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 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 the potential intracellular function of IL-1 alpha, transformed endothelial cells were transfected with the human cDNAs that code for the two forms of IL-1 alpha, the precursor molecule IL-1(1-271) and the mature protein IL-1(113-271). 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-1 alpha gene and the beta-galactosidase open reading frames. The IL-1(113-271) 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-1 alpha nuclear targeting. Moreover, nuclear localization of IL-1 alpha correlates with impaired cell growth and expression of some IL-1 alpha-inducible genes. These results suggest that transport of endogenous IL-1(1-271) into the nucleus is required for it to modulate endothelial cell function.

IL-1/IL-1R Signaling in Head and Neck Cancer

“…Both preIL-1α and mIL-1α are expressed constitutively in epithelial and endothelial cells and are considered to act in an autocrine or paracrine manner [ 27 – 29 ]. IL-1α plays an important role in inflammation acting in a juxtracrine manner [ 17 ] and has been related with several other cellular functions, such as onset of senescence [ 30 – 32 ], cell growth, cell differentiation [ 28 , 33 ], immune response [ 34 ] and regulation of gene expression [ 35 – 37 ].…”

“…To exert its biological function, mIL-1α binds to IL-1R1 to trigger different cellular functions, but preIL-1α and ppIL-1α can also interact directly with the DNA without binding to IL-1R1 in a variety of cells [ 28 , 38 ]. This is because ppIL-1α contains a canonical nuclear localization sequence (NLS) that enables it to interact directly within the nucleus in a non-IL-1R1-dependent manner [ 39 , 40 ].…”

“…This is because ppIL-1α contains a canonical nuclear localization sequence (NLS) that enables it to interact directly within the nucleus in a non-IL-1R1-dependent manner [ 39 , 40 ]. PreIL-1α, via ppIL-1α, interacts with histone acetyltransferases Gcn5, p300, PCAF and with the adaptor component Ada3, inducing protein transcription without activating IL-1R1 [ 41 ], and in doing so exerts different intracellular functions, such as NF-κB and AP-1 activation [ 38 ], modulation of endothelial proliferation [ 28 ], migration [ 42 ] and cytokine production [ 43 ].…”

What Is IL-1 for? The Functions of Interleukin-1 Across Evolution

“…The most likely hypothesis is that IL-1α possesses different functions, non-redundant with those of IL-1β. Indeed, IL-1α is not a typical inflammatory cytokine, as its precursor protein (pro-IL-1α) is constitutively expressed in macrophages and many non-immune stromal cells (epithelial cells, endothelial cells, fibroblasts) in resting conditions, and it localises in the nucleus where it acts as transcription factor thereby regulating cellular functions, proliferation, senescence and apoptosis ( 37 , 38 , 94 , 95 ). Upon inflammatory stimulation, pro-IL-1α can be cleaved and, while the C-terminal portion is exported outside the cell and acts as a cytokine (binding to the same receptor as IL-1β), the pro-piece can still act as transcription factor and upregulate the expression of inflammation-related genes ( 38 , 95 – 98 ).…”

The role of pro-domains in human growth factors and cytokines

“…They all have pro-domains of ∼100 residues, but they lack a signal peptide and hence are not directly secreted from cells. Instead, they are at first localised in the nucleus [ 54 ] or move from cytoplasm to nucleus upon stimulus such as cell stress. The release of the mature domain by proteolysis [ 5 ] can occur intracellularly or, within vesicles, by calpains or caspases [ 55 ].…”