SIGNR1 ligation on murine peritoneal macrophages induces IL-12 production through NFκB activation
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.
KeywordsC-type lectin Interleukin-12 Macrophage Nuclear factor kappa-B SIGNR1
dendritic cell-specific ICAM-3-grabbing nonintegrins
resident peritoneal macrophage
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.
- 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.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
- 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
- 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
- 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.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
- 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