T helper 1 inhibitor TAK-603 inhibits IFN-gamma and IL-12 production with no effect on IL-18: an observation in sarcoidosis patients.

Abstract

BACKGROUND AND AIM:

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.

• Authors: Ryuji Takahashi, Noriharu Shijubo, Katsunori Shigehara, Yohmei Hiraga, Shosaku Abe, Noriyuki Sato
• Journal: Sarcoidosis, vasculitis, and diffuse lung diseases : official journal of WASOG (Sarcoidosis Vasc Diffuse Lung Dis) Vol. 21 Issue 3 Pg. 204-11 (Oct 2004) ISSN: 1124-0490 [Print] Italy
• PMID: 15554077 (Publication Type: Journal Article)

Chemical References

• Interleukin-18
• Quinolines
• Triazoles
• Interleukin-12
• Interferon-gamma
• TAK 603

Topics

• Adult
• Case-Control Studies
• Female
• Humans
• Inflammation
• Interferon-gamma (biosynthesis)
• Interleukin-12 (biosynthesis)
• Interleukin-18 (biosynthesis)
• Leukocytes, Mononuclear (immunology)
• Male
• Middle Aged
• Quinolines (pharmacology)
• Sarcoidosis (immunology, physiopathology)
• T-Lymphocytes (immunology)
• Triazoles (pharmacology)