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J. Biol. Chem., Vol. 280, Issue 23, 21720-21725, June 10, 2005
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Secretion*
From the Center for the Development of Molecular Target Drugs, Cancer Research Institute, Kanazawa University, 13-1 Takaramachi, Kanazawa, Ishikawa 920-0934, Japan
Received for publication, September 1, 2004 , and in revised form, January 31, 2005.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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secretion and NF-
B activation in the presence of the adaptor molecule ASC. On the other hand, we recently discovered that PYNOD, another member of this family, is a suppressor of these responses. Here, we show that PYPAF3 is the second member that inhibits caspase-1-dependent interleukin-1 secretion. In contrast, PYPAF2/NALP2 does not inhibit this response but rather inhibits the NF-B activation that is induced by the combined expression of PYPAF1 and ASC. Both PYPAF2 and PYPAF3 mRNAs are broadly expressed in a variety of tissues; however, neither is expressed in skeletal muscle, and only PYPAF2 mRNA is expressed in heart and brain. They are also expressed in many cell lines of both hematopoietic and non-hematopoietic lineages. Stimulation of monocytic THP-1 cells with lipopolysaccharide or interleukin-1 induced PYPAF3 mRNA expression. Furthermore, the stable expression of PYPAF3 in THP-1 cells abrogated the ability of the cells to produce interleukin-1 in response to lipopolysaccharide. These results suggest that PYPAF3 is a feedback regulator of interleukin-1 secretion. Thus, PYPAF2 and PYPAF3, together with PYNOD, constitute an anti-inflammatory subgroup of PYPAFs. |
INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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is produced upon microbial infection mainly from monocytes/macrophages and neutrophils. IL-1 plays a fundamental role in protecting animals against infectious agents by activating immune cells, inducing a variety of cytokines and acute phase proteins and acting as a pyrogen (1, 2). On the other hand, excessive production of IL-1 induces septic shock and is fatal for animals. Therefore, the regulation of IL-1 production is an important issue in infectious diseases from both the pathophysiological and pharmacological points of view. However, the regulatory mechanisms of IL-1 production are poorly understood.
IL-1 is produced as an inactive proprotein and is converted to the active mature protein through proteolytic cleavage by caspase-1. Recently, IL-1-converting enzyme-protease-activating factor (Ipaf, also called caspase recruitment domain (CARD) 12), which has homology with apoptotic protease-activating factor (Apaf)-1 and promotes caspase-1-dependent IL-1 maturation, was discovered (3). More recently, several members of another subfamily of Apaf-1-like proteins having an N-terminal PYRIN domain (called PYRIN-containing Apaf-1-like proteins (PYPAFs) or NALPs), namely PYPAF1/cryopyrin, PYPAF5, PYPAF7, and NALP1, have been found to promote caspase-1-dependent IL-1 maturation in the presence of an adaptor molecule, ASC (4–6). On the other hand, two other Apaf-1-like proteins, Nod1 and Nod2, were discovered to be cytoplasmic sensors for cell-invading microbes (7). These findings shed light on how microbial infection induces the activation of caspase-1 and the secretion of mature IL-1 (7, 8). On the other hand, little is known about the functions of other Apaf-1-like proteins in caspase-1 activation and/or IL-1 maturation. PYPAF2 has been contradictorily reported both to and not to promote caspase-1-dependent IL-1 secretion (5, 9).
Recently, we discovered that PYNOD, a novel member of the PYPAFs, has the potential to inhibit caspase-1-dependent IL-1 secretion as well as ASC-mediated NF-B activation (10). This was the first example of a PYPAF member playing a negative regulatory role in IL-1 secretion. This finding prompted us to investigate whether other ill-characterized members of this family have activities similar to PYNOD. Here we investigated the effects of PYPAF2 and PYPAF3 expression on NF-B activation and IL-1 secretion. These two proteins are highly homologous and likely to be products of a very recent gene duplication event. We found that PYPAF3 inhibits caspase-1-dependent IL-1 secretion but not ASC-mediated NF-B, while PYPAF2 inhibits the latter but not the former. Further study suggested that PYPAF3 is a feedback regulator of caspase-1-dependent IL-1 secretion.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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and tumor necrosis factor (TNF)-
was purchased from PeproTech (London, UK) and Genzyme (Cambridge, MA), respectively. Lipopolysaccharide from Escherichia coli 055:B5 was purchased from Sigma.
