IL-2-induced IL-5 synthesis, but not proliferation, of human CD4+ T cells is suppressed by FK506.
Regulation of T cell IL-5 synthesis was investigated using human Th cell clones. Immunosuppressant FK506 suppressed IL-5 synthesis of T cells activated through TCR in a dose-dependent manner. IL-5 gene transcription and protein synthesis were also induced in the same T cell clones upon stimulation with IL-2 and were suppressed by FK506 in a dose response similar to that induced by TCR stimulation. In contrast to TCR stimulation, neither activating protein-1, nuclear factor-AT (NF-AT), nor NF-kappaB binding activity was significantly up-regulated by IL-2 stimulation. Human IL-5 promoter/enhancer-luciferase gene construct transfected to T cell clones was transcribed upon either TCR or IL-2 stimulation and was clearly down-regulated by FK506, indicating that the approximately 500-bp human IL-5 gene segment located 5' upstream of the coding region contained FK506-sensitive enhancer elements. Our present findings clearly indicate that FK506-sensitive signaling molecules are involved in T cell IL-5 production induced by both TCR and IL-2 stimulation and suggest that IL-2 receptor signal leading to IL-5 gene transcription is transduced by a unique FK506-sensitive pathway other than the Ca2+-dependent signal transduction pathway, such as the calcineurin-NF-AT system.
Mori
A
A
Department of Medicine, Faculty of Medicine, University of Tokyo, Hongo, Bunkyo-ku, Japan.
Suko
M
M
Kaminuma
O
O
Inoue
S
S
Ohmura
T
T
Hoshino
A
A
Asakura
Y
Y
Terada
E
E
Miyazawa
K
K
Nosaka
C
C
Okumura
Y
Y
Ito
K
K
Okudaira
H
H
D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D002455:Cell Division / Q000187:drug effects; D002999:Clone Cells; D004347:Drug Interactions; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007376:Interleukin-2 / Q000494:pharmacology*; D015848:Interleukin-5 / Q000096:biosynthesis*; D016559:Tacrolimus / Q000494:pharmacology*
D007166:Immunosuppressive Agents; D007376:Interleukin-2; D015848:Interleukin-5; D016559:Tacrolimus