Endogenous Interleukin 1 Alpha Must Be Transported to the Nucleus To Exert Its Activity in Human Endothelial Cells

Abstract

We have previously shown that the signal peptideless cytokine interleukin lα (IL-lα) may play a role as an intracellular regulator of human endothelial cell senescence (J. A. M. Maier, P. Voulalas, D. Roeder, and T. Maciag, Science 249:1570-1574,1990). To investigate the potential intracellular function of IL-lα, transformed endothelial cells were transfected with the human cDNAs that code for the two forms of IL-lα, the precursor molecule IL-1_1-271 and the mature protein IL-1₁₁₃_₂₇₁. The subcellular localization of the two different polypeptides was investigated directly or by using chimeric genes constructed by fusion of different fragments of the IL-lα gene and the β-galactosidase open reading frames. The IL-1₁₁₃_₂₇₁ protein was cytoplasmic, while IL-1_1-271 was nuclear. The basic cluster at the NH₂ terminus of IL-1, KVLKKRR, has been shown to mediate IL-lα nuclear targeting. Moreover, nuclear localization of IL-lα correlates with impaired cell growth and expression of some IL-lα-inducible genes. These results suggest that transport of endogenous IL-l_1-271, into the nucleus is required for it to modulate endothelial cell function.