3cys induced a much higher magnitude and duration of phosphorylation (which was sustained even at 4h; Fig. 3, a and b), compared with Ec.LPS and flagellin. SEA also induced ERK1/2 phosphorylation, which although weaker than that induced by Pam3cys, was sustained at 4 h at levels significantly higher than background levels (up to 4-fold above baseline levels; Fig. 3, a and b). In contrast, Ec.LPS barely induces ERK phosphorylation above background levels and gives at best a 2-fold increase. Importantly, the ratios of p38 to ERK phosphorylation were much higher with Ec.LPS and flagellin stimulation than in the other groups (Fig. 3a). We also examined the phosphorylation of JNK1/2 induced by the various stimuli. As shown in Fig. 3c, stimulation with Ec.LPS and flagellin induced higher levels of JNK 2 than stimulation with Pam3cys and SEA; however, induction of JNK1 was more complex; whereas flagellin induced high levels, Ec.LPS, Pam3cys, and SEA were very weak. The biological significance of this differential induction of JNK1/2 is presently under study. Therefore, distinct TLR ligands induce differences in the magnitude and duration of signaling of MAP-kinases in DCs.
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What roles do p38, JNK1/2, and ERK1/2 play in IL-12p70 induction by DCs? We addressed this question using the well-characterized, highly selective, synthetic inhibitors of p38 (SB203580; Ref.18), ERK1/2 (U0126, a specific inhibitor of the upstream activators of MAP kinase kinase 1 and 2; Ref.18), or JNK1/2 (SP600125; Ref.19). Blocking p38 or JNK1/2 largely abrogated IL-12p70 production induced by Ec.LPS and flagellin (Fig. 3d). IL-12p70 levels, after blocking with inhibitors, are expressed as a percentage of levels without inhibitor (which is 100%). At 10 h, Pam3cys did not induce any IL-12; thus, the value is 0%. At 24 h, Pam3cys induced 20–100 pg/ml IL-12, and this is considered to be 100%.
Interestingly, blocking ERK1/2 activity significantly enhanced IL-12p70 production induced by flagellin, Pam3cys, and Ec.LPS, suggesting an important role for ERK1/2 in the negative regulation of IL-12p70 production (Table I). Despite the donor-to-donor variation, as indicated in Table I, there was a general trend for ERK inhibition to enhance IL-12, consistent with previous reports (18). In the case of SEA, blocking ERK1/2 did not result in consistent increases in IL-12p70, suggesting that additional mechanisms regulate the suppression of IL-12p70 by SEA. Taken together, these data suggest that TLR4 and TLR5 agonists preferentially induce IL-12p70 via a mechanism involving p38 and JNK1/2 phosphorylation. In contrast, Pam3cys and SEA induce enhanced duration or magnitude of ERK1/2 phosphorylation, a negative regulator of IL-12p70.
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How does the enhanced ERK1/2 signaling result in suppression of IL-12p70? Recent work from one of our laboratories (20) suggests that sustained ERK signaling results in the phosphorylation and stabilization of the immediate early gene product c-Fos in a fibroblast cell line. Thus, we determined the kinetics and magnitude of expression off both total c-Fos and phosphorylated c-Fos in DCs stimulated with the various stimuli, using Abs directed against the two different forms of c-Fos. In Fig. 4a, the blue histograms represent expression levels in unstimulated, immature DCs, and the red histograms represent expression levels after stimulation with various stimuli. As observed, all stimuli induced enhanced levels of c-Fos expression, relative to unstimulated DCs, and this c-Fos expression peaked after 2 h of stimulation. However, at this time point, the level of expression of total c-Fos (as assessed by the mean fluorescence intensity of staining), and fraction of cells expressing c-Fos, in DCs stimulated by Pam3cys or SEA is much greater than in DCs stimulated