T helper 1 inhibitor TAK-603 inhibits IFN-gamma and IL-12 production with no effect on IL-18: an observation in sarcoidosis patients.
OBJECTIVE
Sarcoidosis is immunologically characterized by highly enhanced Th1 responses in active stage. TAK-603 is a new quinoline derivative, which selectively suppresses Th1 cytokine production. Thus, the present study was designed to investigate whether TAK-603 ameliorates excess IFN-gamma production in active sarcoidosis.


METHODS
We evaluated inhibitory effects of TAK-603 on IFN-gamma, IL-12 and IL-18 production in stimulated bronchoalveolar lavage (BAL) fluid cells and peripheral blood mononuclear cells (PBMCs) of sarcoidosis patients and healthy subjects.


RESULTS
TAK-603 inhibited IFN-gamma production in stimulated BAL fluid cells and PBMCs of sarcoidosis patients and healthy subjects. TAK-603 inhibited IL-12 production in stimulated BAL fluid cells of sarcoidosis patients and healthy subjects. TAK-603 tended to inhibit IL-12 production in stimulated PBMCs of sarcoidosis patients and healthy subjects. However, TAK-603 did not affect IL-18 production in stimulated BAL fluid cells and PBMCs. TAK-603 did not affect TNF-alpha production in stimulated BAL fluid cells of sarcoidosis patients. TAK-603 inhibited IL-12 production in stimulated blood monocytes of healthy subjects, whereas IL-18 was increased by treatment with TAK-603. TAK-603 inhibited IFN-gamma production in PHA-stimulated blood T lymphocytes of healthy subjects with stimulation of IL-12 or a combination of IL-12 and IL-18. TAK-603 did not increase IL-10 or TGF-beta1 production in LPS-stimulated BAL fluid cells of sarcoidosis patients.


CONCLUSIONS
TAK-603 inhibits IFN-gamma production in activated T lymphocytes and IL-12 production in activated monocytes/macrophages independently of increased production of IL-10 and TGF-beta1. TAK-603 may ameliorate excess IFN-gamma production and be a therapeutic tool for refractory sarcoidosis.
Takahashi
Ryuji
R
Department of Respiratory Medicine, Sapporo Hospital, Hokkaido Railway Company, Japan.
Shijubo
Noriharu
N
Shigehara
Katsunori
K
Hiraga
Yohmei
Y
Abe
Shosaku
S
Sato
Noriyuki
N
D000328:Adult; D016022:Case-Control Studies; D005260:Female; D006801:Humans; D007249:Inflammation; D007371:Interferon-gamma / Q000096:biosynthesis*; D018664:Interleukin-12 / Q000096:biosynthesis*; D020382:Interleukin-18 / Q000096:biosynthesis*; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008297:Male; D008875:Middle Aged; D011804:Quinolines / Q000494:pharmacology*; D012507:Sarcoidosis / Q000276:immunology* / Q000503:physiopathology*; D013601:T-Lymphocytes / Q000276:immunology*; D014230:Triazoles / Q000494:pharmacology*
D020382:Interleukin-18; D011804:Quinolines; D014230:Triazoles; D018664:Interleukin-12; D007371:Interferon-gamma; C104411:TAK 603