TY - JOUR
T1 - The effect of vesnarinone on TNFα production in human peripheral blood mononuclear cells and microglia
T2 - A preclinical study for the treatment of multiple sclerosis
AU - Jiang, H.
AU - Bielekova, B.
AU - Okazaki, H.
AU - Clarence-Smith, K.
AU - Johnson, K. P.
AU - Bergey, G.
AU - Martin, R.
AU - Dhib-Jalbut, S.
N1 - Funding Information:
We would like to thank Mrs. Nayereh Dehghan for typing the manuscript. Supported by a grant from Otsuka Pharmaceutical, Japan.
PY - 1999/6/1
Y1 - 1999/6/1
N2 - Vesnarinone (OPC-8212) is a synthetic quinolinone derivative with inotropic and immunomodulatory effects. Vesnarinone has been shown to inhibit tumor necrosis factor-alpha (TNFα) produced by mitogen stimulated macrophages, and to inhibit phosphodiesterase (PDE) type III in cardiac muscle. TNFα and interferon-gamma (IFNγ) have been implicated in the pathogenesis of autoimmune diseases, and both cytokines are targets for therapeutic intervention. IFNγ can enhance autoimmune disease through direct effects, and indirectly by priming macrophages to produce TNFα. In this study, we demonstrate that while vesnarinone enhances basal TNFα levels, it inhibits TNFα production in peripheral blood mononuclear cells from multiple sclerosis (MS) patients and healthy donors stimulated with lipopolysaccharide (LPS) or primed with IFNγ and stimulated with suboptimal doses of LPS. In addition, vesnarinone inhibited TNFα production in primary adult human microglial cultures. However, in contrast to rolipram, another TNFα inhibiting agent, vesnarinone failed to inhibit TNFα production by myelin basic protein specific T-cell lines. As oral TNF inhibitors are currently being considered in the USA for clinical application in MS, the implications of our findings on the development of vesnarinone for treatment of MS are discussed.
AB - Vesnarinone (OPC-8212) is a synthetic quinolinone derivative with inotropic and immunomodulatory effects. Vesnarinone has been shown to inhibit tumor necrosis factor-alpha (TNFα) produced by mitogen stimulated macrophages, and to inhibit phosphodiesterase (PDE) type III in cardiac muscle. TNFα and interferon-gamma (IFNγ) have been implicated in the pathogenesis of autoimmune diseases, and both cytokines are targets for therapeutic intervention. IFNγ can enhance autoimmune disease through direct effects, and indirectly by priming macrophages to produce TNFα. In this study, we demonstrate that while vesnarinone enhances basal TNFα levels, it inhibits TNFα production in peripheral blood mononuclear cells from multiple sclerosis (MS) patients and healthy donors stimulated with lipopolysaccharide (LPS) or primed with IFNγ and stimulated with suboptimal doses of LPS. In addition, vesnarinone inhibited TNFα production in primary adult human microglial cultures. However, in contrast to rolipram, another TNFα inhibiting agent, vesnarinone failed to inhibit TNFα production by myelin basic protein specific T-cell lines. As oral TNF inhibitors are currently being considered in the USA for clinical application in MS, the implications of our findings on the development of vesnarinone for treatment of MS are discussed.
KW - IFNγ
KW - Microglia
KW - Mononuclear cells
KW - Multiple sclerosis
KW - TNFα
KW - Vesnarinone
UR - http://www.scopus.com/inward/record.url?scp=0032937496&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0032937496&partnerID=8YFLogxK
U2 - 10.1016/S0165-5728(99)00037-5
DO - 10.1016/S0165-5728(99)00037-5
M3 - Article
C2 - 10408967
AN - SCOPUS:0032937496
VL - 97
SP - 134
EP - 145
JO - Advances in Neuroimmunology
JF - Advances in Neuroimmunology
SN - 0165-5728
IS - 1-2
ER -