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INTRODUCTION
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The cDNA of murine secretory leukoprotease inhibitor (SLPI) was cloned from a mouse lung cDNA library. The amino acid sequence deduced from the cDNA showed 58 and 51% homology with those of human and porcine SLPI, respectively. A two-domain structure with similar amino acid sequences, four intradomain disulfide bonds, and high proline content, which are characteristics common to human and porcine SLPI, was also found in the mouse protein. The amino acid residues for the signal sequence and active site are also conserved in mouse SLPI. RNase protection assay showed the expression of the SLPI gene in liver, intestine, spleen, and epididymis, suggesting the distribution of SLPI in tissues other than lung and seminal vesicles. In the lung infected with Streptococcus pneumoniae strain FP1284, 10 h after inoculation of bacteria the number of SLPI mRNA transcripts was three times higher than baseline. The increased level of expression remained constant for at least 48 h. This result clearly contrasts to that obtained for spleen, in which the SLPI mRNA transcript level was mostly unchanged during the course of pneumonia. These facts suggested the local regulation of the SLPI gene expression in vivo in response to inflammatory stimuli at the site of inflammation.
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Secretory leukoprotease inhibitor (SLPI)1 is a 12 kD serine protease inhibitor synthesized and secreted constitutively and locally by specific types of cells that line the lumens in tissues such as airway, seminal vesicles, uterine cervex, and parotid duct, and produce mainly the water component of mucus (1). The characteristic tissue distribution of SLPI suggests that the physiologic function of SLPI is to protect tissues from excessive destruction by neutrophil proteases such as neutrophil elastase at the sites of inflammation. This hypothesis is supported by the observations in the airway that the SLPI gene expression in airway epithelial cells is upregulated at the transcriptional level in vitro when the cells are stimulated with neutrophil elastase (2) or phorbol 12-myristate 13-acetate (PMA) (3), and the serum SLPI level increases in humans with airway inflammation (4). Although a recent in situ hybridization study (5) has shown that the constitutive expression of the SLPI gene in the airway is confined to the serous cells of submucosal glands, no information is available on the changes of the SLPI gene expression at the site of inflammation in vivo.
The purpose of the present study was to assess the SLPI gene expression quantitatively during the course of bacterial pneumonia in vivo in mice. To determine the changes in the amount of the SLPI mRNA transcripts in the mouse lung, we cloned the mouse SLPI cDNA from a mouse lung cDNA library to use as a probe. SLPI mRNA in the lung analyzed by Northern blot hybridization showed a striking increase 10 h after the initiation of the infection, and this level was maintained for at least 48 h. The result indicates that the SLPI gene is activated in the lung tissue by stimulatory signals caused by pneumonia and provides additional evidence for the upregulation of the SLPI gene by PMA as previously reported in cultured airway epithelial cells in vitro.
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Animals
Male C57BL/6 mice 10 to 12 wk of age were used for the tissue distribution analysis of SLPI mRNA. Mice were anesthetized in diethylether vapor and killed by exsanguination through a carotid artery. Tissues and organs were removed, frozen in liquid nitrogen, and used for RNA preparation.
Bacterial pneumonia was established with the ICR strain of mice
(male, 4 wk old) because a preliminary Northern analysis of the total
cellular RNA from this strain with mouse SLPI cDNA labeled with
[
-32P]dCTP by the random primer labeling method (6, 7) showed faint but detectable amounts of SLPI mRNA. Mice were inoculated with 8 × 10 7 colony-forming units (cfu) of Streptococcus pneumoniae
strain FP1284 through the nose. Mice were killed in the same way as
described above 0, 2, 10, 24, and 48 h after the inoculation of bacteria. Lung and spleen from individual animals were processed as described above for the preparation of total cellular RNA.
