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Table of Contents
Vol. 2, No. 2, 2010
Issue release date: February 2010
Section title: Research Article
Free Access
J Innate Immun 2010;2:123–143
(DOI:10.1159/000254790)

Deletion of the Mucin-Like Molecule Muc1 Enhances Dendritic Cell Activation in Response to Toll-Like Receptor Ligands

Williams M.A.a, b · Bauer S.a · Lu W.d · Guo J.a · Walter S.a · Bushnell T.P.c · Lillehoj E.P.e · Georas S.N.a, b
aDivision of Pulmonary and Critical Care Medicine, bDepartment of Environmental Medicine, and cDepartment of Pediatric Biomedical Research, University of Rochester School of Medicine and Dentistry, Rochester, N.Y., dDivision of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, and eDepartment of Pediatrics, School of Medicine, University of Maryland Baltimore, Baltimore, Md., USA
email Corresponding Author

Abstract

Dendritic cells (DC) are potent professional antigen-presenting cells that drive primary immune responses to infections or other agonists perceived as ‘dangerous’. Muc1 is the only cell surface mucin or MUC gene product that is expressed in DC. Unlike other members of this glycoprotein family, Muc1 possesses a unique cytosolic region capable of signal transduction and attenuating toll-like receptor (TLR) activation. The expression and function of Muc1 has been intensively investigated on epithelial and tumor cells, but relatively little is known about its function on DC. We hypothesized that Muc1 would influence in vitro generation and primary DC activation in response to the TLR4 and TLR5 ligands lipopolysaccharide and flagellin. Compared with Muc1+/+ DC, we found that Muc1–/– DC were constitutively activated, as determined by higher expression of co-stimulatory molecules (CD40, CD80 and CD86), greater secretion of immunoregulatory cytokines (TNF-α and VEGF), and better stimulation of allogeneic naïve CD4+ T cell proliferation. After activation by either LPS or flagellin and co-culture with allogeneic CD4+ T cells, Muc1–/– DC also induced greater secretion of TNF-α and IFN-γ compared to similarly activated Muc1+/+ DC. Taken together, our results indicate that deletion of Muc1 promotes a heightened functional response of DC in response to TLR4 and TLR5 signaling pathways, and suggests a previously under-appreciated role for Muc1 in regulating innate immune responses of DC.

© 2009 S. Karger AG, Basel


  

Key Words

  • Inflammation
  • Dendritic cells
  • Muc1
  • Toll-like receptor
  • Innate immunity
  • Immunomodulation
  • Host defence
  • Cytokines

