Glycoconjugate Journal

, Volume 27, Issue 5, pp 525–531 | Cite as

SIGNR1 ligation on murine peritoneal macrophages induces IL-12 production through NFκB activation

  • Chiaki Kato
  • Naoya Kojima


We have previously shown that murine resident peritoneal macrophages (PEMs) are activated in response to uptake of oligomannose-coated liposomes (OMLs), leading to production of interleukin (IL)-12. To understand the mechanism of activation of PEMs by OMLs, in the present study we investigated the role of a mannose-binding C-type lectin receptor, SIGNR1, in production of proinflammatory cytokines by PEMs, in which SIGNR1 acts as a physiological receptor for OMLs. Engagement of SIGNR1 on PEMs with an anti-SIGNR1-specific rat IgM antibody, ERTR9, induced production of IL-12 and tumor necrosis factor (TNF)-α from PEMs, while secretion of IL-6 and IL-1β was not detected with the same treatment. The level of phosphorylated IκB kinase in PEMs also increased in response to ERTR9 treatment of the cells. Treatment of PEMs with a specific nuclear factor kappa-B (NFκB) inhibitor, BAY11-7082, reduced ERTR9-dependent IL-12 production. Intraperitoneal treatment with BAY11-7082 also led to reduction of subsequent OML-induced IL-12 production from PEMs. These results indicate that SIGNR1-mediated intercellular signaling may induce production of cytokines such as IL-12 through NFκB activation.


C-type lectin Interleukin-12 Macrophage Nuclear factor kappa-B SIGNR1 



antigen-presenting cell


dendritic cell-specific ICAM-3-grabbing nonintegrins


oligomannose-coated liposome


resident peritoneal macrophage


SIGN-related 1



This work was supported by the Program for Promotion of Basic Research Activities for Innovative Biosciences (PROBRAIN), and in part by a Grant-in-Aid for Special Research from The Promotion and Mutual Aid Corporation for Private Schools of Japan.


