ENDOGENOUS INTERLEUKIN-1-ALPHA MUST BE TRANSPORTED TO THE NUCLEUS TO EXERT ITS ACTIVITY IN HUMAN ENDOTHELIAL-CELLS

We have previously shown that the signal peptideless cytokine interleu kin 1 alpha (IL-1 alpha) 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 t he potential intracellular function of IL-1 alpha, transformed endothe lial cells were transfected,vith the human cDNAs that code for the two forms of IL-1 alpha, the precursor molecule IL-1(1-271) and the matur e protein IL-1(113-271). The subcellular localization of the two diffe rent polypeptides was investigated directly or by using chimeric genes constructed by fusion of different fragments of the IL-1 alpha gene a nd the beta-galactosidase open reading frames. The IL-1(113-271) prote in was cytoplasmic, while IL-1(1-271) was nuclear. The basic cluster a t the NH2 terminus of IL-1, KVLKKRR, has been shown to mediate IL-1 al pha nuclear targeting. Moreover, nuclear localization of IL-1 alpha co rrelates with impaired cell growth and expression of some IL-1 alpha-i nducible genes. These results suggest that transport of endogenous IL- 1(1-271) into the nucleus is required for it to modulate endothelial c ell function.