References

  1. Vermaelen K, Pauwels R: Pulmonary dendritic cells. Am J Respir Crit Care Med 2005;172:530–551.
  2. Mellman I, Steinman RM: Dendritic cells: specialized and regulated antigen processing machines. Cell 2001;106:255–258.
  3. Lanzavecchia A, Sallusto F: Antigen decoding by T lymphocytes: from synapses to fate determination. Nat Immunol 2001;2:487–492.
  4. Takeda K, Kaisho T, Akira S: Toll-like receptors. Annu Rev Immunol 2003;21:335–376.
  5. Beutler B: Inferences, questions and possibilities in Toll-like receptor signalling. Nature 2004;430:257–263.
  6. Kaisho T, Hoshino K, Iwabe T, Takeuchi O, Yasui T, Akira S: Endotoxin can induce MyD88-deficient dendritic cells to support T(h)2 cell differentiation. Int Immunol 2002;14:695–700.
  7. Means TK, Hayashi F, Smith KD, Aderem A, Luster AD: The Toll-like receptor 5 stimulus bacterial flagellin induces maturation and chemokine production in human dendritic cells. J Immunol 2003;170:5165–5175.
  8. Eisenbarth SC, Piggott DA, Huleatt JW, Visintin I, Herrick CA, Bottomly K: Lipopolysaccharide-enhanced, toll-like receptor 4-dependent T helper cell type 2 responses to inhaled antigen. J Exp Med 2002;196:1645–1651.
  9. Sha Q, Truong-Tran AQ, Plitt JR, Beck LA, Schleimer RP: Activation of airway epithelial cells by toll-like receptor agonists. Am J Respir Cell Mol Biol 2004;31:358–364.
  10. Chang JF, Zhao HL, Phillips J, Greenburg G: The epithelial mucin, MUC1, is expressed on resting T lymphocytes and can function as a negative regulator of T cell activation. Cell Immunol 2000;201:83–88.
  11. Agrawal B, Krantz MJ, Parker J, Longenecker BM: Expression of MUC1 mucin on activated human T cells: implications for a role of MUC1 in normal immune regulation. Cancer Res 1998;58:4079–4081.
  12. Cloosen S, Thio M, Vanclee A, van Leeuwen EB, Senden-Gijsbers BL, Oving EB, Germeraad WT, Bos GM: Mucin-1 is expressed on dendritic cells, both in vitro and in vivo. Int Immunol 2004;16:1561–1571.
  13. Wykes M, MacDonald KP, Tran M, Quin RJ, Xing PX, Gendler SJ, Hart DN, McGuckin MA: MUC1 epithelial mucin (CD227) is expressed by activated dendritic cells. J Leukoc Biol 2002;72:692–701.
  14. Lillehoj EP, Kim H, Chun EY, Kim KC: Pseudomonas aeruginosa stimulates phosphorylation of the airway epithelial membrane glycoprotein Muc1 and activates MAP kinase. Am J Physiol Lung Cell Mol Physiol 2004;287:L809–L815.
  15. Lillehoj EP, Kim BT, Kim KC: Identification of Pseudomonas aeruginosa flagellin as an adhesin for Muc1 mucin. Am J Physiol Lung Cell Mol Physiol 2002;282:L751–L756.
  16. Gewirtz AT, Navas TA, Lyons S, Godowski PJ, Madara JL: Cutting edge: bacterial flagellin activates basolaterally expressed TLR5 to induce epithelial proinflammatory gene expression. J Immunol 2001;167:1882–1885.
  17. Hayashi F, Smith KD, Ozinsky A, Hawn TR, Yi EC, Goodlett DR, Eng JK, Akira S, Underhill DM, Aderem A: The innate immune response to bacterial flagellin is mediated by Toll-like receptor 5. Nature 2001;410:1099–1103.
  18. Smith KD, Andersen-Nissen E, Hayashi F, Strobe K, Bergman MA, Barrett SL, Cookson BT, Aderem A: Toll-like receptor 5 recognizes a conserved site on flagellin required for protofilament formation and bacterial motility. Nat Immunol 2003;4:1247–1253.
  19. Andersen-Nissen E, Smith KD, Bonneau R, Strong RK, Aderem A: A conserved surface on Toll-like receptor 5 recognizes bacterial flagellin. J Exp Med 2007;204:393–403.
  20. Lu W, Hisatsune A, Koga T, Kato K, Kuwahara I, Lillehoj EP, Chen W, Cross AS, Gendler SJ, Gewirtz AT, Kim KC: Cutting edge: enhanced pulmonary clearance of Pseudomonas aeruginosa by Muc1 knockout mice. J Immunol 2006;176:3890–3894.
  21. Kato K, Lu W, Kai H, Kim KC: Phosphoinositide 3-kinase is activated by MUC1 but not responsible for MUC1-induced suppression of Toll-like receptor 5 signaling. Am J Physiol Lung Cell Mol Physiol 2007;293:L686–L692.
  22. Ueno K, Koga T, Kato K, Golenbock DT, Gendler SJ, Kai H, Kim KC: MUC1 mucin is a negative regulator of toll-like receptor signaling. Am J Respir Cell Mol Biol 2008;38:263–268.
  23. Williams MA, Porter M, Horton M, Guo J, Roman J, Williams D, Breysse P, Georas SN: Ambient particulate matter directs nonclassic dendritic cell activation and a mixed T(H)1/T(H)2-like cytokine response by naive CD4(+) T cells. J Allergy Clin Immunol 2007;119:488–497.
  24. Lutz MB, Kukutsch N, Ogilvie AL, Rössner S, Koch F, Romani N, Schuler G: An advanced culture method for generating large quantities of highly pure dendritic cells from mouse bone marrow. J Immunol Methods 1999;223:77–92.