Cloning of Mouse SLPI cDNA
The cloning was performed in two steps. In the first step, to obtain a part of the mouse SLPI cDNA probe for cDNA screening, degenerate primers, HPC22 (forward primer, 5'-TGGCACCTTGGGCNGTGGAAGG-3') and ABE2 (reverse primer, 5'-AAAGAGAAATAGGCTCGTTTATTT-3') were designed to locate at the 5' (base 343 through 364 in the human SLPI gene sequence reported in Reference 8) and 3' (base 2553 through 2575 in Reference 8) ends, respectively, of the SLPI cDNA sequence, which are highly homologous between human and porcine (8). Reverse transcription (RT) was done with a primer [oligo (dT)12-18 or ABE2], lung poly(A)+ RNA from C57BL/ 6 mice, and Moloney murine leukemia virus reverse transcriptase (GIBCO-BRL, Gaithersburg, MD) at 37 ° C for 1 h. Annealing of the primer was preceded by the reaction at 37 ° C for 2 min. Subsequent polymerase chain reaction (PCR) consisted of 30 cycles of denaturing (94° C, 30 s), annealing (54° C, 30 s), and extension (72° C, 2 min) with an initial 2-min denaturation and a final 7 min extension. The resulting fragment (0.6 kb) was confirmed to be an appropriate probe by Southern hybridization with 32P-labeled porcine SLPI cDNA previously prepared by RT-PCR according to the reported sequence (10). Hybridization was performed in the presence of 50% formamide and 0.5% sodium dodecyl sulfate (SDS) at 42 ° C for 16 h and the membrane was washed in 0.1 × SSC containing 0.5% SDS at 37 ° C for 30 min.
The 0.6-kb fragment was reamplified by PCR with the primers containing an additional Eco RI site at each 5' end and inserted into the pGEM-4Z (Promega, Madison, WI). The sequence of the insert revealed a homology of 66% to both the human and the porcine SLPI cDNA with highly conserved deduced amino acid residues.
The subcloned RT-PCR product (pAT3) was used to screen the
mouse lung cDNA library (Mouse Lung cDNA Library in the Uni-ZAPTM-XR Vector; STRATAGENE, La Jolla, CA) for the full-length mouse SLPI cDNA. The insert of one positive clone was subcloned into pBluescript SK(
) (STRATAGENE) by in vivo excision
according to the manufacturer's instructions. The sequence was confirmed for both directions.
Hybridization of the Mouse Genomic DNA to the Mouse SLPI cDNA
The presence of the SLPI gene in the mouse genome was confirmed by Southern hybridization of the mouse genomic DNA to the mouse SLPI cDNA. Ten micrograms of genomic DNA prepared from E.14-1 embryonal stem cells derived from the C57BL /6 strain of mice (11) were treated with 1.2 U of Bam HI, Eco RI or Hind III for 14 h and electrophoresed on 0.7 % agarose gel. Blotting onto a nylon membrane (GeneScreen; NEN Research Products, Boston, MA) and hybridization to the 32P-labeled mouse SLPI cDNA was done according to methods previously described (12). Autoradiography was undertaken using an image analyzer BAS 2000 (Fuji Photo Film Co. Ltd., Tokyo, Japan).
Tissue Distribution of SLPI mRNA Transcripts in Mouse
Total cellular RNA was prepared from mouse (C57BL /6) organs such
as brain heart, lung, liver, kidney, spleen, small intestine, seminal vesicle, epididymis, and muscle by the acid-guanidinium phenol-chloroform method (13). To raise the sensitivity and specificity, the tissue
distribution of the SLPI mRNA transcripts in mice was determined by
RNase protection assay (14) using total cellular RNA from each tissue
or organ as the target. Briefly, 1 × 10 6 cpm of the antisense RNA
probe labeled with 32P-UTP was hybridized to 30 µg of target RNA,
digested with RNase A at a concentration of 37 µg/ml, and electrophoresed on 5% polyacrylamide gel containing 7 M urea. The 32P-
labeled RNA probe was made by in vitro transcription with T7 RNA
polymerase (Promega) and a linearized pAT3. The protected RNA
probe after RNase treatment (expected length: 490 nucleotides) was
detected by autoradiography using BAS 2000. The amount of the
SLPI mRNA transcripts in each tissue was determined by a working curve made from radioactivities with standard sense RNA samples. The integrity of the RNA samples was validated by Northern hybridization with a chicken 
-actin cDNA probe (15).