Plasmids—A cDNA encoding human PYPAF2 (IMAGE:2821428) was purchased from Open Biosystems (Huntsville, AL). A cDNA encoding human PYPAF3 was amplified by RT-PCR from human peripheral blood lymphocyte poly(A)(+) RNA. The cDNAs encoding PYPAF2, PYPAF3, and their leucine-rich repeat (LRR)-truncated mutants (PYPAF2dLRR (amino acids 1–683) and PYPAF3dLRR (amino acids 1–685), respectively) were cloned into the pEF-Bos mammalian expression vector (11). Plasmids expressing human PYPAF1, PYPAF1dLRR (amino acids 1–739), a dominant negative mutant of TRADD (amino acids 196–312 with alanine substitution at amino acids 296–299), procaspase-1, pro-IL-1, ASC, MyD88, and receptor-interacting protein death domain (RIP-DD, amino acids 558–671) with or without an N-terminal FLAG-tag were described previously (10). The human influenza virus hemagglutinin epitope (HA) was introduced as needed using pHA-EAK and pEAK-HA, which are pEAK8-derived mammalian expression vectors in which the sequence for HA is inserted at the N- and C-terminal side of the multicloning site, respectively. pEAK-HA was kindly provided by Dr. Hisashi Miyamori (Kanazawa University, Cancer Research Institute). Human Bcl-XL DNA was a kind gift from Dr. Shigeomi Shimizu (Osaka University Medical School), and it was subcloned into pHA-EAK.
Cell Lines and Transfection—The HEK293, 293T, HepG2, ECV304, PK-1, SW480, K562, Jurkat, U937, and THP-1 cell lines were described previously (10). The HeLa (epitheloid carcinoma) cell line was obtained from Dr. Nobuhiro Nakamura (Kanazawa University, Faculty of Pharmaceutical Science). The HL-60 (promyelocytic leukemia) cell line was obtained from Dr. Shinji Nakao (Kanazawa University Graduate School of Medical Science).
For luciferase reporter assays and IL-1 secretion assays, HEK293 cells were plated onto 48-well plates at a density of 4 x 104 cells/well, and transfection was carried out 18 h later using linear polyethyleneimine (Mr about 25,000, Polysciences Inc., Warrington, PA) as described previously (12). For immunoprecipitation assays, 293T cells were plated onto 6-well plates at density of 5 x 105 cells/well, and transfection was carried out 18 h later using Lipofectamine Plus (Invitrogen). To generate stable transfectants, THP-1 cells were transfected with pHA-EAK-PYPAF3 by electroporation. After selection with puromycin for 4 weeks, stable transfectants expressing HA-tagged PYPAF3 were selected by Western blot analysis.
Luciferase Reporter Assays for NF-B Activity—HEK293 cells in 48-well plates were transfected with plasmids including 15 ng/well of pNF-B-Luc (carrying a firefly luciferase cDNA driven by 5x NF-B-binding sites; Stratagene, La Jolla, CA) and 3 ng/well of pRL-TK (carrying Renilla luciferase cDNA driven by the HSV-TK promoter; Promega, Madison, WI). The total amount of DNA in each transfection was kept constant (300 ng/well) by the addition of empty vector (pEF-BOS). After 24 h, cell lysates were prepared and the firefly, and Renilla luciferase activities were measured using the dual-luciferase reporter assay system (Promega). The relative luciferase activity was calculated as follows: relative luciferase activity = firefly luciferase activity/renilla luciferase activity.
IL-1 Secretion Assays—HEK293 cells in 48-well plates were transfected with plasmids including those expressing pro-IL-1 (80 ng/well) and procaspase-1 (2 ng/well, unless otherwise specified). The total amount of DNA in each transfection was kept constant (300 ng/well) by the addition of empty vector (pEF-BOS). After 26 h, the culture supernatants were collected and subjected to ELISA for IL-1 using the Human IL-1 OptEIA ELISA Set (Pharmingen).
Immunoprecipitation and Western Blot Analysis—Immunoprecipitation and Western blotting were carried out as previously described (10), except that transfection and cell culture were performed in 6-well plates and that rabbit polyclonal and mouse monoclonal anti-HA antibodies (Sigma) were used for immunoprecipitation and Western blots, respectively. PYPAF-3-specific antisera were prepared from mice immunized with purified glutathione S-transferase-fused PYPAF-3 PYRIN domain (amino acids 1–93).