  25. Sallusto F, Lanzavecchia A: Efficient presentation of soluble antigen by cultured human dendritic cells is maintained by granulocyte/macrophage colony-stimulating factor plus interleukin 4 and downregulated by tumor necrosis factor alpha. J Exp Med 1994;179:1109–1118.
  26. Williams MA, Rangasamy T, Bauer SM, Killedar S, Karp M, Kensler TW, Yamamoto M, Breysse P, Biswal S, Georas SN: Disruption of the transcription factor Nrf2 promotes pro-oxidative dendritic cells that stimulate Th2-like immunoresponsiveness upon activation by ambient particulate matter. J Immunol 2008;181:4545–4559.
  27. George TC, Fanning SL, Fitzgerald-Bocarsly P, Medeiros RB, Highfill S, Shimizu Y, Hall BE, Frost K, Basiji D, Ortyn WE, Morrissey PJ, Lynch DH: Quantitative measurement of nuclear translocation events using similarity analysis of multispectral cellular images obtained in flow. J Immunol Methods 2006;311:117–129.
  28. Ortyn WE, Hall BE, George TC, Frost K, Basiji DA, Perry DJ, Zimmerman CA, Coder D, Morrissey PJ: Sensitivity measurement and compensation in spectral imaging. Cytometry 2006;69:852–862.
  29. Wang JC, Kobie JJ, Zhang L, Cochran M, Mosmann TR, Ritchlin CT, Quataert SA: An 11-color flow cytometric assay for identifying, phenotyping, and assessing endocytic ability of peripheral blood dendritic cell subsets in a single platform. J Immunol Methods 2009;341:106–116.
  30. Napoletano C, Rughetti A, Agervig Tarp MP, Coleman J, Bennett EP, Picco G, Sale P, Denda-Nagai K, Irimura T, Mandel U, Clausen H, Frati L, Taylor-Papadimitriou J, Burchell J, Nuti M: Tumor-associated Tn-MUC1 glycoform is internalized through the macrophage galactose-type C-type lectin and delivered to the HLA class I and II compartments in dendritic cells. Cancer Res 2007;67:8358–8367.
  31. Kinlough CL, Poland PA, Bruns JB, Harkleroad KL, Hughey RP: MUC1 membrane trafficking is modulated by multiple interactions. J Biol Chem 2004;279:53071–53077.
  32. Kinlough CL, McMahan RJ, Poland PA, Bruns JB, Harkleroad KL, Stremple RJ, Kashlan OB, Weixel KM, Weisz OA, Hughey RP: Recycling of MUC1 is dependent on its palmitoylation. J Biol Chem 2006;281:12112–12122.
  33. Sancho D, Joffre OP, Keller AM, Rogers NC, Martínez D, Hernanz-Falcón P, Rosewell I, Reis e Sousa C: Identification of a dendritic cell receptor that couples sensing of necrosis to immunity. Nature 2009;458:899–903.
  34. Trinchieri G, Sher A: Cooperation of Toll-like receptor signals in innate immune defence. Nat Rev Immunol 2007;7:179–190.
  35. Ueno K, Koga T, Kato K, Golenbock DT, Gendler SJ, Kai H, Kim KC: MUC1 mucin is a negative regulator of toll-like receptor signaling. Am J Respir Cell Mol Biol 2008;38:263–268.
  36. Singh R, Bandyopadhyay D: MUC1: a target molecule for cancer therapy. Cancer Biol Ther 2007;6:481–486.
  37. Carlos CA, Dong HF, Howard OM, Oppenheim JJ, Hanisch FG, Finn OJ: Human tumor antigen MUC1 is chemotactic for immature dendritic cells and elicits maturation but does not promote Th1 type immunity. J Immunol 2005;175:1628–1635.
  38. Rughetti A, Pellicciotta I, Biffoni M, Backstrom M, Link T, Bennet EP, Clausen H, Noll T, Hansson GC, Burchell JM, Frati L, Taylor-Papadimitriou J, Nuti M: Recombinant tumor-associated MUC1 glycoprotein impairs the differentiation and function of dendritic cells. J Immunol 2005;174:7764–7772.
  39. Mazmanian SK, Round JL, Kasper DL: A microbial symbiosis factor prevents intestinal inflammatory disease. Nature 2008;453:620–625.
  40. Lee CG, Link H, Baluk P, Homer RJ, Chapoval S, Bhandari V, Kang MJ, Cohn L, Kim K, McDonald DM, Elias JA: Vascular endothelial growth factor (VEGF) induces remodeling and enhances TH2-mediated sensitization and inflammation in the lung. Nat Med 2004;10:1095–1103.
  41. Oyama T, Ran S, Ishida T, Nadaf S, Kerr L, Carbone DP, Gabrilovich DI: Vascular endothelial growth factor affects dendritic cell maturation through the inhibition of nuclear factor-kappa B activation in hemopoietic progenitor cells. J Immunol 1998;160:1224–1232.
  42. Ohm JE, Shurin MR, Esche C, Lotze MT, Carbone DP, Gabrilovich DI: Effect of vascular endothelial growth factor and FLT3 ligand on dendritic cell generation in vivo. J Immunol 1999;163:3260–3268.
  43. Dikov MM, Ohm JE, Ray N, Tchekneva EE, Burlison J, Moghanaki D, Nadaf S, Carbone DP: Differential roles of vascular endothelial growth factor receptors 1 and 2 in dendritic cell differentiation. J Immunol 2005;174:215–222.

