Impaired translational response and increased protein kinase PKR expression in T cells from lupus patients
Annabelle Grolleau, … , Laura Beretta, Bruce Richardson
Annabelle Grolleau, … , Laura Beretta, Bruce Richardson
Published December 15, 2000
Citation Information: J Clin Invest. 2000;106(12):1561-1568. https://doi.org/10.1172/JCI9352.
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Article

Impaired translational response and increased protein kinase PKR expression in T cells from lupus patients

Abstract

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.

Authors

Annabelle Grolleau, Mariana J. Kaplan, Samir M. Hanash, Laura Beretta, Bruce Richardson

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Figure 1

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Protein synthesis in normal and lupus T cells. (a) T cells from eight he...
Protein synthesis in normal and lupus T cells. (a) T cells from eight healthy controls, seven patients with active lupus, and six patients with inactive lupus were treated with PMA (10 ng/ml) and ionomycin (400 ng/ml) for 24 hours. (b) T cells from five healthy controls, five patients with active lupus, five patients with inactive lupus, and four patients with RA were treated with PMA (10 ng/ml) and ionomycin (400 ng/ml) for 8 hours. Following treatment, cells were preincubated for 1 hour in methionine-free medium, then [35S]methionine (25 μCi) was added for 2 hours. The radioactivity incorporated into TCA-precipitable material was measured. Incorporation of [35S]methionine is expressed as fold increase as compared with unstimulated cells. Each point represents a single subject. The symbols with error bars represent the mean ± SEM of the group.