with Ec.LPS or flagellin. Consistent with this, the more stable, phosphorylated c-Fos was not expressed in DCs stimulated with flagellin and Ec.LPS but was expressed at significant levels in DCs stimulated with Pam3cys and SEA (Fig. 4a). Furthermore, c-Fos expression was maintained even at 4 h in DCs stimulated with Pam3cys or SEA, but not with Ec.LPS or flagellin (data not shown). Therefore, stimulation of DCs by Pam3cys and SEA, which induce sustained duration of ERK1/2 signaling, result in the phosphorylation and stabilization of c-Fos. What role, if any, does c-Fos play in the regulation of IL-12p70? We addressed this using the RNA interference (siRNA) technique (22), to inhibit c-Fos expression in DCs. Five target sequences of 21 nucleotide si-RNA designed to target the c-fos gene were selected from the Ambion website (http://www.ambion.com/techlib/misc/siRNA_finder.html). The transcription of siRNA and transfection in dendritic cells was done per instructions from the the Ambion kits. siRNA targeting the c-fos gene decreased the amount of corresponding protein (data not shown), but did not lower DC viability. The induction of a neutral cytokine such as IL-6 appeared to be unaffected by the reduction on c-Fos (Fig. 4b). However, there was a profound enhancement of IL-12p70 induction in response to Pam3cys or SEA (Fig. 4b). There was a similar, although much less profound enhancement with LPS and flagellin (data not shown). Strikingly, when c-fos activity is impaired, even a classic Th2 stimulus, such as SEA, induces abundant IL-12p70 and thus behaves as a Th1 stimulus. Taken together, these data suggest that c-Fos plays a important role in the negative regulation of IL-12p70, and that stimuli such as Pam3cys and SEA, which appear to bias the Th response toward the Th2 pathway, induce enhanced levels of c-Fos expression in DCs.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Bali Pulendran, Emory Vaccine Center, 954 Gatewood Road, Atlanta, GA 30329. E-mail address: bpulend{at}rmy.emory.edu
3 Abbreviations used in this paper: DC, dendritic cell; SEA, schistosome egg Ags; TLR, Toll-like receptor; MAP kinase, mitogen-activated protein kinase; ERK, extracellular signal-regulated kinase; JNK, c-Jun N-terminal kinase; siRNA, small interfering RNA; Ec.LPS, Escherichia coli LPS; Pam3Cys, Pam3Cys-Ser-Lys4.
Received for publication July 30, 2003. Accepted for publication September 24, 2003.
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D. Fujiwara, B. Wei, L. L. Presley, S. Brewer, M. McPherson, M. A. Lewinski, J. Borneman, and J. Braun Systemic Control of Plasmacytoid Dendritic Cells by CD8+ T Cells and Commensal Microbiota J. Immunol., May 1, 2008; 180(9): 5843 - 5852. [Abstract] [Full Text] [PDF]
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B. Liang, C. Workman, J. Lee, C. Chew, B. M. Dale, L. Colonna, M. Flores, N. Li, E. Schweighoffer, S. Greenberg, et al. Regulatory T Cells Inhibit Dendritic Cells by Lymphocyte Activation Gene-3 Engagement of MHC Class II J. Immunol., May 1, 2008; 180(9): 5916 - 5926. [Abstract] [Full Text] [PDF]
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K. Page, K. M. Lierl, V. S. Hughes, P. Zhou, J. R. Ledford, and M. Wills-Karp TLR2-Mediated Activation of Neutrophils in Response to German Cockroach Frass J. Immunol., May 1, 2008; 180(9): 6317 - 6324. [Abstract] [Full Text] [PDF]
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A. G. Jarnicki, H. Conroy, C. Brereton, G. Donnelly, D. Toomey, K. Walsh, C. Sweeney, O. Leavy, J. Fletcher, E. C. Lavelle, et al. Attenuating Regulatory T Cell Induction by TLR Agonists through Inhibition of p38 MAPK Signaling in Dendritic Cells Enhances Their Efficacy as Vaccine Adjuvants and Cancer Immunotherapeutics J. Immunol., March 15, 2008; 180(6): 3797 - 3806. [Abstract] [Full Text] [PDF]