  

Author Contacts

Dr. Marc A. Williams, Cardiopulmonary and Immunotoxicology Branch
Environmental Public Health Division
National Health and Environmental Effects Research Laboratory
U.S. Environmental Protection Agency
Research Triangle Park, NC 27711 (USA), E-Mail mawilliams888@aol.com

  

Article Information

Received: July 17, 2009
Accepted after revision: August 7, 2009
Published online: November 2, 2009
Number of Print Pages : 21
Number of Figures : 10, Number of Tables : 1, Number of References : 43

  

Publication Details

Journal of Innate Immunity

Vol. 2, No. 2, Year 2010 (Cover Date: February 2010)

Journal Editor: Herwald H. (Lund), Egesten A. (Lund)
ISSN: 1662-811X (Print), eISSN: 1662-8128 (Online)

For additional information: http://www.karger.com/JIN


Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

Abstract

Dendritic cells (DC) are potent professional antigen-presenting cells that drive primary immune responses to infections or other agonists perceived as ‘dangerous’. Muc1 is the only cell surface mucin or MUC gene product that is expressed in DC. Unlike other members of this glycoprotein family, Muc1 possesses a unique cytosolic region capable of signal transduction and attenuating toll-like receptor (TLR) activation. The expression and function of Muc1 has been intensively investigated on epithelial and tumor cells, but relatively little is known about its function on DC. We hypothesized that Muc1 would influence in vitro generation and primary DC activation in response to the TLR4 and TLR5 ligands lipopolysaccharide and flagellin. Compared with Muc1+/+ DC, we found that Muc1–/– DC were constitutively activated, as determined by higher expression of co-stimulatory molecules (CD40, CD80 and CD86), greater secretion of immunoregulatory cytokines (TNF-α and VEGF), and better stimulation of allogeneic naïve CD4+ T cell proliferation. After activation by either LPS or flagellin and co-culture with allogeneic CD4+ T cells, Muc1–/– DC also induced greater secretion of TNF-α and IFN-γ compared to similarly activated Muc1+/+ DC. Taken together, our results indicate that deletion of Muc1 promotes a heightened functional response of DC in response to TLR4 and TLR5 signaling pathways, and suggests a previously under-appreciated role for Muc1 in regulating innate immune responses of DC.