Analysis of the SLPI mRNA Transcripts in the Lung and Spleen during the Course of Bacterial Pneumonia
The lung and spleen were removed from the mice 0, 2, 10, 24, and 48 h
after nasal inoculation of streptococci as described. At each time
point, three animals were used for the analysis. Total cellular RNA
was prepared from each organ individually by the acid-guanidium
phenol-chloroform method, and 20 µg each were analyzed by Northern blot hybridization with the 32P-labeled mouse SLPI cDNA probe.
After autoradiography, the nylon membrane (Nytran; Schleicher & Schuell, Dassel, Germany) was washed in the probe-removing buffer
(50% formamide/6 × SSPE) and rehybridized to the 32P-labeled
chicken -actin cDNA probe to validate the integrity of the RNA
samples. The amount of SLPI mRNA transcripts was expressed as the
relative ratio of the radioactivity obtained with the SLPI cDNA probe
to that with the chicken -actin cDNA probe.
Statistical Analysis
Statistical analysis was done with Student's t test. A p value below 0.05 was considered to indicate significant difference.
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Cloning of the Mouse SLPI cDNA
Failure to obtain directly a mouse SLPI cDNA-containing clone from the mouse lung cDNA library using the porcine SLPI cDNA probe led to the preparatory step to amplify a part of the mouse SLPI cDNA by RT-PCR with degenerate primers and poly(A)+ RNA prepared from mouse lung. Among the DNA fragments amplified by this procedure, a fragment with an expected size of 0.6 kb hybridized weakly to the 32P- labeled porcine SLPI cDNA probe (data not shown). After confirming the base sequence and deduced conserved amino acid residues by comparison with those of human and porcine SLPI cDNA, this 0.6 kb pAT3 insert was used to screen the mouse lung cDNA library.
After screening 7 × 105 clones with the pAT3 insert as a probe, one positive clone was obtained. DNA sequencing revealed that the cloned DNA fragment was 682 bp long and showed 66% homology with both those of human and porcine SLPI cDNA (Figure 1A). The deduced amino acid sequence between the start codon (ATG) and stop codon (TGA) showed 58 and 51% homology with those of human (8, 9) and porcine (10) SLPI, respectively. The following characteristics of the amino acid sequence indicated that the obtained cDNA clone contained a full-length cDNA of mouse SLPI: first, 16 cysteine residues, which are assumed to form eight intramolecular disulfide bonds, were completely conserved at the locations corresponding to those of human or porcine SLPI (Figure 1B). Second, the amino acid sequence around the active site (CMMLNPPM) (Figure 1B) is highly conserved in human, porcine, and mouse. Finally, the signal sequence of mouse SLPI, which is expected to be composed of 25 residues from the N-terminal (Figure 1B), also shows a homology of 76% with that of human SLPI (8, 9, 16, 17).
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Southern Blot Hybridization of Mouse Genomic DNA with the Mouse SLPI cDNA Probe
Mouse genomic DNA treated with Eco RI contained only one approximately 3.6 kb-long fragment that hybridized with the mouse SLPI cDNA (Figure 1C). The size of this Eco RI fragment is comparable to that observed in human genomic DNA (3.7 kb) hybridized with human SLPI cDNA (8), indicating that there is only one locus of the SLPI gene in the mouse genome. Bam HI generated fragment with a size of 2.3 kb, and Hind III generated at least two bands with sizes of 8.8 and 0.8 kb (Figure 1C).
Tissue Distribution of the SLPI mRNA Transcripts in the Mouse
To evaluate more clearly the tissue distribution of SLPI mRNA transcripts in mice, RNase protection assay was performed instead of the usual Northern analysis. The protected probe was clearly seen in lung, spleen, small intestine, and epididymis at a 490 nucleotide length (Figure 2). Among them, lung and spleen showed the highest mRNA levels of 3.4 and 4.2 pg /µg of total cellular RNA, respectively, when calculated by authentic sense SLPI RNA (Figure 2). Lower amounts of the transcripts (below 1 pg /µg of total cellular RNA) were also detected in the RNA samples from liver and seminal vesicle (Figure 2). No transcripts were detected by RNase protection assay in brain, heart, kidney, and muscle (Figure 2).