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J. J. Lazarus, M. A. Kay, A. L. McCarter, and R. M. Wooten Viable Borrelia burgdorferi Enhances Interleukin-10 Production and Suppresses Activation of Murine Macrophages Infect. Immun., March 1, 2008; 76(3): 1153 - 1162. [Abstract] [Full Text] [PDF]
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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]
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A. S. MacDonald and R. M. Maizels Alarming dendritic cells for Th2 induction J. Exp. Med., January 21, 2008; 205(1): 13 - 17. [Abstract] [Full Text] [PDF]
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F. Fransen, C. J. Boog, J. P. van Putten, and P. van der Ley Agonists of Toll-Like Receptors 3, 4, 7, and 9 Are Candidates for Use as Adjuvants in an Outer Membrane Vaccine against Neisseria meningitidis Serogroup B Infect. Immun., December 1, 2007; 75(12): 5939 - 5946. [Abstract] [Full Text] [PDF]
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A. Urzainqui, G. Martinez del Hoyo, A. Lamana, H. de la Fuente, O. Barreiro, I. M. Olazabal, P. Martin, M. K. Wild, D. Vestweber, R. Gonzalez-Amaro, et al. Functional Role of P-Selectin Glycoprotein Ligand 1/P-Selectin Interaction in the Generation of Tolerogenic Dendritic Cells J. Immunol., December 1, 2007; 179(11): 7457 - 7465. [Abstract] [Full Text] [PDF]
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J. Yu, N. Mookherjee, K. Wee, D. M. E. Bowdish, J. Pistolic, Y. Li, L. Rehaume, and R. E. W. Hancock Host Defense Peptide LL-37, in Synergy with Inflammatory Mediator IL-1beta, Augments Immune Responses by Multiple Pathways J. Immunol., December 1, 2007; 179(11): 7684 - 7691. [Abstract] [Full Text] [PDF]
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 N. W. J. Schroder and M. Arditi IEIIS Meeting minireview: The role of innate immunity in the pathogenesis of asthma: evidence for the involvement of Toll-like receptor signaling Innate Immunity, October 1, 2007; 13(5): 305 - 312. [Abstract] [PDF]
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M. Bevelander, J. Mayette, L. A. Whittaker, S. A. Paveglio, C. C. Jones, J. Robbins, D. Hemenway, S. Akira, S. Uematsu, and M. E. Poynter Nitrogen Dioxide Promotes Allergic Sensitization to Inhaled Antigen J. Immunol., September 15, 2007; 179(6): 3680 - 3688. [Abstract] [Full Text] [PDF]
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M. M. Medeiros, J. R. Peixoto, A.-C. Oliveira, L. Cardilo-Reis, V. L. G. Koatz, L. Van Kaer, J. O. Previato, L. Mendonca-Previato, A. Nobrega, and M. Bellio Toll-like receptor 4 (TLR4)-dependent proinflammatory and immunomodulatory properties of the glycoinositolphospholipid (GIPL) from Trypanosoma cruzi J. Leukoc. Biol., September 1, 2007; 82(3): 488 - 496. [Abstract] [Full Text] [PDF]
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 S. Voltan, I. Castagliuolo, M. Elli, S. Longo, P. Brun, R. D'Inca, A. Porzionato, V. Macchi, G. Palu, G. C. Sturniolo, et al. Aggregating Phenotype in Lactobacillus crispatus Determines Intestinal Colonization and TLR2 and TLR4 Modulation in Murine Colonic Mucosa Clin. Vaccine Immunol., September 1, 2007; 14(9): 1138 - 1148. [Abstract] [Full Text] [PDF]
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G. Hajishengallis, M.-A. K. Shakhatreh, M. Wang, and S. Liang Complement Receptor 3 Blockade Promotes IL-12-Mediated Clearance of Porphyromonas gingivalis and Negates Its Virulence In Vivo J. Immunol., August 15, 2007; 179(4): 2359 - 2367. [Abstract] [Full Text] [PDF]
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M. E. Handley, J. Rasaiyaah, J. Barnett, M. Thakker, G. Pollara, D. R. Katz, and B. M. Chain Expression and function of mixed lineage kinases in dendritic cells Int. Immunol., August 13, 2007; (2007) dxm050v1. [Abstract] [Full Text] [PDF]
