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The Precursor Form of IL-1 Is an Intracrine Proinflammatory Activator

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The Precursor Form of IL-1 Is an Intracrine Proinflammatory Activator The precursor form of IL-1␣ is an intracrine proinflammatory activator of transcription Ariel Werman*†, Rachel Werman-Venkert*, Rosalyn White*, Jae-Kwon Lee†, Batsheva Werman†, Yakov Krelin*, Elena Voronov*, Charles A. Dinarello†, and Ron N. Apte*‡ *Department of Microbiology and Immunology, Faculty of Health Sciences and Cancer Research Center, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel; and †Department of Medicine, University of Colorado Health Sciences Center, Denver, CO 80262 Contributed by Charles A. Dinarello, December 31, 2003 Although most cytokines are studied for biological effects after additional external stimulus. For example, mice deficient in engagement of their specific cell surface membrane receptors, IL-1␣ are resistant to experimental colitis (unpublished obser- increasing evidence suggests that some function in the nucleus. In vations), and IL-1␣-deficient but not IL-1␤-deficient mice fail to the present study, the precursor form of IL-1␣ was overexpressed prime antigen-specific T cells (9). in various cells and assessed for activity in the presence of satu- The possibility that, upon nuclear localization sequence- rating concentrations of IL-1 receptor antagonist to prevent recep- dependent nuclear translocation, pIL-1␣ and propiece IL-1␣ tor signaling. Initially diffusely present in the cytoplasm of resting (ppIL-1␣) might exhibit functionality has been the focus of cells, IL-1␣ translocated to the to nucleus after activation by several studies. Indeed, overexpression of the propiece results in endotoxin, a Toll-like receptor ligand. The IL-1␣ precursor, but not transformation to a malignant phenotype (10). The propiece also the C-terminal mature form, activated the transcriptional machin- has been shown to induce apoptosis in some tumor cells by ery in the GAL4 system by 90-fold; a 50-fold increase was observed affecting alternate splicing of RNA (11). Antisense directed using only the IL-1␣ propiece, suggesting that transcriptional against IL-1␣ mRNA reverses the natural senescence of human activation was localized to the N terminus where the nuclear umbilical vascular endothelial cells (12). Such findings support localization sequence resides. Under conditions of IL-1 receptor the hypothesis of a nuclear site of action for IL-1␣. blockade, intracellular overexpression of the precursor and pro- The intracellular accumulation of cytokines like IL-1␣ lacking piece forms of IL-1␣ were sufficient to activate NF-␬B and AP-1. a signal peptide likely represent an evolutionary advantage, Stable transfectants overproducing precursor IL-1␣ released the because readily secreted proteins in aquatic life forms would not cytokines IL-8 and IL-6 but also exhibited a significantly lower be able to function during regenerative processes. An example is threshold of activation to subpicomolar concentrations of tumor the ability of the Asterias forbesi starfish to regenerate a severed necrosis factor ␣ or IFN-␥. Thus, intracellular functions of IL-1␣ arm. The macrophage-like coelomocytes of these animals con- might play an unforeseen role in the genesis of inflammation. tain a preformed IL-1-like molecule (13, 14) that is delivered to During disease-driven events, the cytosolic precursor moves to the the site of injury as an intracellular growth factor. If growth nucleus, where it augments transcription of proinflammatory factors in starfish were secreted proteins, diffusion into the genes. Because this mechanism of action is not affected by extra- surrounding seawater would markedly reduce the concentration cellular inhibitors, reducing intracellular functions of IL-1␣ might needed at the site for repair. That IL-1␣ and other intracellular prove beneficial in some inflammatory conditions. cytokines persist after the evolution of extracellular receptors in terrestrial life suggests a duality of function, one function being he IL-1 family has 10 known members, and the precursor solely in intracellular processes and the second as a mechanism Tform of each member lacks a clear signal peptide, suggesting to trigger the extracellular receptor and to initiate signal trans- persistence of an early evolutionary role as intracellular proteins duction. The two functions are not necessarily related. In the (1). Although one form of the IL-1 receptor (IL-1R) antagonist case of high-mobility group box 1 (HMGB1), one function is to (IL-1Ra) possesses a signal peptide and is secreted by means of facilitate gene transcription by stabilizing nucleosomes and the Golgi, the IL-1Ra gene has alternative splice͞insertion sites; allowing bending of DNA, and the second function is to trigger thus, in nearly all cells, variants of the antagonist cytokine extracellular receptors as typical proinflammatory cytokine pro- remain intracellular (reviewed in ref. 2). Although recombinant duced late in endotoxemia (15). forms of mature IL-1␣ (mIL-1␣), mIL-1␤, and