Context: Dual activation by TSH (TSH) of the phospholipase C and cAMP cascades has been reported in human thyroid cells. In contrast, Singh et al. (Biochem. J. 1996, 316, 175-82) reported convincing data in FRTL-5 thyrocytes arguing against such an effect in this model. Their data in FRTL-5 cells indicated no increase in inositol 1,4,5-trisphosphate (Ins(1,4,5)P₃) in response to TSH. The authors therefore questioned results previously obtained on human cells by cruder methodology.

Objective: we investigated the formation of inositol phosphates by HPLC techniques in human thyroid slices to separate the inositol phosphate isomers.

Results: Ins(1,4,5)P₃, Ins(1,3,4)P₃ and inositol 1,3,4,5-tetrakisphosphate (InsP₄) were increased after TSH stimulation. The effect of TSH in human thyroid cells was reproduced by recombinant TSH and prevented by antibodies blocking the TSH receptor. Thyroid stimulating antibodies (TSAbs) at concentrations eliciting a cAMP response equivalent to TSH failed to stimulate inositol phosphate generation.

Conclusions: TSH but not TSAbs activate both cAMP and the PLC cascade in human thyroid as now demonstrated by an increase in Ins(1,4,5)P₃ and its inositol phosphate metabolites. This effect can therefore not be extrapolated to the FRTL-5 cell line. The apparent discrepancy may be due to a difference between species (human vs. rat) or to the loss of the fresh tissue properties in a cell line. The dual effect of TSH in human cells, through cAMP on secretion of thyroid hormones and through the diacylglycerol, Ins(1,4,5)P₃ Ca²⁺ pathway on thyroid hormone synthesis, implies the possible separation of these effects in thyroid disease.