[8-(Diethylamino)octyl-3,4,5-trimethoxybenzoate, HCl], the inhibitor of intracellular calcium mobilization, blocked mitogen-induced T cell proliferation by interfering with the sustained phase of protein Kinase C activation

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Abstract
The physiological role of IP3‐dependent Ca2+ release in T cell activation was in question due to the contradictory findings that [8‐(Diethylamino)octyl‐3,4,5‐trimethoxybenzoate, HCl] (TMB‐8), an inhibitor of intracellular Ca2+ mobilization, blocked T cell proliferation, curtailing specifically the level of released Ca2+ did not affect T cell activation and T cell line lacking IP3 receptor was defective in IL‐2 production in response to TCR/CD3 ligand. In the present study we found that TMB‐8 inhibited Concanavalin A (Con A)‐ but not PMA/Ionomycin‐induced T cell proliferation in a reversible and dose‐dependent manner. The kinetic study revealed that TMB‐8 exerted the inhibitory effect at a very early step of T cell activation. The Ca2+ ionophore ionomycin augmented instead of overcoming the inhibitory effect of TMB‐8, although the same doses of ionomycin alone had no effect on Con A‐induced T cell proliferation. PMA the metabolically stable, but not diacylglycerol (DAG) the metabolically labile, activator of protein Kinase C (PKC) completely overcome the antiproliferative effect of TMB‐8. A specific DAG lipase inhibitor RHC80267 also overcome the effect of TMB‐8. Taken together, these results showed that the process of Ca2+ release through IP3 receptor, not the released Ca2+, is essential for the sustained phase of PKC activation during T cell proliferation. J. Cell. Biochem. 76:539–547, 2000.