Assays for mRNA Expression—Panels of first-strand cDNA from multiple human tissues (Human I and Human II) were purchased from Clontech (Palo Alto, CA). Total RNA from cultured cell lines was prepared using the RNeasy mini kit (Qiagen, Hilden, Germany). RT-PCR analysis was performed as described previously (13). The primers used to detect human PYPAF2 mRNA were as follows: sense, 5'-gcaaaggatgaagtcagaga-3'; antisense, 5'-ccctccacccttatgtagat-3', while those for PYPAF3 mRNA were as follows: sense, 5'-gcagtgggctgaattcttct-3'; antisense, 5'-gcctgacagagaatccacaa-3'. The amount of template cDNA was adjusted so that a similar amount of a PCR fragment of -actin was generated within the linear range of the PCR.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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B Activation Induced by the Combined Expression of PYPAF1 and ASC—We first investigated the effect of PYPAF2 and PYPAF3 expression on ASC-mediated NF-B activation in HEK293 cells using luciferase reporter assays. Consistent with a previous report (14), PYPAF1 promoted this response, and truncation of the LRRs (PYPAF1dLRR) enhanced this activity (Fig. 1A). In contrast, PYPAF2 and PYPAF3 and even their LRR-truncated mutants failed to show such an activity (Fig. 1A). Instead, PYPAF2 dose-dependently inhibited the NF-B activation induced by PYPAF1dLRR plus ASC (Fig. 1B). PYPAF3 showed little or no such activity. It was previously shown that PYPAF4 inhibits NF-B activation induced by TNF- or IL-1 (15). In contrast, PYPAF2 did not inhibit TNF--induced NF-B activation, while a dominant negative mutant of TRADD inhibited this response, serving as a positive control (Fig. 1C). In this context, PYPAF2 is more similar to PYNOD (10) than PYPAF4.
PYPAF3 Inhibits Caspase-1-dependent IL-1 Secretion— Next, we investigated whether PYPAF2 and PYPAF3 promotes caspase-1-dependent IL-1 secretion in the presence of ASC in HEK293 cells. Previous reports lack agreement on whether or not PYPAF2 promotes this response (5, 9). In our hands, IL-1 secretion was not induced by PYPAF2, PYPAF3, or their LRR-deletion mutants, irrespective of the presence or absence of ASC (Fig. 2A and supplemental Fig. S1, A and B), while it was efficiently induced by PYPAF1 and PYPAF1dLRR in the presence of ASC as reported previously (4, 10). We then investigated the effect of PYPAF2 or PYPAF3 expression on the caspase-1-dependent IL-1 secretion induced by PYPAF1dLRR plus ASC. In contrast to its lack of inhibitory activity against ASC-mediated NF-B activation described above, PYPAF3 strongly and dose-dependently inhibited the IL-1 secretion, while PYPAF2, which successfully inhibited the ASC-mediated NF-B activation, did not (Fig. 2B). To further examine the mechanism by which PYPAF3 inhibits caspase-1-dependent IL-1 secretion, we investigated the effect of PYPAF3 on the IL-1 secretion induced by caspase-1 overexpression. In the absence of ASC and PYPAF1, caspase-1 induced IL-1 secretion dose-dependently (Fig. 2C). The expression of PYPAF3 but not PYPAF2 inhibited this response dose-dependently, indicating that PYPAF3 affects caspase-1 activation or downstream events.
PYPAF3 Inhibits Processing of Pro-IL-1 and Procaspase-1—To explore how PYPAF3 inhibited the caspase-1-dependent IL-1 secretion in more detail, we investigated the processing of pro-IL-1 and procaspase-1 by Western blot analysis. First, C-terminal HA-tagged pro-IL-1 was coexpressed with procaspase-1 in 293T cells. Under these conditions, an anti-HA antibody detected the mature form of IL-1 (p17) (Fig. 3A, lane 2). The expression of PYPAF3 (Fig. 3A, lanes 6–8) but not PYPAF2 (Fig. 3A, lanes 3–5) dose-dependently inhibited the generation of p17. Next, N-terminal FLAG-tagged procaspase-1 was overexpressed in 293T cells to induce its auto- or cognate cleavage. Under these conditions, p33, which corresponds to the N-terminal fragment after the p10 subunit cleavage, was detected by Western blotting using an anti-FLAG antibody (Fig. 3B, lanes 2–4). PYPAF3 strongly and dose-dependently inhibited the generation of p33 (Fig. 3B, lanes 8–10), indicating that PYPAF3 inhibits procaspase-1 processing. PYPAF2 partially inhibited this processing at a high dose but much less efficiently than did PYPAF3 (Fig. 3B, lanes 5–7).
