[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
✍ Scribed by Sanjeev Kumar; Rabindranath Chakrabarti
- Publisher
- John Wiley and Sons
- Year
- 2000
- Tongue
- English
- Weight
- 177 KB
- Volume
- 76
- Category
- Article
- ISSN
- 0730-2312
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✦ Synopsis
The physiological role of IP 3 -dependent Ca 2ϩ 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 Ca 2ϩ mobilization, blocked T cell proliferation, curtailing specifically the level of released Ca 2ϩ did not affect T cell activation and T cell line lacking IP 3 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 Ca 2ϩ 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 Ca 2ϩ release through IP 3 receptor, not the released Ca 2ϩ , is essential for the sustained phase of PKC activation during T cell proliferation.