  1. 1.
    Kawai, T., Akira, S.: Pathogen recognition with Toll-like receptors. Curr. Opin. Immunol. 17, 338–344 (2005)CrossRefPubMedGoogle Scholar
  2. 2.
    Robinson, M.J., Sancho, D., Slack, E.C., Leibundgut-Landmann, S., Sousa, C.R.: Myeloid C-type lectins in innate immunity. Nat. Immunol. 7, 1258–1265 (2006)CrossRefPubMedGoogle Scholar
  3. 3.
    Avraméas, A., McIlroy, D., Hosmalin, A., Autran, B., Debré, P., Monsigny, M., Roche, A.C., Midoux, P.: Expression of a mannose/fucose membrane lectin on human dendritic cells. Eur. J. Immunol. 26, 394–400 (1996)CrossRefPubMedGoogle Scholar
  4. 4.
    Geijtenbeek, T.B., Torensma, R., van Vliet, S.J., van Duijnhoven, G.C., Adema, G.J., van Kooyk, Y., Figdor, C.G.: Identification of DC-SIGN, a novel dendritic cell-specific ICAM-3 receptor that supports primary immune responses. Cell 100, 575–585 (2000)CrossRefPubMedGoogle Scholar
  5. 5.
    Mitchell, D.A., Fadden, A.J., Drickamer, K.: A novel mechanism of carbohydrate recognition by the C-type lectins DC-SIGN and DC-SIGNR: subunit organization and binding to multivalent ligands. J. Biol. Chem. 276, 28939–28945 (2001)CrossRefPubMedGoogle Scholar
  6. 6.
    Geijtenbeek, T.B., Van Vliet, S.J., Koppel, E.A., Sanchez-Hernandez, M., Vandenbroucke-Grauls, C.M., Appelmelk, B., Van Kooyk, Y.: Mycobacteria target DC-SIGN to suppress dendritic cell function. J Exp Med. 97, 7–17 (2003)Google Scholar
  7. 7.
    Caparrós, E., Munoz, P., Sierra-Filardi, E., Serrano-Gómez, D., Puig-Kröger, A., Rodríguez-Fernández, J.L., Mellado, M., Sancho, J., Zubiaur, M., Corbí, A.L.: DC-SIGN ligation on dendritic cells results in ERK and PI3K activation and modulates cytokine production. Blood 107, 3950–3958 (2006)CrossRefPubMedGoogle Scholar
  8. 8.
    Park, C.G., Takahara, K., Umemoto, E., Yashima, Y., Matsubara, K., Matsuda, Y., Clausen, B.E., Inaba, K., Steinman, R.M.: Five mouse homologues of the human dendritic cell C-type lectin. DC-SIGN. Int. Immunol. 13, 1283–1290 (2001)CrossRefPubMedGoogle Scholar
  9. 9.
    Takahara, K., Yashima, Y., Omatsu, Y., Yoshida, H., Kimura, Y., Kang, Y.S., Steinman, R.M., Park, C.G., Inaba, K.: Functional comparison of the mouse DC-SIGN, SIGNR1, SIGNR3 and Langerin. C-type lectins. Int. Immunol. 16, 819–829 (2004)Google Scholar
  10. 10.
    Taylor, P.R., Brown, G.D., Herre, J., Williams, D.L., Willment, J.A., Gordon, S.: The role of SIGNR1 and the beta-glucan receptor (dectin-1) in the nonopsonic recognition of yeast by specific macrophages. J. Immunol. 172, 1157–1162 (2004)PubMedGoogle Scholar
  11. 11.
    Nagaoka, K., Takahara, K., Tanaka, K., Yoshida, H., Steinman, R.M., Saitoh, S., Akashi-Takamura, S., Miyake, K., Kang, Y.S., Park, C.G., Inaba, K.: Association of SIGNR1 with TLR4-MD-2 enhances signal transduction by recognition of LPS in gram-negative bacteria. Int. Immunol. 17, 827–836 (2005)CrossRefPubMedGoogle Scholar
  12. 12.
    Lanoue, A., Clatworthy, M.R., Smith, P., Green, S., Townsend, M.J., Jolin, H.E., Smith, K.G., Fallon, P.G., McKenzie, A.N.: SIGN-R1 contributes to protection against lethal pneumococcal infection in mice. J. Exp. Med. 200, 1383–1393 (2004)CrossRefPubMedGoogle Scholar
  13. 13.
    Takagi, H., Numazaki, M., Kajiwara, T., Abe, Y., Ishii, M., Kato, C., Kojima, N.: Cooperation of specific ICAM-3 grabbing nonintegrin related 1 (SIGNR1) and complement receptor type 3 (CR3) in uptake of oligomannose-coated liposomes by macrophages. Glycobiology 19, 258–266 (2009)CrossRefPubMedGoogle Scholar
  14. 14.
    Shimizu, Y., Takagi, H., Nakayama, T., Yamakami, K., Tadakuma, T., Yokoyama, N., Kojima, N.: Intraperitoneal immunization with oligomannose-coated liposome-entrapped soluble leishmanial antigen induces antigen-specific T-helper type 1 immune response in BALB/c mice through uptake by peritoneal macrophages. Parasit. Immunol. 29, 229–239 (2007)CrossRefGoogle Scholar
  15. 15.
    Kojima, N., Biao, L., Nakayama, T., Ishii, M., Ikehara, Y., Tsujimura, K.: Oligomannose-coated liposomes as a therapeutic antigen-delivery and an adjuvant vehicle for induction of in vivo tumor immunity. J. Control. Release 129, 26–32 (2008)CrossRefPubMedGoogle Scholar
  16. 16.
    Numazaki, M., Kato, C., Kawauchi, Y., Kajiwara, T., Ishii, M., Kojima, N.: Cross-linking of SIGNR1 activates JNK and induces TNF-α production in RAW264.7 cells that express SIGNR1. Biochem. Biophys. Res. Commun. 386, 202–206 (2009)CrossRefPubMedGoogle Scholar
  17. 17.
    Ishii, M., Kojima, N.: Mucosal adjuvant activity of oligomannose-coated liposomes for nasal immunization. Glycoconj. J. 27, 115–123 (2010)CrossRefPubMedGoogle Scholar
  18. 18.
    Takagi, H., Furuya, N., Kojima, N.: Preferential production of IL-12 by peritoneal macrophages activated by liposomes prepared from neoglycolipids containing oligomannose residues. Cytokine 40, 241–250 (2007)CrossRefPubMedGoogle Scholar
  19. 19.
    May, M.J., Ghosh, S.: Signal transduction through NF-κ B. Immunol. Today 19, 80–88 (1998)CrossRefPubMedGoogle Scholar
  20. 20.
    Delhase, M., Hayakawa, M., Chen, Y., Karin, M.: Positive and negative regulation of IκB kinase activity through IKKβ subunit phosphorylation. Science 284, 309–313 (1999)CrossRefPubMedGoogle Scholar
  21. 21.
    Trinchieri, G.: Immunobiology of interleukin 12. Immunol. Res. 17, 269–278 (1998)CrossRefPubMedGoogle Scholar
  22. 22.
    Gantner, B.N., Simmons, R.M., Canavera, S.J., Akira, S., Underhill, D.M.: Collaborative induction of inflammatory responses by dectin-1 and Toll-like receptor 2. J. Exp. Med. 197, 1107–1119 (2003)CrossRefPubMedGoogle Scholar
  23. 23.
    Abe, Y., Kuroda, Y., Kuboki, N., Matsushita, M., Yokoyama, N., Kojima, N.: Contribution of complement component C3 and complement receptor type 3 to carbohydrate-dependent uptake of oligomannose-coated liposomes by peritoneal macrophages. J. Biochem 144, 563–570 (2008)CrossRefPubMedGoogle Scholar
  24. 24.
    Pierce, J.W., Schoenleber, R., Jesmok, G., Best, J., Moore, S.A., Collins, T., Gerritsen, M.E.: Novel inhibitors of cytokine-induced IκBα phosphorylation and endothelial cell adhesion molecule expression show anti-inflammatory effects in vivo. J Biol Chem 272, 21096–21103 (1997)CrossRefPubMedGoogle Scholar
  25. 25.
    Tailor, P., Tamura, T., Ozato, K.: IRF family proteins and type I interferon induction in dendritic cells. Cell Res. 16, 134–140 (2006)CrossRefPubMedGoogle Scholar
  26. 26.
    Hoshino, K., Sugiyama, T., Matsumoto, M., Tanaka, T., Saito, M., Hemmi, H., Ohara, O., Akira, S.: and KaishoT.: IkappaB kinase-alpha is critical for interferon-alpha production induced by Toll-like receptors 7 and 9. Nature 440, 949–953 (2006)CrossRefPubMedGoogle Scholar
  27. 27.
    Balkhi, M.Y., Fitzgerald, K.A., Pitha, P.M.: IKKalpha negatively regulates IRF-5 function in a MyD88-TRAF6 pathway. Cell Signal. 22, 117–127 (2010)CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Institute of GlycoscienceTokai UniversityHiratsukaJapan
  2. 2.Hiratsuka-shiJapan

Personalised recommendations