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H. S. Bandukwala, B. S. Clay, J. Tong, P. D. Mody, J. L. Cannon, R. A. Shilling, J. S. Verbeek, J. V. Weinstock, J. Solway, and A. I. Sperling Signaling through Fc{gamma}RIII is required for optimal T helper type (Th)2 responses and Th2-mediated airway inflammation J. Exp. Med., August 6, 2007; 204(8): 1875 - 1889. [Abstract] [Full Text] [PDF]
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A. Agrawal, S. Agrawal, J.-N. Cao, H. Su, K. Osann, and S. Gupta Altered Innate Immune Functioning of Dendritic Cells in Elderly Humans: A Role of Phosphoinositide 3-Kinase-Signaling Pathway J. Immunol., June 1, 2007; 178(11): 6912 - 6922. [Abstract] [Full Text] [PDF]
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Y. Yanagawa and K. Onoe Enhanced IL-10 Production by TLR4- and TLR2-Primed Dendritic Cells upon TLR Restimulation J. Immunol., May 15, 2007; 178(10): 6173 - 6180. [Abstract] [Full Text] [PDF]
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C.-H. Liu, F. S. Machado, R. Guo, K. E. Nichols, A. W. Burks, J. C. Aliberti, and X.-P. Zhong Diacylglycerol kinase {zeta} regulates microbial recognition and host resistance to Toxoplasma gondii J. Exp. Med., April 16, 2007; 204(4): 781 - 792. [Abstract] [Full Text] [PDF]
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L. Pompei, S. Jang, B. Zamlynny, S. Ravikumar, A. McBride, S. P. Hickman, and P. Salgame Disparity in IL-12 Release in Dendritic Cells and Macrophages in Response to Mycobacterium tuberculosis Is Due to Use of Distinct TLRs J. Immunol., April 15, 2007; 178(8): 5192 - 5199. [Abstract] [Full Text] [PDF]
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T. Uchida, P. O. Scumpia, D. M. Murasko, S. Seki, S. Woulfe, M. J. Clare-Salzler, and L. L. Moldawer Variable Requirement of Dendritic Cells for Recruitment of NK and T Cells to Different TLR Agonists J. Immunol., March 15, 2007; 178(6): 3886 - 3892. [Abstract] [Full Text] [PDF]
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A. Agrawal, P. Kaushal, S. Agrawal, S. Gollapudi, and S. Gupta Thimerosal induces TH2 responses via influencing cytokine secretion by human dendritic cells J. Leukoc. Biol., February 1, 2007; 81(2): 474 - 482. [Abstract] [Full Text] [PDF]
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J. Sun and E. J. Pearce Suppression of Early IL-4 Production Underlies the Failure of CD4 T Cells Activated by TLR-Stimulated Dendritic Cells to Differentiate into Th2 Cells J. Immunol., February 1, 2007; 178(3): 1635 - 1644. [Abstract] [Full Text] [PDF]
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R. Lang, M. Hammer, and J. Mages DUSP Meet Immunology: Dual Specificity MAPK Phosphatases in Control of the Inflammatory Response J. Immunol., December 1, 2006; 177(11): 7497 - 7504. [Abstract] [Full Text] [PDF]
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A. Boonstra, R. Rajsbaum, M. Holman, R. Marques, C. Asselin-Paturel, J. P. Pereira, E. E. M. Bates, S. Akira, P. Vieira, Y.-J. Liu, et al. Macrophages and Myeloid Dendritic Cells, but Not Plasmacytoid Dendritic Cells, Produce IL-10 in Response to MyD88- and TRIF-Dependent TLR Signals, and TLR-Independent Signals J. Immunol., December 1, 2006; 177(11): 7551 - 7558. [Abstract] [Full Text] [PDF]
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S. C. Higgins, A. G. Jarnicki, E. C. Lavelle, and K. H. G. Mills TLR4 Mediates Vaccine-Induced Protective Cellular Immunity to Bordetella pertussis: Role of IL-17-Producing T Cells J. Immunol., December 1, 2006; 177(11): 7980 - 7989. [Abstract] [Full Text] [PDF]
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C. Fujimoto, C.-R. Yu, G. Shi, B. P. Vistica, E. F. Wawrousek, D. M. Klinman, C.-C. Chan, C. E. Egwuagu, and I. Gery Pertussis Toxin Is Superior to TLR Ligands in Enhancing Pathogenic Autoimmunity, Targeted at a Neo-Self Antigen, by Triggering Robust Expansion of Th1 Cells and Their Cytokine Production J. Immunol., November 15, 2006; 177(10): 6896 - 6903. [Abstract] [Full Text] [PDF]
