TY - JOUR
T1 - Impaired translational response and increased protein kinase PKR expression in T cells from lupus patients
AU - Grolleau, A.
AU - Kaplan, M. J.
AU - Hanash, S. M.
AU - Beretta, L.
AU - Richardson, B.
PY - 2000
Y1 - 2000
N2 - Activation of peripheral blood T cells results in a rapid and substantial rise in translation rates and proliferation, but proliferation in response to mitogen stimulation is impaired in systemic lupus erythematosus (SLE). We have investigated translation rates and initiation factor activities in T cells from SLE patients in response to activating signals. Activation by PMA plus ionomycin strongly increased protein synthesis in control T cells but not in T cells from SLE patients. The rate of protein synthesis is known to be strongly dependent on the activity of two eukaryotic translation initiation factors, eIF4E and eIF2α. We show that following stimulation, eIF4E expression and phosphorylation increased equivalently in control and SLE T cells. Expression of eIF4E interacting proteins - eIF4G, an inducer, and 4E-BP1 and 4E-BP2, two specific repressors of eIF4E function - and the phosphorylation level of 4E-BP1, were all identical in control and SLE T cells. In contrast, the protein kinase PKR, which is responsible for the phosphorylation and consequent inhibition of eIF2α activity, was specifically overexpressed in activated SLE T cells, correlating with an increase in eIF2α phosphorylation. Therefore, high expression of PKR and subsequent eIF2α phosphorylation is likely responsible, at least in part, for impaired translational and proliferative responses to mitogens in T cells from SLE patients.
AB - Activation of peripheral blood T cells results in a rapid and substantial rise in translation rates and proliferation, but proliferation in response to mitogen stimulation is impaired in systemic lupus erythematosus (SLE). We have investigated translation rates and initiation factor activities in T cells from SLE patients in response to activating signals. Activation by PMA plus ionomycin strongly increased protein synthesis in control T cells but not in T cells from SLE patients. The rate of protein synthesis is known to be strongly dependent on the activity of two eukaryotic translation initiation factors, eIF4E and eIF2α. We show that following stimulation, eIF4E expression and phosphorylation increased equivalently in control and SLE T cells. Expression of eIF4E interacting proteins - eIF4G, an inducer, and 4E-BP1 and 4E-BP2, two specific repressors of eIF4E function - and the phosphorylation level of 4E-BP1, were all identical in control and SLE T cells. In contrast, the protein kinase PKR, which is responsible for the phosphorylation and consequent inhibition of eIF2α activity, was specifically overexpressed in activated SLE T cells, correlating with an increase in eIF2α phosphorylation. Therefore, high expression of PKR and subsequent eIF2α phosphorylation is likely responsible, at least in part, for impaired translational and proliferative responses to mitogens in T cells from SLE patients.
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U2 - 10.1172/JCI9352
DO - 10.1172/JCI9352
M3 - Article
C2 - 11120763
AN - SCOPUS:0034519709
SN - 0021-9738
VL - 106
SP - 1561
EP - 1568
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 12
ER -