Inhibition of TSH-induced hydrogen peroxide production by TNF- through a sphingomyelinase signaling pathway

¹ Laboratory of Signal Transduction, Institute for Molecular and Cellular Regulation, and Department of Laboratory Medicine, School of Medicine, Gunma University, Maebashi 371, Japan
² Laboratory of Signal Iransduction, Institute for Molecular and Cellular Regulation, and Department of Laboratory Medicine, School of Medicine, Gunma University, Maebashi 371, Japan

Tumor necrosis factor- (TNF-) 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- influences growth and/or differentiated functions mediated by thyroid-stimulating hormone (TSH), including ¹²⁵I organification. In the present study, we found that TNF- 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- induced ceramide production and the addition of exogenous ceramide or sphingomyelinase treatment of the cells simulated TNF- actions. Although TSH stimulation of H₂O₂ production is mediated by the phospholipase C (PLC)-Ca²⁺ pathway, TNF- and 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-, through a sphingomyelinase-ceramide pathway, regulates 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- in thyroid disorder in hormone synthesis induced by thyroid disease associated with the activation of immune systems.

Submitted on December 27, 1996
Accepted on May 30, 1997