Inhibition of tsh-induced hydrogen peroxide production by tumor
necrosis factor-a through sphingomyelinase signaling pathway.
Kimura, Takao, Fumikazu Okajima, Takashi Kikuchi, Atsushi Kuwabara,
Hideaki Tomura, Kimie Sho, Isao Kobayashi, and Yoichi Kondo.
Laboratory of Signal Transduction, Institute for Molecular and
Cellular Regulation, Gunma University, Maebashi 371; and Department
of Laboratory Medicine, School of Medicine, Gunma University,
Maebashi 371, Japan
APStracts 4:0120E, 1997.
Tumor necrosis factor-a (TNF-a) has been suggested to be related to
the pathogenesis of autoimmune thyroid diseases, nonthyroid illness
and other thyroid dysfunctions induced by infectious diseases. In
relation to these, in vitro studies demonstrated that TNF-a
influences growth and/or differentiated functions mediated by TSH
including 125I organification. In the present study, we found that
TNF-a inhibits TSH-induced H2O2 production which is an inevitable
process for iodide organification and hence thyroid hormone synthesis
in FRTL-5 thyroid cells. In the cells, TNF-a induced ceramide
production and the addition of exogenous ceramide or sphingomyelinase
treatment of the cells simulated TNF-a actions. Although TSH
stimulation of H2O2 production is mediated by the phospholipase C
(PLC)-Ca2+ pathway, TNF-a, exogenous and endogenous ceramide affected
neither TSH-dependent PLC activation and Ca2+ mobilization nor TSH
-induced cAMP accumulation but attenuated Ca2+-induced H2O2
production. We conclude that TNF-a, through a sphingomyelinase
-ceramide pathway, regulates the TSH-induced H2O2 production at steps
beyond the Ca2+ mobilization step in the PLC-Ca2+ signaling pathway
coupled to TSH. This suggests participation of TNF-a in thyroid
disorder in hormone synthesis induced by thyroid disease associated
with the activation of immune systems.
Received 1996 December 27; accepted in final form 1997 May 30
APS Manuscript Number E629-6.
Article publication pending Am. J. Physiol. (Endocrinol. Metab.).
ISSN 1080-4757 Copyright 1997 The American Physiological Society.
Published in APStracts on 11 June 1997