PYPAF3 Interacts with Both Procaspase-1 and Pro-IL-1—We next investigated whether there are physical interactions between PYPAF3 and caspase-1 or IL-1. These proteins were transiently expressed in 293T cells, and the cell lysates were subjected to immunoprecipitation analysis. Immunoprecipitation of caspase-1 or IL-1 but not RIP-DD resulted in the coprecipitation of PYPAF3 (Fig. 4, A and B, left panels). In addition, the immunoprecipitation of PYPAF3 but not Bcl-XL resulted in the coprecipitation of caspase-1 and IL-1 (Fig. 4, A and B, right panels). These results indicate that PYPAF3 physically interacts with both caspase-1 and IL-1.
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was endogenously expressed in 293T cells, it was possible that caspase-1 or IL-1 indirectly interacted with PYPAF3 through the other one. Therefore, We examined the expression of caspase-1 and IL-1 mRNA in 293T cells. No RT-PCR product corresponding to caspase-1 cDNA was detected (see supplemental Fig. S2A), indicating that caspase-1 is not expressed in this cell line. On the other hand, we detected a faint band corresponding to IL-1 cDNA (see supplemental Fig. S2A). Then we investigated whether a significant amount of IL-1 is present in 293T cells. We could not detect any IL-1 protein in the culture supernatants or cell lysates from 293T cells using ELISA irrespective of the presence or absence of exogenous caspase-1, unless IL-1 was exogenously expressed by transfection (see supplemental Fig. S2B). Thus, the expression level of endogenous IL-1 protein in 293T cells was very low, if any. These results suggest that caspase-1 and IL-1 interacted with PYPAF3 independent of each other.
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Induce PYPAF3 Expression in Monocytic THP-1 Cells and Peripheral Blood Mononuclear Cells—We next investigated whether inflammatory stimuli induce PYPAF3 expression in hematopoietic cell lines, using HL-60 promyelocytic leukemia, Jurkat acute T cell leukemia, U937 histiocytic lymphoma, and THP-1 acute monocytic leukemia cells. Interestingly, LPS potently enhanced the expression level of PYPAF3 but not PYPAF2 mRNA in THP-1 cells (Fig. 6A). Such induction was not observed in HL-60, Jurkat, or U937 cells. IL-1 also induced PYPAF3 mRNA expression in THP-1 cells in a stimulation time- and dose-dependent manner (Fig. 6B). Furthermore, LPS and IL-1 enhanced PYPAF3 mRNA expression in peripheral blood mononuclear cells as revealed by RT-PCR analyses (Fig. 6C). These results suggest that elevation of the IL-1 concentration results in the induction of PYPAF3, which has the potential to inhibit IL-1 production, in monocytes.
PYPAF-3 Inhibits LPS-induced IL-1 Secretion from THP-1 Cells—Finally, to obtain more insight into the biological significance of the ability of PYPAF3 to inhibit IL-1 secretion, we investigated whether PYPAF3 inhibits the LPS-induced endogenous IL-1 production in THP-1 cells. To this end, we established stable transfectants expressing N-terminal HA-tagged PYPAF3. Western blot analysis using anti-HA or anti-PYPAF3 antibodies failed to detect a protein corresponding to full-length PYPAF3; however, we reproducibly detected a 35-kDa band with either anti-HA or anti-PYPAF3 antibodies specifically in PYPAF3-expressing but not in control transfectants (Fig. 7A and data not shown). We established five independent clones of PYPAF3 transfectants, and all of them produced little or no IL-1 upon LPS stimulation (Fig. 7B, showing two representative clones), while control transfectants receiving empty vector produced a large amount of IL-1 under these conditions. These results indicate that PYPAF3 inhibits the endogenous IL-1 production in THP-1 cells.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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processing, while PYPAF2 inhibits ASC-mediated NF-B activation. We recently found that a novel PYPAF member, which we named PYNOD, inhibits both of these activities (10). In addition, PYPAF4 was previously reported to inhibit the NF-B activation induced by TNF- or IL-1 (15). Therefore, these members seem to constitute an anti-inflammatory subgroup of PYPAFs, in contrast to the proinflammatory members, which include PYPAF1, PYPAF5, PYPAF7, and NALP1. PYPAF3 interacted with both caspase-1 and IL-1 and inhibited the processing of both. At present, it is not clear whether PYPAF3 can inhibit the processing of IL-1 by already-activated caspase-1. On the other hand, PYPAF2, like PYNOD, inhibited the ASC-mediated but not TNF--mediated NF-B activation. These results suggest that the molecular mechanisms by which PYPAF2 and PYNOD inhibit NF-B activation are different from that of PYPAF4, which directly binds to IKK and inhibits NF-B activation induced by cytokines (15).
