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Lovastatin inhibits T-cell antigen receptor signaling independent of its effects on ras
F Goldman1, R J Hohl, J Crabtree
1Department of Pediatrics, University of Iowa Hospital and Clinics, Iowa City 52242, USA.
Abstract:
Lovastatin, a cholesterol-lowering drug, has antiproliferative properties that may be related to its inhibition of protein isoprenylation. We examined the effects of lovastatin on signal transduction via the T-cell antigen receptor (TCR). Lovastatin inhibited both proximal and distal TCR-mediated signaling events in a time- and concentration-dependent manner in the human Jurkat T-cell line. Upregulation of CD69 surface expression after TCR stimulation was blocked by lovastatin, although no inhibition of phorbol ester-induced CD69 expression was noted. Proximal TCR-mediated signaling events, including intracellular calcium mobilization, inositol phosphate production, and tyrosine phosphorylation of phospholipase Cgamma1, were similarly inhibited by lovastatin, although global protein tyrosine kinase activity remained intact. In a Jurkat variant transfected with the human type-1 muscarinic receptor, lovastatin also inhibited TCR-mediated calcium mobilization and inositol phosphate production but failed to affect muscarinic receptor-induced responses. Lovastatin, at similar doses, also disrupted post-translational processing of ras and inhibited ras-dependent signals, including phosphorylation and activation of mitogen-associated protein kinase after TCR stimulation. These findings suggest that the antiproliferative properties of lovastatin may be independent of ras and could result from uncoupling protein tyrosine kinases from distinct signal transduction pathways.
Insights
Lovastatin, a cholesterol drug, inhibits T-cell receptor (TCR) signaling pathways. This suggests its anti-proliferative effects may stem from disrupting protein tyrosine kinases, independent of ras signaling.
Area of Science:
- Immunology
- Cell Biology
- Pharmacology
Background:
- Lovastatin is a cholesterol-lowering drug with potential antiproliferative properties.
- Its mechanism may involve the inhibition of protein isoprenylation.
- The impact of lovastatin on T-cell receptor (TCR) signaling remains to be fully elucidated.
Purpose of the Study:
- To investigate the effects of lovastatin on signal transduction pathways mediated by the TCR.
- To determine if lovastatin's antiproliferative effects are linked to its impact on TCR signaling.
- To explore the role of ras signaling in lovastatin's effects on T-cells.
Main Methods:
- Utilized the human Jurkat T-cell line and a variant transfected with the human type-1 muscarinic receptor.
- Administered lovastatin in a time- and concentration-dependent manner.
- Assessed TCR-mediated signaling events, including CD69 expression, calcium mobilization, inositol phosphate production, and mitogen-associated protein kinase activation.
Main Results:
- Lovastatin inhibited proximal and distal TCR-mediated signaling events.
- It blocked TCR-induced CD69 surface expression but not phorbol ester-induced expression.
- Lovastatin inhibited calcium mobilization, inositol phosphate production, and phospholipase Cgamma1 phosphorylation, while global protein tyrosine kinase activity was unaffected.
- Lovastatin disrupted ras post-translational processing and inhibited ras-dependent signals, including mitogen-associated protein kinase activation after TCR stimulation.
Conclusions:
- Lovastatin inhibits TCR-mediated signaling in Jurkat T-cells.
- These inhibitory effects appear to be independent of ras signaling.
- Lovastatin's antiproliferative properties may result from uncoupling protein tyrosine kinases from specific signal transduction pathways.