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 M. Poupot, L. Griffe, P. Marchand, A. Maraval, O. Rolland, L. Martinet, F.-E. L'Faqihi-Olive, C.-O. Turrin, A.-M. Caminade, J.-J. Fournie, et al. Design of phosphorylated dendritic architectures to promote human monocyte activation FASEB J, November 1, 2006; 20(13): 2339 - 2351. [Abstract] [Full Text] [PDF]
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R. S. Kornbluth and G. W. Stone Immunostimulatory combinations: designing the next generation of vaccine adjuvants J. Leukoc. Biol., November 1, 2006; 80(5): 1084 - 1102. [Abstract] [Full Text] [PDF]
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P. Sun, C. M. Celluzzi, M. Marovich, H. Subramanian, M. Eller, S. Widjaja, D. Palmer, K. Porter, W. Sun, and T. Burgess CD40 Ligand Enhances Dengue Viral Infection of Dendritic Cells: A Possible Mechanism for T Cell-Mediated Immunopathology J. Immunol., November 1, 2006; 177(9): 6497 - 6503. [Abstract] [Full Text] [PDF]
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W. G. Shreffler, R. R. Castro, Z. Y. Kucuk, Z. Charlop-Powers, G. Grishina, S. Yoo, A. W. Burks, and H. A. Sampson The Major Glycoprotein Allergen from Arachis hypogaea, Ara h 1, Is a Ligand of Dendritic Cell-Specific ICAM-Grabbing Nonintegrin and Acts as a Th2 Adjuvant In Vitro J. Immunol., September 15, 2006; 177(6): 3677 - 3685. [Abstract] [Full Text] [PDF]
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X. Shan, A. Hu, H. Veler, S. Fatma, J. S. Grunstein, S. Chuang, and M. M. Grunstein Regulation of Toll-like receptor 4-induced proasthmatic changes in airway smooth muscle function by opposing actions of ERK1/2 and p38 MAPK signaling Am J Physiol Lung Cell Mol Physiol, September 1, 2006; 291(3): L324 - L333. [Abstract] [Full Text] [PDF]
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S. Agaugue, L. Perrin-Cocon, F. Coutant, P. Andre, and V. Lotteau 1-Methyl-Tryptophan Can Interfere with TLR Signaling in Dendritic Cells Independently of IDO Activity J. Immunol., August 15, 2006; 177(4): 2061 - 2071. [Abstract] [Full Text] [PDF]
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P. G. Tipping Toll-Like Receptors: The Interface between Innate and Adaptive Immunity J. Am. Soc. Nephrol., July 1, 2006; 17(7): 1769 - 1771. [Full Text] [PDF]
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R. L. Chelvarajan, Y. Liu, D. Popa, M. L. Getchell, T. V. Getchell, A. J. Stromberg, and S. Bondada Molecular basis of age-associated cytokine dysregulation in LPS-stimulated macrophages J. Leukoc. Biol., June 1, 2006; 79(6): 1314 - 1327. [Abstract] [Full Text] [PDF]
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L. Sfondrini, A. Rossini, D. Besusso, A. Merlo, E. Tagliabue, S. Menard, and A. Balsari Antitumor Activity of the TLR-5 Ligand Flagellin in Mouse Models of Cancer. J. Immunol., June 1, 2006; 176(11): 6624 - 6630. [Abstract] [Full Text] [PDF]
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A. Agrawal, S. Dillon, T. L. Denning, and B. Pulendran ERK1-/- Mice Exhibit Th1 Cell Polarization and Increased Susceptibility to Experimental Autoimmune Encephalomyelitis J. Immunol., May 15, 2006; 176(10): 5788 - 5796. [Abstract] [Full Text] [PDF]
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 E. Caparros, P. Munoz, E. Sierra-Filardi, D. Serrano-Gomez, A. Puig-Kroger, J. L. Rodriguez-Fernandez, M. Mellado, J. Sancho, M. Zubiaur, and A. L. Corbi DC-SIGN ligation on dendritic cells results in ERK and PI3K activation and modulates cytokine production Blood, May 15, 2006; 107(10): 3950 - 3958. [Abstract] [Full Text] [PDF]
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M. A. Delgado, J. F. Poschet, and V. Deretic Nonclassical Pathway of Pseudomonas aeruginosa DNA-Induced Interleukin-8 Secretion in Cystic Fibrosis Airway Epithelial Cells. Infect. Immun., May 1, 2006; 74(5): 2975 - 2984. [Abstract] [Full Text] [PDF]