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Changes in the Amount of the SLPI mRNA Transcripts in the Lung and Spleen during the Course of Bacterial Pneumonia
To investigate the physiologic roles of SLPI in inflammation,
the changes of the SLPI mRNA transcripts in lung and spleen were examined. Total cellular RNA in the lungs of mice up to
2 h after nasal inoculation of Streptococcus pneumoniae strain
FR1284 contained only a trace amount of SLPI mRNA when
examined by Northern blot analysis (Figure 3A). However,
10 h after inoculation, the SLPI mRNA transcripts in the lung
showed a marked increase, and the level of the mRNA continued to be elevated 48 h after inoculation. When the radioactivities of the 0.7 kb SLPI mRNA were corrected with those obtained after hybridization with the -actin cDNA probe, the
amounts of SLPI mRNA transcripts in the lung 10, 24, and
48 h after inoculation were about three times greater than those obtained at 0 h (Figure 3C). In spleen, the SLPI mRNA
transcripts were positive at 0 and 2 h, but also continued to increase at 10, 24, and 48 h (Figure 3B). Statistical analysis with
three animals at each time point after the inoculation of bacteria showed a significant difference in the amount of SLPI
mRNA transcripts in the lung between 0 and 10 h (Figure 3C)
(p < 0.01). In contrast, the SLPI mRNA in the spleen did not
show any significant differences during the course of infection
(Figure 3C).
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ABSTRACT
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Although there have been several reports on the changes of the SLPI concentration in serum, sputum, and bronchoalveolar lavage fluid in patients with airway inflammation (4, 18), an animal model is required to examine the time dependency of the SLPI gene expression at the sites of inflammation. For this purpose, an experimental streptococcal pneumonia in mice was used in the present study. As the preliminary Northern hybridization with porcine SLPI cDNA probe could not detect mouse SLPI mRNA in the lung, cloning of the mouse SLPI cDNA was necessary for quantitative analyses of the mouse SLPI mRNA transcripts in the mouse lung. A clone containing a 708 bp-long, full-length cDNA was obtained from a mouse lung cDNA library by screening with a probe generated by RT-PCR.
The amino acid sequence deduced from the base sequence of the cDNA showed homologies of 58 and 51% with those of human and porcine SLPI cDNA, respectively. A repeat of a similar amino acid sequence in the first and second halves (domains) of the molecule, which was one of the characteristic features of human and porcine SLPI (16, 17), was also found in mouse SLPI (Figure 1B). In terms of the characteristic eight cysteine residues forming four intramolecular disulfide bonds in each domain (21), the structure is completely conserved in mouse, human, and porcine (Figure 1B). The amino acid sequence around the active site, determined to be 72Leu for human SLPI by site-directed mutagenesis (22), was highly conserved among the three species, although 72Leu of human SLPI is substituted with Met both in porcine and mouse (Figure 1B). The signal sequence of mouse SLPI, also delineated by comparison of the N-terminal sequence reported for the scatter-factor-inducing factor (KNDAIKIGA) of mouse (23, 24), showed a high homology (76%) with that of human SLPI. Finally, the number of proline residues in both domains of mouse SLPI was 12, and nine of them are conserved in human and porcine SLPI (Figure 1B).
The tissue distribution of SLPI protein has already been reported in human by immunohistochemical analysis using antihuman SLPI antibody (25). According to the report, SLPI was detected in such organs or tissues as submucosal glands of the nose, bronchus and esophagus, terminal and respiratory bronchioles, alveolar ducts, middle ear, salivary glands, seminal vesicles, cervical crypts of the uterus, and lacrimal gland, but it was undetectable in intestine, liver, epididymis, and spleen. In our study, a comparable amount of SLPI mRNA transcripts was detected in lung, spleen, intestines, and epididymis, and lower amounts were detected in liver and seminal vesicles. No transcripts were detected in brain, heart, kidney, or muscle. This pattern of tissue distribution of SLPI mRNA indicates that the transcription of the SLPI gene is not necessarily confined to the organs or tissues that contain mucus (e.g., liver and spleen). Although performing an assay evaluating antiprotease activity is mandatory to analyze the tissue distribution of the functional SLPI protein, the distribution of the SLPI mRNA transcripts in mouse, especially in spleen and in liver, suggests possible unknown functions of SLPI other than as an inhibitor of serine proteases in mucus.
