Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Prostaglandin E2–EP4 signaling initiates skin immune responses by promoting migration and maturation of Langerhans cells

Abstract

Antigen-specific immune responses in the skin are initiated by antigen uptake into Langerhans cells and the subsequent migration of these cells to draining lymph nodes. Although prostaglandin E2 (PGE2) is produced substantially in skin exposed to antigen, its role remains unclear. Here we show that although Langerhans cells express all four PGE receptor subtypes, their migration to regional lymph nodes was decreased only in EP4-deficient (Ptger4−/−) mice and in wild-type mice treated with an EP4 antagonist. An EP4 agonist promoted the migration of Langerhans cells, increased their expression of costimulatory molecules and enhanced their ability to stimulate T cells in the mixed lymphocyte reaction in vitro. Contact hypersensitivity to antigen was impaired in Ptger4−/− mice and in wild-type mice treated with the EP4 antagonist during sensitization. PGE2-EP4 signaling thus facilitates initiation of skin immune responses by promoting the migration and maturation of Langerhans cells.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Impaired Langerhans cell accumulation in regional lymph nodes in Ptger4−/− mice.
Figure 2: Effects of EP4 deficiency or antagonism on the density, morphology and phagocytotic activity of Langerhans cells.
Figure 3: Effects of EP4 deficiency or EP4-selective drugs on Langerhans cell migration and maturation in vitro.
Figure 4: Effects of an EP4 agonist and COX inhibitors on T-cell proliferation and cytokine production in the MLR.
Figure 5: Impaired initiation of immune responses in Ptger4−/− mice.

Similar content being viewed by others

References

  1. Silberberg-Sinakin, I. et al. Antigen-bearing Langerhans cells in skin, dermal lymphatics and in lymph nodes. Cell. Immunol. 25, 137–151 (1976).

    Article  CAS  Google Scholar 

  2. Schuler, G. & Steinman, R.M. Murine epidermal Langerhans cells mature into potent immunostimulatory dendritic cells in vitro. J. Exp. Med. 161, 526–546 (1985).

    Article  CAS  Google Scholar 

  3. Inaba, K. et al. Immunologic properties of purified epidermal Langerhans cells. Distinct requirements for stimulation of unprimed and sensitized T lymphocytes. J. Exp. Med. 164, 605–613 (1986).

    Article  CAS  Google Scholar 

  4. Grabbe, S. & Schwarz, T. Immunoregulatory mechanisms involved in elicitation of allergic contact hypersensitivity. Immunol. Today 19, 37–44 (1998).

    Article  CAS  Google Scholar 

  5. Kimber, I., Cumberbatch, M., Dearman, R.J., Bhushan, M. & Griffiths, C.E. Cytokines and chemokines in the initiation and regulation of epidermal Langerhans cell mobilization. Br. J. Dermatol. 142, 401–412 (2000).

    Article  CAS  Google Scholar 

  6. Robbiani, D.F. et al. The leukotriene C4 transporter MRP1 regulates CCL19 (MIP-3β, ELC)-dependent mobilization of dendritic cells to lymph nodes. Cell 103, 757–768 (2000).

    Article  CAS  Google Scholar 

  7. Aliberti, J., Hieny, S., Reis e Sousa, C., Serhan, C.N. & Sher, A. Lipoxin-mediated inhibition of IL-12 production by DCs: a mechanism for regulation of microbial immunity. Nat. Immunol. 3, 76–82 (2002).

    Article  CAS  Google Scholar 

  8. Aliberti, J., Serhan, C. & Sher, A. Parasite-induced lipoxin A4 is an endogenous regulator of IL-12 production and immunopathology in Toxoplasma gondii infection. J. Exp. Med. 196, 1253–1262 (2002).

    Article  CAS  Google Scholar 

  9. Spanbroek, R. et al. IL-4 determines eicosanoid formation in dendritic cells by down-regulation of 5-lipoxygenase and up-regulation of 15-lipoxygenase 1 expression. Proc. Natl. Acad. Sci. USA 98, 5152–5157 (2001).

    Article  CAS  Google Scholar 

  10. Ruzicka, T. & Printz, M.P. Arachidonic acid metabolism in skin: experimental contact dermatitis in guinea pigs. Int. Arch. Allergy Appl. Immunol. 69, 347–352 (1982).

    Article  CAS  Google Scholar 

  11. Eberhard, J., Jepsen, S., Pohl, L., Albers, H.K. & Acil, Y. Bacterial challenge stimulates formation of arachidonic acid metabolites by human keratinocytes and neutrophils in vitro. Clin. Diagn. Lab. Immunol. 9, 132–137 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Goodwin, J., Bankhurst, A. & Messner, R. Suppression of human T-cell mitogenesis by prostaglandin. Existence of a prostaglandin-producing suppressor cell. J. Exp. Med. 146, 1719–1734 (1977).