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N. Ray, M. Kuwahara, Y. Takada, K. Maruyama, T. Kawaguchi, H. Tsubone, H. Ishikawa, and K. Matsuo c-Fos suppresses systemic inflammatory response to endotoxin Int. Immunol., May 1, 2006; 18(5): 671 - 677. [Abstract] [Full Text] [PDF]
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Y.-T.A. Teng Protective and Destructive Immunity in the Periodontium: Part 1--Innate and Humoral Immunity and the Periodontium Journal of Dental Research, March 1, 2006; 85(3): 198 - 208. [Abstract] [Full Text] [PDF]
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J.-S. Chang, J. F. Huggett, K. Dheda, L. U. Kim, A. Zumla, and G. A. W. Rook Myobacterium tuberculosis Induces Selective Up-Regulation of TLRs in the Mononuclear Leukocytes of Patients with Active Pulmonary Tuberculosis. J. Immunol., March 1, 2006; 176(5): 3010 - 3018. [Abstract] [Full Text] [PDF]
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A. Banerjee, R. Gugasyan, M. McMahon, and S. Gerondakis Diverse Toll-like receptors utilize Tpl2 to activate extracellular signal-regulated kinase (ERK) in hemopoietic cells PNAS, February 28, 2006; 103(9): 3274 - 3279. [Abstract] [Full Text] [PDF]
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T. Querec, S. Bennouna, S. Alkan, Y. Laouar, K. Gorden, R. Flavell, S. Akira, R. Ahmed, and B. Pulendran Yellow fever vaccine YF-17D activates multiple dendritic cell subsets via TLR2, 7, 8, and 9 to stimulate polyvalent immunity J. Exp. Med., February 21, 2006; 203(2): 413 - 424. [Abstract] [Full Text] [PDF]
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M. F. Tomczak, M. Gadjeva, Y. Y. Wang, K. Brown, I. Maroulakou, P. N. Tsichlis, S. E. Erdman, J. G. Fox, and B. H. Horwitz Defective Activation of ERK in Macrophages Lacking the p50/p105 Subunit of NF-{kappa}B Is Responsible for Elevated Expression of IL-12 p40 Observed after Challenge with Helicobacter hepaticus J. Immunol., January 15, 2006; 176(2): 1244 - 1251. [Abstract] [Full Text] [PDF]
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C.-C. Chen, S. Louie, B. A. McCormick, W. A. Walker, and H. N. Shi Helminth-Primed Dendritic Cells Alter the Host Response to Enteric Bacterial Infection J. Immunol., January 1, 2006; 176(1): 472 - 483. [Abstract] [Full Text] [PDF]
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M. Yasutomi, Y. Ohshima, N. Omata, A. Yamada, H. Iwasaki, Y. Urasaki, and M. Mayumi Erythromycin Differentially Inhibits Lipopolysaccharide- or Poly(I:C)-Induced but Not Peptidoglycan-Induced Activation of Human Monocyte-Derived Dendritic Cells J. Immunol., December 15, 2005; 175(12): 8069 - 8076. [Abstract] [Full Text] [PDF]
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H. Tada, S. Aiba, K.-I. Shibata, T. Ohteki, and H. Takada Synergistic Effect of Nod1 and Nod2 Agonists with Toll-Like Receptor Agonists on Human Dendritic Cells To Generate Interleukin-12 and T Helper Type 1 Cells Infect. Immun., December 1, 2005; 73(12): 7967 - 7976. [Abstract] [Full Text] [PDF]
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S. Appel, V. Mirakaj, A. Bringmann, M. M. Weck, F. Grunebach, and P. Brossart PPAR-{gamma} agonists inhibit toll-like receptor-mediated activation of dendritic cells via the MAP kinase and NF-{kappa}B pathways Blood, December 1, 2005; 106(12): 3888 - 3894. [Abstract] [Full Text] [PDF]
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C. A. A. van der Graaf, M. G. Netea, I. Verschueren, J. W. M. van der Meer, and B. J. Kullberg Differential Cytokine Production and Toll-Like Receptor Signaling Pathways by Candida albicans Blastoconidia and Hyphae Infect. Immun., November 1, 2005; 73(11): 7458 - 7464. [Abstract] [Full Text] [PDF]