Induction of the SLPI gene expression in cultured airway
epithelial cells by neutrophil elastase (2) or by PMA (3) suggests that SLPI is one of the protease inhibitors acting against
proteolytic activities during airway inflammation. The elevated level of the serum SLPI protein in humans with airway
inflammation can be explained by the transfer of this protein
into the bloodstream after local synthesis by serous cells of
submucosal glands at the site of inflammation (18). Northern blot analysis of the total cellular RNA from the infected
lung tissue transcripts showed a remarkable augmentation of
the SLPI gene expression in vivo during airway inflammation
(Figure 3), suggesting increased SLPI protein synthesis by airway epithelial cells at the site of inflammation. This is the first
direct evidence showing the induction of the SLPI gene expression in vivo during airway inflammation. In this context, it
is of interest that the SLPI mRNA transcripts in spleen also showed augmented expression during bacterial infection, but
not significantly when normalized by -actin expression.
Whether the upregulation of the SLPI gene expression occurs
only in serous cells of submucosal glands or other types of
cells in the airway needs to be determined by in situ hybridization.
Recently, a protein factor that induces hepatocyte growth factor (HGF) in mouse fibroblasts was isolated and purified from the conditioned medium of ras-transformed NIH-3T3 cells (23), and the cDNA sequence of this factor was found to be identical to that which we cloned in the present study (24). This suggests an additional physiologic role of SLPI concerning the regulation of pleiotropic functions of HGF in vivo. Targeted disruption of the SLPI gene will answer such questions as whether SLPI functions as a protease inhibitor to protect the tissues from excessive destruction during inflammation in vivo, and whether the induction of HGF by SLPI is mediated by the protease inhibitor activities or by other mechanisms.
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Footnotes |
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Correspondence and requests for reprints should be addressed to Tatsuya Abe, M.D., Ph.D. Department of Respiratory Oncology and Molecular Medicine, Division of Cancer Control, Institute of Development, Aging and Cancer, Tohoku University, 4-1 Seiryomachi, Aoba-ku, Sendai 980, Japan.
(Received in original form January 23, 1997 and in revised form May 12, 1997).
1 The GenBank accession numbers for mouse SLPI are U73004, U88093, and U94341.Acknowledgments: The writers thank Dr. J. Miyazaki (Department of Nutrition and Physiological Chemistry, Osaka University Medical School, Osaka, Japan) for making the embryonal stem cell E.14-1 available.
Supported by Grant-in-Aid for Scientific Research No. 06670601 from the Ministry of Education, Science, Sports, and Culture of Japan.
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Addendum |
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After submission of our manuscript two reports describing the cloning of a murine SLPI cDNA have been published (Jin, F.-y., C. Nathan, D. Radzioch, and A. Ding. 1997. Secretory leukocyte protease inhibitor: a macrophage product induced by and antagonistic to bacterial lipopolysaccharide. Cell 88:417-426. Zitnik, R. J., J. Zhang, M. A. Kashem, T. Kohno, D. E. Lyons, C. D. Wright, E. Rosen, I. Goldberg, and A. C. Hayday. 1997. The cloning and characterization of a murine secretory leukocyte protease inhibitor cDNA. Biochem. Biophys. Res. Commun. 232:687-697). Although their approaches to clone the cDNA were different from each other and from ours reported in this article, the nucleotide sequences in these three reports are identical in the open reading frame and 3' untranslated region.
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References |
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REFERENCES
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T. Kikuchi, T. Abe, S. Hoshi, N. Matsubara, Y. Tominaga, K. Satoh, and T. Nukiwa Structure of the Murine Secretory Leukoprotease Inhibitor (Slpi) Gene and Chromosomal Localization of the Human and Murine SLPI Genes Am. J. Respir. Cell Mol. Biol., December 1, 1998; 19(6): 875 - 880. [Abstract] [Full Text]
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