© 2009 S. Karger AG, Basel


  

Author Contacts

Dr. Marc A. Williams, Cardiopulmonary and Immunotoxicology Branch
Environmental Public Health Division
National Health and Environmental Effects Research Laboratory
U.S. Environmental Protection Agency
Research Triangle Park, NC 27711 (USA), E-Mail mawilliams888@aol.com

  

Article Information

Received: July 17, 2009
Accepted after revision: August 7, 2009
Published online: November 2, 2009
Number of Print Pages : 21
Number of Figures : 10, Number of Tables : 1, Number of References : 43

  

Publication Details

Journal of Innate Immunity

Vol. 2, No. 2, Year 2010 (Cover Date: February 2010)

Journal Editor: Herwald H. (Lund), Egesten A. (Lund)
ISSN: 1662-811X (Print), eISSN: 1662-8128 (Online)

For additional information: http://www.karger.com/JIN


Article / Publication Details

First-Page Preview
Abstract of Research Article

Received: 7/17/2009
Accepted: 8/7/2009
Published online: 11/2/2009
Issue release date: February 2010

Number of Print Pages: 21
Number of Figures: 10
Number of Tables: 1

ISSN: 1662-811X (Print)
eISSN: 1662-8128 (Online)

For additional information: http://www.karger.com/JIN


Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

References

  1. Vermaelen K, Pauwels R: Pulmonary dendritic cells. Am J Respir Crit Care Med 2005;172:530–551.
  2. Mellman I, Steinman RM: Dendritic cells: specialized and regulated antigen processing machines. Cell 2001;106:255–258.
  3. Lanzavecchia A, Sallusto F: Antigen decoding by T lymphocytes: from synapses to fate determination. Nat Immunol 2001;2:487–492.
  4. Takeda K, Kaisho T, Akira S: Toll-like receptors. Annu Rev Immunol 2003;21:335–376.
  5. Beutler B: Inferences, questions and possibilities in Toll-like receptor signalling. Nature 2004;430:257–263.
  6. Kaisho T, Hoshino K, Iwabe T, Takeuchi O, Yasui T, Akira S: Endotoxin can induce MyD88-deficient dendritic cells to support T(h)2 cell differentiation. Int Immunol 2002;14:695–700.
  7. Means TK, Hayashi F, Smith KD, Aderem A, Luster AD: The Toll-like receptor 5 stimulus bacterial flagellin induces maturation and chemokine production in human dendritic cells. J Immunol 2003;170:5165–5175.
  8. Eisenbarth SC, Piggott DA, Huleatt JW, Visintin I, Herrick CA, Bottomly K: Lipopolysaccharide-enhanced, toll-like receptor 4-dependent T helper cell type 2 responses to inhaled antigen. J Exp Med 2002;196:1645–1651.
  9. Sha Q, Truong-Tran AQ, Plitt JR, Beck LA, Schleimer RP: Activation of airway epithelial cells by toll-like receptor agonists. Am J Respir Cell Mol Biol 2004;31:358–364.
  10. Chang JF, Zhao HL, Phillips J, Greenburg G: The epithelial mucin, MUC1, is expressed on resting T lymphocytes and can function as a negative regulator of T cell activation. Cell Immunol 2000;201:83–88.
  11. Agrawal B, Krantz MJ, Parker J, Longenecker BM: Expression of MUC1 mucin on activated human T cells: implications for a role of MUC1 in normal immune regulation. Cancer Res 1998;58:4079–4081.
  12. Cloosen S, Thio M, Vanclee A, van Leeuwen EB, Senden-Gijsbers BL, Oving EB, Germeraad WT, Bos GM: Mucin-1 is expressed on dendritic cells, both in vitro and in vivo. Int Immunol 2004;16:1561–1571.
  13. Wykes M, MacDonald KP, Tran M, Quin RJ, Xing PX, Gendler SJ, Hart DN, McGuckin MA: MUC1 epithelial mucin (CD227) is expressed by activated dendritic cells. J Leukoc Biol 2002;72:692–701.