mIL-18 are active In the present report, we studied a nuclear function of ␣ agonists, the precursor forms of IL-1␤ and IL-18 (pIL-1␤ and intracellular IL-1 as an activator of transcriptional machinery with its effects on the progression of inflammation. Expression pIL-18) are inactive. These precursors use the intracellular ␣ cysteine protease caspase-1 to cleave the precursor to an active vectors encoding the three forms of human IL-1 were con- ␣ structed: the full-length pIL-1␣ (amino acids 1–271), ppIL-1␣ mature form and exit the cell. The precursor form of IL-1 ␣ (pIL-1␣), in contrast, is fully active when it engages the IL-1 (amino acids 1–112), and mIL-1 (amino acids 113–271). We surface receptor. Unlike IL-1␤, IL-1␣ is rarely found in the also blocked all signal transduction by means of the surface extracellular compartment but rather is primarily associated with receptors by using saturating concentrations of IL-1Ra. It ap- pears that one of the functions of intracellular IL-1␣ is to lower the cell as either an intracellular protein or a membrane form (3, ␬ 4). A membrane-associated calcium-dependent protease, cal- the threshold of NF- B- and AP-1-dependent gene expression to pain, can process pIL-1␣ to a mature form (5). However, many subpicomolar concentrations of inflammatory stimuli. Two ob- vious implications of these results are priming (memory) and cells are devoid of this processing ability, leaving the intracellular ␣ precursor form in abundance. pIL-1␣ possesses a KVLKKRR chronicity. Cells previously primed to express IL-1 will hyper- nuclear localization site in its N-terminal propiece (6). In fact, pIL-1␣ translocates to the nucleus in a variety of cells, and this Abbreviations: TNF, tumor necrosis factor; CFP, cyan fluorescent protein; YFP, yellow appears to be necessary for specific downstream events (7). fluorescent protein; IL-1R, IL-1 receptor; IL-1Ra, IL-1R antagonist; pIL, precursor IL; ppIL, pIL-1␣ is found in keratinocytes and epithelial cells of healthy propiece IL; mIL, mature IL; HMGB1, high-mobility group box 1; DBD, DNA binding domain; subjects, and mice deficient in IL-1␣ do not exhibit an apparent UAS, upstream activator sequence; MIP-2, macrophage inflammatory protein 2. phenotype (8) unless challenged by disease processes, suggesting ‡To whom correspondence should be addressed. E-mail: [email protected]. that a putative function for the intracellular pIL-1␣ requires an © 2004 by The National Academy of Sciences of the USA 2434–2439 ͉ PNAS ͉ February 24, 2004 ͉ vol. 101 ͉ no. 8 www.pnas.org͞cgi͞doi͞10.1073͞pnas.0308705101 Downloaded by guest on September 26, 2021 respond to minute concentrations of various inflammatory chal- lenges as compared with previously unprimed cells. In contrast, overexpression of intracellular IL-1␣ often seen in chronic diseases might play a pivotal role in the pathogenesis and maintenance of chronicity in an IL-1R-independent manner. Materials and Methods Cloning of Human IL-1␣, IL-18, and IL-1␤ cDNA. IL-1␣ and IL-18 were cloned by PCR amplification using a human keratinocyte cDNA library as a template. The primers contained a random pen- tamer, an endonuclease restriction site, and the first and last 24 bp of the coding region of the gene for the 5Ј and 3Ј primers, respectively. pIL-1␤ was amplified by using cDNA derived from human peripheral blood mononuclear cells. Amplified PCR Fig. 1. pIL-1␣ is translocated to the nucleus upon inflammatory stimuli. fragments were cloned into pCR3.1 or pcDNA6͞His-Myc (In- NIH͞3T3 cells (20,000 per well) were plated on a cover slip placed in six-well vitrogen). Positive clones were verified by direct sequencing. plates. Twenty-four hours later, cells were transfected with both the vectors encoding the fusion proteins pIL-1␣͞EYFP-N1 and pIL-1␣͞ECFP-C1 (a). Twenty- Fluorescence Constructs. pECFP-C1 and pEYFP-N1 were pur- four hours after transfection, an aliquot of cells were stimulated with lipo- chased from Clontech. IL-1␣–enhanced cyan fluorescent pro- polysaccharide (10 ␮g͞ml). Twenty-four hours later, cover slips were observed tein (ECFP) constructs were generated by inserting a PCR- by fluorescent microscopy. (a) Fusion proteins used (calpain cleavage site marked by arrow). (b and c) Unstimulated cells observed through yellow and generated fragment into a BglII and EcoRI sites in pECFP-C1 ␣ cyan filters, respectively. (d–f) Stimulated cells observed through light micro- keeping an ORF from ECFP through pIL-1 coding region. The scopy and yellow and cyan filters, respectively. pEYFP construct was produced by ligating a PCR-generated fragment of pIL-1␣ synthesized by using a 3Ј primer lacking the TAG stop codon. This fragment was ligated to the BamHI͞ of 10% pRL Null-Renilla (Promega), 20% reporter vector (when EcoRI sites of the enhanced yellow fluorescent protein (EYFP) used), and 70% expression vector. Stable transfectants were vector, creating an ORF from pIL-1␣ through EYFP. performed similarly, except that 3 days posttransfection the cells were trypsinized and plated in 10-cm-diameter plates in the Fluorescence Microscopy.
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