Bucillamine inhibits CD40-mediated Akt activation and antibody production in mouse B-cell lymphoma.
The improvement of rheumatoid factor titers in patients with rheumatoid arthritis is one of the significant clinical effects of bucillamine (Buc). In this study, we investigated the effects of SA981, an active metabolite of Buc, and methotrexate (MTX) on CD40-mediated antibody production using mouse B-cell lymphoma, BCL1. SA981 significantly attenuated CD40-mediated antibody production in a concentration-dependent manner, but weakly affected cell proliferation. In contrast, MTX did not attenuate CD40-mediated antibody production until it had strongly inhibited cell proliferation at a concentration of 100 nM. CD40 signaling induced protein phosphorylation, including Akt phosphorylation, p38 mitogen-activated protein kinase (p38MAPK), and IκBα. SA981 at a concentration of 30 μM attenuated CD40-mediated Akt phosphorylation, but not p38MAPK or IκBα phosphorylation. MTX at a concentration of 100 nM did not affect CD40-mediated Akt, p38MAPK, or IκBα phosphorylation. Commercially available Akt inhibitor VIII significantly attenuated CD40-mediated IgM production at a concentration of 100 nM without significant inhibition of cell proliferation. These results suggest that SA981 inhibits CD40-mediated antibody production in mouse B-cell lymphoma, at least in part, by attenuation of Akt phosphorylation.
Research and Development Center, Santen Pharmaceutical Co., Ltd., Ikoma-shi, Nara, Japan. fumio.tsuji@santen.co.jp
Fumio
F
Tsuji
Chikako
C
Setoguchi
Masahiro
M
Okamoto
Iwao
I
Seki
Minoru
M
Sasano
Hiroyuki
H
Aono
D000818:Animals; D000917:Antibody Formation / Q000187:drug effects*; D019013:CD40 Antigens / Q000276:immunology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003545:Cysteine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry; D004789:Enzyme Activation / Q000187:drug effects / Q000276:immunology; D008727:Methotrexate / Q000008:administration & dosage; D051379:Mice; D051058:Oncogene Protein v-akt / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects / Q000276:immunology
D019013:CD40 Antigens; C513116:bucillamine disulfide; D051058:Oncogene Protein v-akt; D003545:Cysteine; C026535:bucillamine; D008727:Methotrexate