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processing and ASC-mediated NF-B activation, and separable regions are responsible for each of these functions,2 it is possible that the common ancestor gene for PYPAF2 and PYPAF3 encoded a protein that possessed both of these activities, which might have been separately inherited by PYPAF2 and PYPAF3. In this context, it would be interesting to test whether the mouse protein representing these two human proteins has both functions. This structural similarity and functional difference between PYPAF2 and PYPAF3 may be useful for investigating the structure-function relationship of these proteins.
PYPAF2 and PYPAF3 mRNAs were broadly expressed in most tissues, with a few exceptions. Skeletal muscle expressed neither PYPAF2 nor PYPAF3, while heart and brain expressed PYPAF2 but not PYPAF3. Interestingly, PYNOD is mainly expressed in skeletal muscle, heart, and brain (10). Thus, it is likely that PYNOD and PYPAF2/PYPAF3 play similar functions in different tissues and/or different contexts. Despite the broad expression of PYPAF2 and PYPAF3 mRNA, their expression levels in a given tissue or cell line were not well correlated with each other. Furthermore, LPS stimulation induced the expression of PYPAF3 but not PYPAF2 mRNA in THP-1 cells. These results suggest that the expression of these mRNAs is differently regulated despite their genes being adjacent on the chromosome.
When we examined the N-terminal HA-tagged PYPAF3 protein expressed in stable transfectants of THP-1, we could detect only a 35-kDa fragment, which corresponds to the N-terminal fragment of PYPAF3 consisting of the PYRIN domain and the NAIP/CIITA/HET-E/TP1 (NACHT) domain, suggesting that PYPAF3 is quickly degraded in these cells. In addition, when we transfected HEK293 cells with a plasmid expressing the N-terminal portion of PYPAF3 corresponding to the p35 fragment together with expression plasmids for caspase-1 and pro-IL-1, it inhibited the IL-1 secretion significantly but less efficiently than a plasmid expressing full-length PYPAF3 (data not shown). We are now trying to determine the essential region of PYPAF3 for its caspase-1-inhibitory activity.
Stimulation by LPS or IL-1 induced the expression of PYPAF3 mRNA in monocytic THP-1 cells. Furthermore, stable transfectants of this cell line expressing PYPAF3 were severely defective in the LPS-induced IL-1 production. Therefore, it is likely that the PYPAF3 is a feedback regulator for IL-1 secretion. Considering that an exaggerated production of IL-1 is highly toxic to animals, such a feedback regulation mechanism should be very important under pathophysiological conditions. ICEBERG, COP, and CARD8 are CARD-containing proteins that have been reported to interact with caspase-1 and inhibit caspase-1-dependent IL-1 secretion (17–19). However, the genes for these proteins have been found in humans but not in mice (16). In contrast, PYPAF3 and PYNOD have counterparts in mice (10, 16). Therefore, these proteins may play fundamental roles as caspase-1 inhibitors in mammals. This notion should be investigated by gene-targeting experiments in the future.
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FOOTNOTES |
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The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1 and S2.
To whom correspondence should be addressed. Tel.: 81-76-265-2736; Fax: 81-76-234-4525; E-mail: sudat{at}kenroku.kanazawa-u.ac.jp.
1 The abbreviations used are: IL-1, interleukin-1; Ipaf, IL-1-converting enzyme-protease-activating factor; CARD, caspase recruitment domain; Apaf, apoptotic protease-activating factor; PYPAF, PYRIN-containing Apaf-1-like protein; TNF, tumor necrosis factor; LRR, leucine-rich repeat; RIP-DD, receptor-interacting protein death domain; HA, human influenza virus hemagglutinin epitope; LPS, lipopolysaccharide; RT, reverse transcription; ELISA, enzyme-linked immunosorbent assay.
2 Y. Wang and T. Suda, unpublished observation.
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ACKNOWLEDGMENTS |
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