  14. Lillehoj EP, Kim H, Chun EY, Kim KC: Pseudomonas aeruginosa stimulates phosphorylation of the airway epithelial membrane glycoprotein Muc1 and activates MAP kinase. Am J Physiol Lung Cell Mol Physiol 2004;287:L809–L815.
  15. Lillehoj EP, Kim BT, Kim KC: Identification of Pseudomonas aeruginosa flagellin as an adhesin for Muc1 mucin. Am J Physiol Lung Cell Mol Physiol 2002;282:L751–L756.
  16. Gewirtz AT, Navas TA, Lyons S, Godowski PJ, Madara JL: Cutting edge: bacterial flagellin activates basolaterally expressed TLR5 to induce epithelial proinflammatory gene expression. J Immunol 2001;167:1882–1885.
  17. Hayashi F, Smith KD, Ozinsky A, Hawn TR, Yi EC, Goodlett DR, Eng JK, Akira S, Underhill DM, Aderem A: The innate immune response to bacterial flagellin is mediated by Toll-like receptor 5. Nature 2001;410:1099–1103.
  18. Smith KD, Andersen-Nissen E, Hayashi F, Strobe K, Bergman MA, Barrett SL, Cookson BT, Aderem A: Toll-like receptor 5 recognizes a conserved site on flagellin required for protofilament formation and bacterial motility. Nat Immunol 2003;4:1247–1253.
  19. Andersen-Nissen E, Smith KD, Bonneau R, Strong RK, Aderem A: A conserved surface on Toll-like receptor 5 recognizes bacterial flagellin. J Exp Med 2007;204:393–403.
  20. Lu W, Hisatsune A, Koga T, Kato K, Kuwahara I, Lillehoj EP, Chen W, Cross AS, Gendler SJ, Gewirtz AT, Kim KC: Cutting edge: enhanced pulmonary clearance of Pseudomonas aeruginosa by Muc1 knockout mice. J Immunol 2006;176:3890–3894.
  21. Kato K, Lu W, Kai H, Kim KC: Phosphoinositide 3-kinase is activated by MUC1 but not responsible for MUC1-induced suppression of Toll-like receptor 5 signaling. Am J Physiol Lung Cell Mol Physiol 2007;293:L686–L692.
  22. Ueno K, Koga T, Kato K, Golenbock DT, Gendler SJ, Kai H, Kim KC: MUC1 mucin is a negative regulator of toll-like receptor signaling. Am J Respir Cell Mol Biol 2008;38:263–268.
  23. Williams MA, Porter M, Horton M, Guo J, Roman J, Williams D, Breysse P, Georas SN: Ambient particulate matter directs nonclassic dendritic cell activation and a mixed T(H)1/T(H)2-like cytokine response by naive CD4(+) T cells. J Allergy Clin Immunol 2007;119:488–497.
  24. Lutz MB, Kukutsch N, Ogilvie AL, Rössner S, Koch F, Romani N, Schuler G: An advanced culture method for generating large quantities of highly pure dendritic cells from mouse bone marrow. J Immunol Methods 1999;223:77–92.
  25. Sallusto F, Lanzavecchia A: Efficient presentation of soluble antigen by cultured human dendritic cells is maintained by granulocyte/macrophage colony-stimulating factor plus interleukin 4 and downregulated by tumor necrosis factor alpha. J Exp Med 1994;179:1109–1118.
  26. Williams MA, Rangasamy T, Bauer SM, Killedar S, Karp M, Kensler TW, Yamamoto M, Breysse P, Biswal S, Georas SN: Disruption of the transcription factor Nrf2 promotes pro-oxidative dendritic cells that stimulate Th2-like immunoresponsiveness upon activation by ambient particulate matter. J Immunol 2008;181:4545–4559.
  27. George TC, Fanning SL, Fitzgerald-Bocarsly P, Medeiros RB, Highfill S, Shimizu Y, Hall BE, Frost K, Basiji D, Ortyn WE, Morrissey PJ, Lynch DH: Quantitative measurement of nuclear translocation events using similarity analysis of multispectral cellular images obtained in flow. J Immunol Methods 2006;311:117–129.
  28. Ortyn WE, Hall BE, George TC, Frost K, Basiji DA, Perry DJ, Zimmerman CA, Coder D, Morrissey PJ: Sensitivity measurement and compensation in spectral imaging. Cytometry 2006;69:852–862.
