Caspase-Dependent Cleavage of Carbamoyl Phosphate Synthetase II during Apoptosis

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Abstract
The expression of the intercellular adhesion molecule 1 (ICAM-1) on the surface of endothelial cells plays an important role in immune-mediated processes. The induction by the proinflammatory cytokine interleukin (IL)-1β is regulated by nuclear transcription factor κB (NF-κB). We studied the effect of an inosine-5′-monophosphate dehydrogenase (IMPDH) inhibitor, mycophenolic acid (MPA), on constitutive and IL-1β–induced expression of ICAM-1 in human umbilical vein endothelial cells (HUVECs). Unexpectedly, pretreatment with MPA enhanced the constitutive expression and potentiated the induction of ICAM-1 by IL-1β, as detected by flow cytometry. Northern blot analysis revealed an increase in ICAM-1 mRNA levels in cells treated with MPA. This was associated with an increase in phosphorylation of IκB-α (an inhibitor of NF-κB), nuclear translocation of the NF-κB subunits p50 and p65 and their binding to DNA as detected by Western blotting, confocal microscopy, and electrophoretic mobility shift assay. The up-regulation of ICAM-1 by MPA was prevented by high doses (100 μM) of guanine or guanosine but not by physiological doses (0.1 μM), indicating that guanylates are involved in endothelial responses to IL-1β. Cultivation of HUVECs in the absence of guanine enhanced further ICAM-1 expression during IMPDH inhibition. These results demonstrate that cytokine-mediated endothelial ICAM-1 expression can be modulated by IMPDH inhibition. We believe this represents a novel interaction between endothelial guanylate metabolism, NF-κB activation, and adhesion molecule expression.

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