    Article  CAS  Google Scholar 

  13. Narumiya, S., Sugimoto, Y. & Ushikubi, F. Prostanoid receptors: structures, properties, and functions. Physiol. Rev. 79, 1193–1226 (1999).

    Article  CAS  Google Scholar 

  14. Ushikubi, F. et al. Impaired febrile response in mice lacking the prostaglandin E receptor subtype EP3. Nature 395, 281–284 (1998).

    Article  CAS  Google Scholar 

  15. Segi, E. et al. Patent ductus arteriosus and neonatal death in prostaglandin receptor EP4-deficient mice. Biochem. Biophys. Res. Commun. 246, 7–12 (1998).

    Article  CAS  Google Scholar 

  16. Hizaki, H. et al. Abortive expansion of the cumulus and impaired fertility in mice lacking the prostaglandin E receptor subtype EP2 . Proc. Natl. Acad. Sci. USA 96, 10501–10506 (1999).

    Article  CAS  Google Scholar 

  17. Kabashima, K. et al. The prostaglandin receptor EP4 suppresses colitis, mucosal damage and CD4 cell activation in the gut. J. Clin. Invest. 109, 883–893 (2002).

    Article  CAS  Google Scholar 

  18. Macatonia, S.E., Knight, S.C., Edwards, A.J., Griffiths, S. & Fryer, P. Localization of antigen on lymph node dendritic cells after exposure to the contact sensitizer fluorescein isothiocyanate. Functional and morphological studies. J. Exp. Med. 166, 1654–1667 (1987).

    Article  CAS  Google Scholar 

  19. Larsen, C.P. et al. Migration and maturation of Langerhans cells in skin transplants and explants. J. Exp. Med. 172, 1483–1493 (1990).

    Article  CAS  Google Scholar 

  20. Weinlich, G. et al. Entry into afferent lymphatics and maturation in situ of migrating murine cutaneous dendritic cells. J. Invest. Dermatol. 110, 441–448 (1998).

    Article  CAS  Google Scholar 

  21. Warren, H.S., Vogel, F.R. & Chedid, L.A. Current status of immunological adjuvants. Annu. Rev. Immunol. 4, 369–388 (1986).

    Article  CAS  Google Scholar 

  22. Grabbe, S., Steinbrink, K., Steinert, M., Luger, T.A. & Schwarz, T. Removal of the majority of epidermal Langerhans cells by topical or systemic steroid application enhances the effector phase of murine contact hypersensitivity. J. Immunol. 155, 4207–4217 (1995).

    CAS  PubMed  Google Scholar 

  23. Rao, T.S., Currie, J.L., Shaffer, A.F. & Isakson, P.C. Comparative evaluation of arachidonic acid (AA)- and tetradecanoylphorbol acetate (TPA)-induced dermal inflammation. Inflammation 17, 723–741 (1993).

    Article  CAS  Google Scholar 

  24. Feng, L., Xia, Y., Garcia, G.E., Hwang, D. & Wilson, C.B. Involvement of reactive oxygen intermediates in cyclooxygenase-2 expression induced by interleukin-1, tumor necrosis factor-α, and lipopolysaccharide. J. Clin. Invest. 95, 1669–1675 (1995).

    Article  CAS  Google Scholar 

  25. Rys-Sikora, K.E., Konger, R.L., Schoggins, J.W., Malaviya, R. & Pentland, A.P. Coordinate expression of secretory phospholipase A2 and cyclooxygenase-2 in activated human keratinocytes. Am. J. Physiol. 278, C822–C833 (2000).

    Article  CAS  Google Scholar 

  26. Whittaker, D.S., Bahjat, K.S., Moldawer, L.L. & Clare-Salzler, M.J. Autoregulation of human monocyte-derived dendritic cell maturation and IL-12 production by cyclooxygenase-2-mediated prostanoid production. J. Immunol. 165, 4298–4304 (2000).

    Article  CAS  Google Scholar 

  27. Scandella, E., Men, Y., Gillessen, S., Forster, R. & Groettrup, M. Prostaglandin E2 is a key factor for CCR7 surface expression and migration of monocyte-derived dendritic cells. Blood 100, 1354–1361 (2002).

    Article  CAS  Google Scholar 

  28. Luft, T. et al. Functionally distinct dendritic cell (DC) populations induced by physiologic stimuli: prostaglandin E2 regulates the migratory capacity of specific DC subsets. Blood 100, 1362–1372 (2002).