  29. Wang JC, Kobie JJ, Zhang L, Cochran M, Mosmann TR, Ritchlin CT, Quataert SA: An 11-color flow cytometric assay for identifying, phenotyping, and assessing endocytic ability of peripheral blood dendritic cell subsets in a single platform. J Immunol Methods 2009;341:106–116.
  30. Napoletano C, Rughetti A, Agervig Tarp MP, Coleman J, Bennett EP, Picco G, Sale P, Denda-Nagai K, Irimura T, Mandel U, Clausen H, Frati L, Taylor-Papadimitriou J, Burchell J, Nuti M: Tumor-associated Tn-MUC1 glycoform is internalized through the macrophage galactose-type C-type lectin and delivered to the HLA class I and II compartments in dendritic cells. Cancer Res 2007;67:8358–8367.
  31. Kinlough CL, Poland PA, Bruns JB, Harkleroad KL, Hughey RP: MUC1 membrane trafficking is modulated by multiple interactions. J Biol Chem 2004;279:53071–53077.
  32. Kinlough CL, McMahan RJ, Poland PA, Bruns JB, Harkleroad KL, Stremple RJ, Kashlan OB, Weixel KM, Weisz OA, Hughey RP: Recycling of MUC1 is dependent on its palmitoylation. J Biol Chem 2006;281:12112–12122.
  33. Sancho D, Joffre OP, Keller AM, Rogers NC, Martínez D, Hernanz-Falcón P, Rosewell I, Reis e Sousa C: Identification of a dendritic cell receptor that couples sensing of necrosis to immunity. Nature 2009;458:899–903.
  34. Trinchieri G, Sher A: Cooperation of Toll-like receptor signals in innate immune defence. Nat Rev Immunol 2007;7:179–190.
  35. Ueno K, Koga T, Kato K, Golenbock DT, Gendler SJ, Kai H, Kim KC: MUC1 mucin is a negative regulator of toll-like receptor signaling. Am J Respir Cell Mol Biol 2008;38:263–268.
  36. Singh R, Bandyopadhyay D: MUC1: a target molecule for cancer therapy. Cancer Biol Ther 2007;6:481–486.
  37. Carlos CA, Dong HF, Howard OM, Oppenheim JJ, Hanisch FG, Finn OJ: Human tumor antigen MUC1 is chemotactic for immature dendritic cells and elicits maturation but does not promote Th1 type immunity. J Immunol 2005;175:1628–1635.
  38. Rughetti A, Pellicciotta I, Biffoni M, Backstrom M, Link T, Bennet EP, Clausen H, Noll T, Hansson GC, Burchell JM, Frati L, Taylor-Papadimitriou J, Nuti M: Recombinant tumor-associated MUC1 glycoprotein impairs the differentiation and function of dendritic cells. J Immunol 2005;174:7764–7772.
  39. Mazmanian SK, Round JL, Kasper DL: A microbial symbiosis factor prevents intestinal inflammatory disease. Nature 2008;453:620–625.
  40. Lee CG, Link H, Baluk P, Homer RJ, Chapoval S, Bhandari V, Kang MJ, Cohn L, Kim K, McDonald DM, Elias JA: Vascular endothelial growth factor (VEGF) induces remodeling and enhances TH2-mediated sensitization and inflammation in the lung. Nat Med 2004;10:1095–1103.
  41. Oyama T, Ran S, Ishida T, Nadaf S, Kerr L, Carbone DP, Gabrilovich DI: Vascular endothelial growth factor affects dendritic cell maturation through the inhibition of nuclear factor-kappa B activation in hemopoietic progenitor cells. J Immunol 1998;160:1224–1232.
  42. Ohm JE, Shurin MR, Esche C, Lotze MT, Carbone DP, Gabrilovich DI: Effect of vascular endothelial growth factor and FLT3 ligand on dendritic cell generation in vivo. J Immunol 1999;163:3260–3268.
  43. Dikov MM, Ohm JE, Ray N, Tchekneva EE, Burlison J, Moghanaki D, Nadaf S, Carbone DP: Differential roles of vascular endothelial growth factor receptors 1 and 2 in dendritic cell differentiation. J Immunol 2005;174:215–222.