Intracellular signals involved in zinc deficit-mediated T lymphocyte apoptosis

BARREIRO ARCOS M.L.; PAULAZO M.L.; STERLE H.A.; KLECHA A.J.; GENARO A.M.; CREMASCHI G.A.

Creta, Grecia

Workshop; 5 th International Leukocyte Signal Transduction Workshop; 2009

AEGEAN CONFERENCES

Zinc (Zn) is a requiered cofactor for key enzymes involved in signaling cascades that regulate T lymphocyte physiology. Its deficiency lead to lymphocyte apoptosis,but the exact biochemical mechanisms involved in this effect have not been clearly elucidated. We here anlyze the intracellular events related to Zn deficiency in two T cell types regulated by different signaling molecules, namely T lymphocytes purified from murine lymph nodes (LTN) and T cells from BW 5147 lymphoma cell line (BW).Both extra- and intracellular Zn chelators were able to inhibit LTN and BW division leading to apoptosis. This was a accompanied by an increase in reactive oxygen species. Both effects were reverted by the addition of Zn and of a precursor of glutathione, N-acetyl-L-cysteine. Furthermore, both chelators were able to induce mitochondrial damage as they diminished the activity of mitochondrial dehydrogenase on the two cell types. As protein kinase C (PKC) is a crucial enzyme in T lymphocyte activity  that utilized Zn as a cofactor, its participation in these mechanisms was evaluated. DTPA and TPEN equally inhibit the activation of PKC both on LTN and BW cells. Additionally, Zn chelators down-regulate the protein expression of PKC isoforms, with a decrease in PKCa on both cell types, but of PKCq only on LTN and PKCb1 and PKCz on BW cells, with this last isoform depicting minor molecular weight fragments. Also chelators induce activation of caspase 3 on LTN and BW. Results indicate that Zn deficiency-induced apoptosis in T lymphocytes through the decreased levels of specific PKC isoenzymes. This is probably related to the activation of caspase 3 leading to mitochondrial damage and cell death