A novel Syk kinase-selective inhibitor blocks antigen presentation of immune complexes in dendritic cells.
The initiation of antigen presentation by dendritic cells requires proper internalization of antigens through various mechanisms. Internalization of immune complexes via Fc receptors has been shown to be around 100 times more efficient than the internalization of non-complexed antigens. Spleen tyrosine kinase (Syk) plays an essential role in the signaling cascade initiated by immunoglobulin receptors. We used a selective Syk inhibitor, 7-(3,4-dimethoxyphenyl)-N-1H-indazol-6-ylimidazo[1,2-c]pyrimidin-5-amine dihydrochloride (compound-D), to evaluate the role of Syk in antigen presentation by mouse bone marrow-derived dendritic cells. In line with our expectation, compound-D concentration-dependently inhibited the internalization of immune complexes but not that of antigen itself. Furthermore, when dendritic cells were pretreated with compound-D, the ability of dendritic cells to present immune complex antigens to Th2 cells was attenuated, parallel by a reduced release of interleukin-4 production in Th2 cells. Therefore, Syk kinase activity is a critical component in the process of Fcgamma receptor-mediated internalization of immune complex antigens in dendritic cells, and Syk kinase inhibitors may be beneficial in selectively suppressing antibody-mediated antigen presentation in allergic diseases.
Nakashima
Kosuke
K
Research Center Kyoto, Bayer Yakuhin, Ltd., Kyoto, Japan. nakashima_kosuke@yahoo.co.jp
Kokubo
Toshio
T
Shichijo
Michitaka
M
Li
Ying-Fu
YF
Yura
Takeshi
T
Yamamoto
Noriyuki
N
D000818:Animals; D017951:Antigen Presentation / Q000187:drug effects*; D002478:Cells, Cultured; D018920:Coculture Techniques; D003207:Conalbumin / Q000276:immunology / Q000494:pharmacology; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D007093:Imidazoles / Q000494:pharmacology*; D007074:Immunoglobulin G / Q000276:immunology / Q000494:pharmacology; D015847:Interleukin-4 / Q000096:biosynthesis; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism
C500326:7-(3,4-dimethoxyphenyl)-N-1H-indazol-6-ylimidazo(1,2-c)pyrimidin-5-amine dihydrochloride; D007093:Imidazoles; D007074:Immunoglobulin G; D011743:Pyrimidines; D003207:Conalbumin; D015847:Interleukin-4; D011505:Protein-Tyrosine Kinases