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H. Tsujimoto, T. Uchida, P. A. Efron, P. O. Scumpia, A. Verma, T. Matsumoto, S. K. Tschoeke, R. F. Ungaro, S. Ono, S. Seki, et al. Flagellin enhances NK cell proliferation and activation directly and through dendritic cell-NK cell interactions J. Leukoc. Biol., October 1, 2005; 78(4): 888 - 897. [Abstract] [Full Text] [PDF]
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S. E. Applequist, E. Rollman, M. D. Wareing, M. Liden, B. Rozell, J. Hinkula, and H.-G. Ljunggren Activation of Innate Immunity, Inflammation, and Potentiation of DNA Vaccination through Mammalian Expression of the TLR5 Agonist Flagellin J. Immunol., September 15, 2005; 175(6): 3882 - 3891. [Abstract] [Full Text] [PDF]
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L. Freeman, M. Hewison, S. V. Hughes, K. N. Evans, D. Hardie, T. K. Means, and R. Chakraverty Expression of 11{beta}-hydroxysteroid dehydrogenase type 1 permits regulation of glucocorticoid bioavailability by human dendritic cells Blood, September 15, 2005; 106(6): 2042 - 2049. [Abstract] [Full Text] [PDF]
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K. Minami, Y. Yanagawa, K. Iwabuchi, N. Shinohara, T. Harabayashi, K. Nonomura, and K. Onoe Negative feedback regulation of T helper type 1 (Th1)/Th2 cytokine balance via dendritic cell and natural killer T cell interactions Blood, September 1, 2005; 106(5): 1685 - 1693. [Abstract] [Full Text] [PDF]
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P. G. Thomas, M. R. Carter, A. A. Da'dara, T. M. DeSimone, and D. A. Harn A Helminth Glycan Induces APC Maturation via Alternative NF-{kappa}B Activation Independent of I{kappa}B{alpha} Degradation J. Immunol., August 15, 2005; 175(4): 2082 - 2090. [Abstract] [Full Text] [PDF]
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P. O. Krutzik, M. B. Hale, and G. P. Nolan Characterization of the Murine Immunological Signaling Network with Phosphospecific Flow Cytometry J. Immunol., August 15, 2005; 175(4): 2366 - 2373. [Abstract] [Full Text] [PDF]
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J. C. Salazar, C. D. Pope, M. W. Moore, J. Pope, T. G. Kiely, and J. D. Radolf Lipoprotein-Dependent and -Independent Immune Responses to Spirochetal Infection Clin. Vaccine Immunol., August 1, 2005; 12(8): 949 - 958. [Abstract] [Full Text] [PDF]
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I. Zanoni, M. Foti, P. Ricciardi-Castagnoli, and F. Granucci TLR-Dependent Activation Stimuli Associated with Th1 Responses Confer NK Cell Stimulatory Capacity to Mouse Dendritic Cells J. Immunol., July 1, 2005; 175(1): 286 - 292. [Abstract] [Full Text] [PDF]
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S. Bluml, S. Kirchberger, V. N. Bochkov, G. Kronke, K. Stuhlmeier, O. Majdic, G. J. Zlabinger, W. Knapp, B. R. Binder, J. Stockl, et al. Oxidized Phospholipids Negatively Regulate Dendritic Cell Maturation Induced by TLRs and CD40 J. Immunol., July 1, 2005; 175(1): 501 - 508. [Abstract] [Full Text] [PDF]
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| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
, 104 DCs; 
, 2 x 103 DCs; and 
, 0 DCs. b, The secretion of Th1 and Th2 cytokines in culture was assessed by ELISA. c, The ratios of Th1 to Th2 cytokines were evaluated for each of the stimuli. Representative of seven experiments.
), and 4 h (
). a, At each time point, the expression of phosphorylated and total ERK was evaluated by ELISA. Data are presented as the fold increases in the phosphorylated to total protein ratios, relative to the 0-min value. b, Flow cytometric analyses of phospho-ERK expression in DCs. ·····, Staining in unstimulated DCs; ——, staining after stimulation. c, Expression of JNK1, JNK2, and total JNK was determined by Western blot analysis. d, The effect of blocking p38 or JNK1/2 on IL-12p70 secretion. IL-12p70 levels, after blocking with inhibitors, are expressed as a percentage of levels without inhibitor (which is 100%). Representative of five experiments.