    Article  CAS  Google Scholar 

  29. Angeli, V. et al. Role of the parasite-derived prostaglandin D2 in the inhibition of epidermal Langerhans cell migration during Schistosomiasis infection. J. Exp. Med. 193, 1135–1147 (2001).

    Article  CAS  Google Scholar 

  30. Banchereau, J., Schuler-Thurner, B., Palucka, A.K. & Schuler, G. Dendritic cells as vectors for therapy. Cell 106, 271–274 (2001).

    Article  CAS  Google Scholar 

  31. Thurner, B. et al. Vaccination with mage-3A1 peptide-pulsed mature, monocyte-derived dendritic cells expands specific cytotoxic T cells and induces regression of some metastases in advanced stage IV melanoma. J. Exp. Med. 190, 1669–1678 (1999).

    Article  CAS  Google Scholar 

  32. Jonuleit, H. et al. Pro-inflammatory cytokines and prostaglandins induce maturation of potent immunostimulatory dendritic cells under fetal calf serum-free conditions. Eur. J. Immunol. 27, 3135–3142 (1997).

    Article  CAS  Google Scholar 

  33. Dormond, O., Foletti, A., Paroz, C. & Ruegg, C. NSAIDs inhibit αvβ3 integrin-mediated and Cdc42/Rac-dependent endothelial-cell spreading, migration and angiogenesis. Nat. Med. 7, 1041–1047 (2001).

    Article  CAS  Google Scholar 

  34. Jaffer, S., Mattana, J. & Singhal, P.C. Effects of prostaglandin E2 on mesangial cell migration. Am. J. Nephrol. 15, 300–305 (1995).

    Article  CAS  Google Scholar 

  35. Daugschies, A. & Ruttkowski, B. Modulation of migration of Oesophagostomum dentatum larvae by inhibitors and products of eicosanoid metabolism. Int. J. Parasitol. 28, 355–362 (1998).

    Article  CAS  Google Scholar 

  36. Sheng, H., Shao, J., Washington, M.K. & DuBois, R.N. Prostaglandin E2 increases growth and motility of colorectal carcinoma cells. J. Biol. Chem. 276, 18075–18081 (2001).

    Article  CAS  Google Scholar 

  37. Shinomiya, S. et al. Regulation of TNFα and interleukin-10 production by prostaglandins I2 and E2: studies with prostaglandin receptor-deficient mice and prostaglandin E-receptor subtype-selective synthetic agonists. Biochem. Pharmacol. 61, 1153–1160 (2001).

    Article  CAS  Google Scholar 

  38. Tang, H.L. & Cyster, J.G. Chemokine up-regulation and activated T cell attraction by maturing dendritic cells. Science 284, 819–822 (1999).

    Article  CAS  Google Scholar 

  39. Ortner, U. et al. An improved isolation method for murine migratory cutaneous dendritic cells. J. Immunol. Meth. 193, 71–79 (1996).

    Article  CAS  Google Scholar 

  40. Sallusto, F., Cella, M., Danieli, C. & Lanzavecchia, A. Dendritic cells use macropinocytosis and the mannose receptor to concentrate macromolecules in the major histocompatibility complex class II compartment: down-regulation by cytokines and bacterial products. J. Exp. Med. 182, 389–400 (1995).

    Article  CAS  Google Scholar 

  41. Kurimoto, I. & Streilein, J.W. Studies of contact hypersensitivity induction in mice with optimal sensitizing doses of hapten. J. Invest. Dermatol. 101, 132–136 (1993).

    Article  CAS  Google Scholar 

  42. Chen, A.I. et al. Ox40-ligand has a critical costimulatory role in dendritic cell: T cell interactions. Immunity 11, 689–698 (1999).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank A. Takashima for XS106 cells; Ono Pharmaceutical Co. Ltd. for ONO-AE3-208 and ONO-AE1-734; T. Murata, E. Segi and J. Cyster for critical reading of the manuscript; K. Deguchi for animal care; and T. Arai for secretarial assistance. This work was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science, Sports, and Culture of Japan, a grant from the Organization for Pharmaceutical Safety and Research and a grant from Ono Pharmaceutical Co. Ltd.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Shuh Narumiya.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kabashima, K., Sakata, D., Nagamachi, M. et al. Prostaglandin E2–EP4 signaling initiates skin immune responses by promoting migration and maturation of Langerhans cells. Nat Med 9, 744–749 (2003). https://doi.org/10.1038/nm872

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm872

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing