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* Ludwig Institute for Cancer Research, São Paulo, Brazil; Departments of
Microbiology, and
Biochemistry and Immunology, UFMG, Minas Gerais, Brazil;
Department of Microbiology, New York University School of Medicine, New York, New York; and
|| Department of Physiology and Pharmacodynamics, Instituto Oswaldo Cruz, Rio de Janeiro, Brazil
Correspondence: Luiz F. L. Reis, Ludwig Institute for Cancer Research, Rua Prof. Antonio Prudente 109, 4th Floor, CEP 01509-010, São Paulo, Brazil. E-mail: lreis{at}ludwig.org.br
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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and IL-1ß-stimulated gene from normal, human
foreskin fibroblasts and vascular endothelial cells, respectively.
TSG-14 gene encodes a 42-kDa-secreted glycoprotein with a
carboxy-terminal half that shares homology with the entire sequence of
C-reactive protein (CRP) and serum amyloid P component (SAP),
acute-phase proteins of the pentraxin family. Some experimental
evidence suggests that TSG-14 plays a role in inflammation, yet its
function and mechanism of action remain unclear. We have generated
transgenic mice that overexpress the murine TSG-14 gene under the
control of its own promoter. From eight transgenic founders, two
lineages were derived and better characterized: Tg2 and Tg4, carrying
two and four copies of the transgene, respectively. TSG-14 transgenic
mice were found to be more resistant to the endotoxic shock induced by
LPS and to the polymicrobial sepsis caused by cecal ligation and
puncture (CLP). Moreover, macrophages derived from the transgenic mice
produced higher amounts of nitric oxide in response to IFN-
,
TNF-, and LPS as compared with macrophages from wild-type animals,
and the augmented response appears to be the consequence of a higher
responsiveness of transgenic macrophages to IFN-. The data shown
here are the first in vivo evidence of the involvement of
TSG-14 in the inflammatory process and suggest a role for TSG-14 in the
defense against bacterial infections.
Key Words: TNF • lipopolysaccharide • endotoxin • inflamma-tion • nitric oxide
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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-treated, human FS-4, diploid foreskin
fibroblasts [1
] and from human umbilical vein endothelia
cells exposed to interleukin (IL)ß-1 [2
]. A murine
homologue of TSG-14 gene was also identified, and the promoter
structure of the gene and its complete cDNA sequence were determined
[3
, 4
]. TSG-14 is a single-copy gene,
organized into three exons and two introns on murine chromosome 3 and
on human chromosome 3 band q25 [2
, 4
]. The
gene encodes a 42-kDa-secreted glycoprotein with its carboxy-terminus
displaying up to 27% amino acid sequence identity to human C-reactive
protein (CRP) and serum amyloid protein (SAP) [2
,
5
]. CRP and SAP are acute-phase proteins that are members
of the pentraxin family, characterized by a discoid arrangement of five
noncovalently bound subunits and presence of an eight amino acid domain
("the pentraxin signature") [6
]. TSG-14 protein
contains the pentraxin signature, but it is approximately twice as
large as a CRP or SAP subunit. The amino-terminal portion of TSG-14
protein does not show significant sequence homology with the pentraxins
or other known proteins [2
, 5
]. The recent discovery of several new proteins that, like TSG-14, contain carboxy-termini homologous to CRP and SAP but have divergent amino-terminal sequences suggests that a new group of proteins emerged from fusions of novel, amino-terminal domains to an ancestral, pentraxin domain [7 ]. The new family of pentraxins is known as the "long pentraxins" and comprises the Xenopus laevis pentraxin (XL-PXN1) [8 ], the guinea pig apexin [9 , 10 ], the rat neuronal pentraxin (NPI) [11 ] and its receptor (NPR) [12 ], the human neuronal pentraxin (NPTX2) [13 ], the human neuronal activity-related pentraxin (NARP) [14 ], and TSG-14. Unlike TSG-14, the other long pentraxins have relatively restricted patterns of expression and are not regulated by cytokines.
TSG-14 is produced by fibroblasts [1
], endothelial cells
[2
], chondrocytes and synoviocytes [15
],
and cells of the monocyte/macrophage lineage [16
]
stimulated with TNF- [1
] or IL-1ß
[2
] and also with lipopolysaccharides (LPS)
[17
] or components of the mycobacterial cell wall
[18
]. TSG-14 expression in monocytes and macrophages is
regulated negatively by interferon- (IFN-) [19
,
20
]. It was shown that, like CRP, TSG-14 protein forms
multimers [7
, 21
]. The capacity of TSG-14
to bind to the C1q complement component is suggestive of a role for
TSG-14 as a local regulator of innate immunity [21
].
Upon LPS injection, TSG-14 protein level in the serum rises with
kinetics similar to other acute-phase proteins [4
,
17
]. However, in contrast to classic acute-phase
proteins, TSG-14 is not expressed in the liver, and its expression is
not stimulated by IL-6 [4
, 17
]. The major
sites of TSG-14 expression in vivo are skeletal muscle and
heart [4
].
To investigate the physiological function of TSG-14 and its role in the
inflammatory response, we generated transgenic (Tg) mice overexpressing
the murine gene under the control of its own promoter. Two lineages of
Tg mice containing two and four extra copies of the gene were
characterized. We show that TSG-14 Tg mice are more resistant to the
systemic administration of LPS, compared with macrophages from
wild-type (Wt) animals and to sepsis caused by cecal ligation
and puncture (CLP). We also show that, compared with macrophages from
Wt animals, peritoneal macrophages from TSG-14 Tg animals produce
larger amounts of nitric oxide (NO) in response to IFN- or IFN-
in combination with LPS or TNF-.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Southern blot analysis of genomic DNA
Genomic DNA was obtained from a 1-cm-long fragment of the tail
tip as previously described [22
]. Purified, genomic DNA
was digested with the restriction enyme NcoI, electrophoresed through a
0.9% agarose gel, transferred to Hybond nylon membrane (Amersham,
Arlington Heights, IL), and hybridized [23
] with a
[32P]dCTP-labeled BamHI/NsiI fragment (374 bp) derived
from the pGEM(2.7)TSG-14 genomic sequence (Fig. 1B
, hatched bars). To estimate the number of integrated transgenes,
densitometric analyses of the radioactive signals in the filters were
performed by using the Gel-Pro AnalyzerTM software (Media Cybernetics,
L.P., Baltimore, MD).
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Induction of endotoxic shock
To determine the best dose of LPS for the induction of
endotoxemia, 6- to 8-week-old, CD1 Wt mice were injected i.p. with five
different doses of LPS (E. coli endotoxin serotype 0111:B4;
Sigma): 1.5 mg/kg, 2.7 mg/kg, 5.5 mg/kg, 13.5 mg/kg, 27.0 mg/kg.
Because 100% of animals died upon injection with 13.5 mg/kg LPS, and
90% of the mice injected with 5.5 mg/kg survived, we decided to use 11
mg/kg to compare the survival of Wt and Tg lineages. For the
experiments, the LPS was dissolved in 0.2 ml phosphate-buffered saline
(PBS) and injected i.p., and lethality was monitored every 12 h
for 7 days after injection. The survival curve was calculated with the
aid of the Kaplan-Meier life-table method [25
]. All
statistic tests were performed with 95% confidence interval (CI;
=0.05) using the Stata program (Stata Corp., College Station, TX).
CLP
Sepsis was induced through CLP as previously described
[26
]. Briefly, 6- to 8-week-old, CD1 Wt and TSG-14 Tg
mice were anesthetized with an i.p. injection of 0.2 ml of a mixture of
100 mg/ml tyazine (Vetanarcol-König, Avellaneda,
Argentina) and 2% ketamin (Rompun-Bayer, Merriam, KS)
in saline (0.9% NaCl). A laparotomy was performed, and the cecum was
exposed and ligated below the ileocecal junction, without causing bowel
obstruction. The cecum was punctured once with an 18-gauge needle and
then gently squeezed to ensure the leakage of the cecum contents
through the puncture. The cecum was returned to the peritoneal cavity,
and the body wall and skin incision were closed with a 6-0 silk suture.
The animals were analyzed for the survival rate, assessed every 12 h for 6 days.
Isolation of peritoneal macrophages and nitrite determination
Peritoneal macrophages were isolated from mice 4 days after an
i.p. injection of thioglycollate broth (2 ml/mice). The cells were then
recovered by lavage of the peritoneal cavity with ice-cold PBS. The
resulting cell suspension was washed twice with PBS containing 50 mg/ml
gentamicin sulfate by centrifugation for 10 min at 200 g.
Cells (50,000) were plated in each well of a 96-well plate in 200 µl
RPMI 1640 (Sigma) supplemented with 10% of heat-inactivated fetal
bovine serum and 50 mg/ml gentamycin sulfate and incubated for 18 h. The adherent macrophages were then treated with the indicated doses
of IFN- (R&D Systems, Minneapolis, MN), TNF- (R&D Systems), or
LPS (E. coli serotype 0127; Sigma) or with a combination of
stimuli. Nitrite (NO2-) concentration in the
culture supernatants was determined as a measure that reflects NO
production, because the released NO reacts rapidly with water and
oxygen to produce NO2-, which can be measured
as described by Hibbs and co-workers [27
]. Supernatants
(100 µl) were collected 24, 48, 72, and 96 h after each
treatment, mixed with an equal volume of Griess reagent [1%
sulfanilamide (Sigma), 0.1% naphthylethylenediamine hydrochloride
(Sigma), 2.5% orthophosphoric acid (Riedel-de Haën, Hannover,
Germany)], and left for 10 min at room temperature. Standards
were prepared by using serial dilutions of sodium nitrite (2–200
µM). Absorbance was measured at 540 nm in a SpectramaxTM 340 UV-Vis
spectrophotometer. Macrophage viability was evaluated using the MTT
assay [28
]. Briefly, after the removal of the culture
supernatant for the NO2- assay, fresh culture
medium containing MTT (final concentration, 500 µg/ml) was added, and
the cells were incubated for 4 h. The medium was then removed, and
MTT-formazan was solubilized by adding 10% sodium dodecyl sulfate
(SDS), prepared in dymethylformamide/H20 (1:1 v/v), and
measured spectrophotometrically at 550 nm.
Cytokine levels in LPS-injected mice
Wt and Tg2 mice were injected i.p. with LPS (11 mg/kg), and
plasma was collected 1.5 or 6 h after injection (n=5
for each time-point). TNF, IL-6, and IL-10 were measured by
enzyme-linked immunosorbent assay (ELISA) using a kit from R&D Systems
(for TNF) or reagents from PharMingen (San Diego, CA; for IL-6 and
IL-10), following instructions of the manufacturers.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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and IL-1
[3
]. Eight TSG-14 Tg founders were obtained. The number
of the transgenes incorporated into these founders and transmission to
progeny were determined by Southern blot hybridization and found to
vary between one and four copies. All of the founders containing extra
copies of the TSG-14 gene appeared normal phenotypically and
transmitted all copies of the transgenes to their progeny with the
expected frequency. From these eight founders, two Tg lines were
derived. We refer to these lines as Tg2 and Tg4 because the number of
extra copies of the TSG-14 genomic locus integrated in each Tg line is
2 and 4, respectively. For the analysis of the genotypes, the genomic
DNA was digested with the restriction enzyme NcoI and hybridized with a
probe corresponding to the 5' end of the promoter region of TSG-14
(Fig. 1B
, hatched portion). As indicated in Figure 1B
, one NcoI
restriction site is located at position 2045 of the TSG-14 gene, and
the other NcoI site is approximately 8000 bp up-stream of position 1 of
the 8.3-kb fragment. Digestion of genomic DNA from Wt and TSG-14 Tg
mice with the restriction enzyme NcoI generates fragments of
approximately 10 kb (Fig. 1A)
, corresponding to the endogenous alleles
that hybridize with the probe. In the lines Tg2 and Tg4, digestion with
NcoI revealed additional copies, and the number of integrated
transgenes and their orientation is depicted in Figure 1B
. The number
of the additional copies was estimated from the intensity of
hybridization signals as measured by scanning densitometry.
LPS-induced, TSG-14 gene expression in TSG-14 Tg mice
To evaluate the level of TSG-14 expression, mice were
injected i.p. with 30 µg LPS. Northern blot analysis of total RNA
isolated from the heart (Fig. 2A
), skeletal muscle (Fig. 2B)
, and liver (Fig. 2C)
of these animals
and of control, noninjected mice was performed. No constitutive TSG-14
expression was observed in the tested organs of Wt- or Tg-control mice.
LPS-induced expression of TSG-14 was readily detectable in the heart
and skeletal muscle of LPS-treated mice with higher mRNA levels present
in the organs of Tg animals (Fig. 2
and unpublished results). Different
from other acute-phase response proteins, TSG-14 is not expressed in
the liver [4
]. In agreement with this observation, no
TSG-14 mRNA was detected in the liver of Wt or Tg mice (Fig. 2C)
. The
same blot was rehybridized with a murine probe specific for the
chemokine N51/KC mRNA (Fig. 2C) to demonstrate that LPS administration
was inducing gene expression in the liver, indicative of an acute-phase
response. Furthermore, there was no significant difference in the
levels of IL-6 mRNA in liver, heart, and muscle of LPS-injected Wt or
Tg mice (unpublished results).
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, TNF-, and LPS.
NO2- concentration was measured in the culture
supernatants collected at 24, 48, 72, and 96 h after stimulation.
Four independent experiments were performed in which we examined
macrophages from Tg2, Tg4, and Wt mice stimulated with IFN- (40
U/ml), LPS (10 ng/ml), and TNF- (500 U/ml), individually or with the
combinations of IFN- + LPS and IFN- + TNF-. In all
four independent experiments, macrophages from Tg mice released more NO
than macrophages from Wt mice at all time-points analyzed, i.e., 24,
48, 72, and 96 h (unpublished results).
To further dissect the increased NO production by Tg macrophages, we
performed a dose-response analysis using macrophages from Wt or Tg4
mice treated with different doses of each agent separately or with a
combination of IFN- + LPS or IFN- + TNF-, as
illustrated in Figure 5
. The different doses of LPS and TNF- tested alone were not
sufficient to induce the production of NO by the peritoneal macrophages
from the Tg or Wt mice at any of the time-points examined (Fig. 5A
and
unpublished results). It is interesting that at 24-h post-induction,
IFN- alone stimulated NO production in Tg4 macrophages but not in Wt
macrophages (Fig. 5A)
. At later time-points, it was possible to detect
IFN--stimulated NO production by Wt macrophages, but the levels were
much less than in Tg-derived macrophages. TNF and LPS dose-dependently
synergized with IFN- in NO induction in Wt and Tg4 macrophages (Fig. 5B
and 5C) . However, under all conditions tested, NO yields were about
threefold greater in Tg4 macrophages than in Wt macrophages. Although
Figure 5B and 5C
, represents the levels of NO production at 48 h
after stimulation, similar differences between NO production in Wt and
Tg4 macrophages were observed at 24, 72, and 96 h (unpublished
results). To confirm that equal amounts of macrophages were seen in
every well (5x104 cells/well), we performed the MTT assay,
which confirmed a comparable density of viable cells in all groups
(unpublished results).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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and
IL-1ß [1
, 4
, 17
]. However,
the actual function of TSG-14 and its mode of action are still unknown. We have generated TSG-14 Tg mice as a model for the functional characterization of TSG-14 in vivo and for the investigation of its role in inflammation. From eight Tg founders obtained, two lineages were derived and characterized. No constitutive expression of the transgene was detected in the liver, heart, and skeletal muscle. TSG-14 induction by LPS was observed at the sites where the resident gene was also induced, i.e., heart and skeletal muscle, but not in the liver (Fig. 2) . This observation suggests that the Tg TSG-14 promoter activity was not affected by the neighboring sequences at the sites of integration. The two Tg lineages, containing either two or four extra copies of the gene, showed an average increase of four- to sixfold as compared with Wt in the levels of induced, TSG-14 mRNA expression (Fig. 2 and unpublished results). It is also noteworthy that no single base pair was changed within the entire 8.3 kb of the TSG-14 transgene, making the mRNA derived from the transgene identical to that derived from the resident gene. It appears that in the Tg mice, TSG-14 is expressed at higher levels but in a physiologically coordinated manner. Therefore, the phenotypic changes observed in the Tg mice can be attributed to the higher abundance of TSG-14 mRNA and, consequently, to TSG-14 protein.
We demonstrate that overexpression of TSG-14 confers resistance to the
lethal effects of LPS. LPS is used commonly for inducing a sepsis-like
state in experimental animals. LPS injection elicits the secretion of
several cytokines, including TNF- and IL-1ß, and these cytokines
orchestrate the responses observed in endotoxemia by affecting changes
in thermoregulation, vascular permeability and resistance, cardiac
function, bone marrow function, and activity of key enzymes
[31
, 32
]. TNF- and IL-1ß also
stimulate the production of additional cytokines along with other
inflammatory mediators, playing a role in the activation of the
complement as well as the coagulation and kinin cascades
[33
]. TSG-14 Tg mice injected i.p. with endotoxin had a
significantly higher survival rate (Fig. 3)
. It has been shown
previously that mice overexpressing the acute-phase, response-protein
CRP have a higher survival rate than control mice when injected with
gram-positive bacteria or with LPS [34
,
35
]. In the latter model, the protective mechanism was
attributed, at least in part, to the augmentation of
complement-mediated phagocytosis or to a reduced, LPS-induced,
cytokine-gene expression by macrophages [34
]. Our
observation that TSG-14 Tg mice have a higher survival rate than Wt
mice when challenged with LPS is in agreement with a role for TSG-14 as
an acute-phase protein that, like CRP, has a potential, protective role
in LPS-induced shock.TSG-14 Tg mice also showed an improved survival
after CLP-induced, polymicrobial infection (Fig. 4)
.
It remains to be shown how TSG-14 affects the mechanisms of the inflammatory response and exerts its protective effect in LPS and CLP models. The higher levels of IL-10 observed in untreated or in the very early stage of the LPS-induced response (Fig. 6) could be part of this mechanism. The beneficial role of IL-10 during sepsis has been documented widely. For example, it has been shown that injection of IL-10 can decrease lethality in endotoxemia [36 ] or in sepsis [37 ]. The protective mechanism of IL-10 could be related to its ability to inhibit activation of coagulatin and fibrinolysis during endotoxemia [38 ] and reduced production of pro-inflammatory cytokines (reviewed in [39 ]). Thus, the fact that TSG-14 Tg mice have augmented levels of IL-10 even prior to LPS injection might be related to its higher resistance to LPS and CLP.
Also, TSG-14 Tg mice have augmented levels of TNF, at least during the early phase of the LPS-induced response. It is thus possible that, during this early phase, higher production of TNF confers a beneficial advantage for survival by activating pro-inflammatory activities. It has been shown that injection of TNF can reduce lethality in the CLP model [40 ], and it was suggested by Echtenacher and co-workers [41 ] that during the early phase of peritonitis, endogenous TNF may stimulate nonlymphoid cells such as granulocytes, macrophages, platelets, and fibroblasts to ingest bacteria and localize inflammation.
Available data suggest several other possibilities including the demonstrated capacity of TSG-14 protein to bind the C1q complement component [21 ] and as we show here, augmented production of NO by macrophages derived from TSG-14 Tg mice (Fig. 5) . Activation of complement is essential for the initial containment of systemic, bacterial infection, as demonstrated by the susceptibility of complement-deficient mice to bacterial infection [42 , 43 ]. Macrophages play a central role in the inflammatory response and are targets for several pro-inflammatory cytokines and acute-phase proteins. The pentraxin CRP, for example, can modulate gene expression in macrophages, leading to an increased production of pro-inflammatory cytokines [44 , 45 ] or their antagonists [46 ]. Production of NO by activated macrophages affects a multitude of biological functions [47 , 48 ].
Macrophages from Tg2 and Tg4 mice produced higher amounts of NO than
control, Wt mice, when stimulated with IFN- alone or with IFN- in
combination with LPS or TNF- (Fig. 5)
. It appears that the major
difference between Wt and Tg macrophages is a significantly greater
responsiveness of the latter cells to IFN-. It was demonstrated
recently that IFN- can inhibit the expression of TSG-14 in monocytes
and macrophages [19
, 20
]. Thus, it is
possible that TSG-14 leads to a higher responsiveness of cells to
IFN-, which, in turn, could inhibit TSG-14 expression, leading to a
suppression of the inflammatory response.
In infection as well as inflammation, NO generated by macrophages appears to act as a direct effector and also as a regulator of other effector molecules [49 ]. Experiments using NO inhibitors implicated NO in anti-microbial, inflammatory responses. However, whether NO is beneficial or detrimental in endotoxin-induced shock is still controversial. Mice lacking inducible NO synthase (iNOS) are more susceptible to infection by Listeria [50 ] and Leishmania [51 ] as well as to sepsis induced by the CLP procedure [52 ]. However, it has been shown that, in spite of being a mediator of LPS-induced, endotoxic shock, NO can also protect mice against LPS because mice deficient in iNOS were shown to be more resistant to endotoxin-induced shock [50 , 51 , 53 ]. In addition, mice overexpressing the endothelial NO synthase (eNOS) as a transgene show a higher resistance to the lethal effects of LPS than control mice [54 ]; the protective effect of NO was ascribed to a reduced, vascular reactivity to NO. It was also shown that the deletion of eNOS results in increased myocardial dysfunction following ischemia-reperfusion [55 ] and that NO synthesis during endotoxemia is associated with prevention of hepatic damage and intravascular thrombosis [56 ]. Other evidence of an anti-inflammatory effect of NO rests on the ability of NO to limit endothelial activation and inhibit leukocyte adhesion [57 ]. In addition, it was demonstrated recently that NO can increase the shedding of a soluble form of TNF receptor 1 [58 ] as well as other cytokines, cytokine receptors, and adhesion molecules by the activation of TNF-converting enzyme mediated ectodomain shedding [59 ]; that the iNOS-derived NO mediates protective activities indispensable to survive a TNF challenge [60 ]; and that iNOS gene function provides a survival benefit in septic mice [52 ].
Thus, although it may be premature to conclude that the greater resistance to endotoxin and to sepsis of the TSG-14 Tg mice is caused by an increased production of NO by peritoneal macrophages, these two features are not paradoxical necessarily. It has been pointed out that NO can deliver death- and life-promoting messages [49 , 60 ]. It is well possible that in the TSG-14 Tg mice, the protective role prevails.
Although the precise, molecular aspects of TSG-14 function remain to be elucidated, our data represent the first in vivo evidence for a role of TSG-14 as an important component of the innate, immune response and as part of the host mechanisms that control endotoxemia and bacterial infection.
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ACKNOWLEDGEMENTS |
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FOOTNOTES |
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Current address of Anne Altmeyer: Merck & Co., 126 E. Lincoln Avenue, Rahway, NJ 07065.
Received December 4, 2000; revised February 2, 2001; accepted February 7, 2001.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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