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Previous Article | Next Article 
Infection and Immunity, May 2001, p. 3175-3180, Vol. 69, No. 5
0019-9567/01/$04.00+0 DOI: 10.1128/IAI.69.5.3175-3180.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
Extensive Mycobacterium bovis BCG
Infection of Liver Parenchymal Cells in Immunocompromised
Mice
John W.
Mills,
Lynn
Ryan,
Ronald
LaCourse, and
Robert J.
North*
The Trudeau Institute, Saranac Lake, New York
12983
Received 8 December 2000/Returned for modification 3 January
2001/Accepted 29 January 2001
 |
ABSTRACT |
A histologic study was performed on the livers of wild-type (WT),
severe combined immunodeficient (SCID), hydrocortisone acetate (HC)-treated WT, and HC-treated SCID mice infected intravenously with
105 CFU of Mycobacterium bovis BCG. It was
found that infection progressed faster in SCID mice than in WT mice and
that HC treatment caused exacerbation of infection in both types of
mice. In all cases infection in the liver was confined to granulomas
that were populated predominantly by macrophages. Higher levels of
infection in HC-treated SCID mice, but not HC-treated WT mice, were
associated with extensive infection and destruction of parenchymal
cells at the margins of granulomas. The results indicate that in the
absence of T-cell-mediated immunity and of HC-sensitive
T-cell-independent defense mechanisms, macrophages are incapable of
restricting BCG growth and of confining infection to their cytoplasm.
Consequently, BCG bacilli are released into the extracellular
environment, where they are ingested by neighboring parenchymal cells.
| |
INTRODUCTION |
It is generally believed that
Mycobacterium tuberculosis, Mycobacterium bovis, and other
members of the Mycobacterium tuberculosis complex are
intracellular pathogens that reside in their hosts almost exclusively
in macrophages. Therefore, these pathogens remain confined to the
cytoplasm of the very host cells that are equipped to express innate
and acquired antimicrobial defense mechanisms against them. The
apparent absence of evidence showing that M. tuberculosis
and M. bovis can also infect parenchymal cells means either
that parenchymal cells are not capable of phagocytosing these pathogens
or that parenchymal cells are not provided the opportunity to ingest
M. tuberculosis or M. bovis bacilli during the
normal course of infection. The second possibility seems more likely
given the evidence (9-12, 18) that a variety of
nonphagocytic cells are capable of ingesting and supporting the growth
of M. tuberculosis in vitro. There is no reason to
postulate, moreover, that parenchymal cells would not be capable of
ingesting M. tuberculosis and M. bovis in the in
vivo setting if given the opportunity to do so. Presumably, parenchymal
cells do not become infected because of the ability of the host to
rapidly mobilize enough macrophages to sites of M. tuberculosis or M. bovis multiplication to ensure that
the pathogens are always confined to the cytoplasm of these phagocytic
cells. The relatively slow doubling times of M. tuberculosis or M. bovis would help to prevent M. tuberculosis
or M. bovis from reaching overwhelming numbers before
specific, T-cell-mediated immunity is acquired. The upregulation of
macrophage antimycobacterial defenses subsequent to the acquisition of
specific immunity would further ensure that infection is confined to
macrophage cytoplasm. If this line of reasoning is correct, one would
expect to see infection of parenchymal cells in a host in which
macrophages are prevented from expressing innate and acquired
antibacterial defenses. It was shown by a previous study
(13), in this connection, that whereas immunocompetent
mice are capable of slowly resolving BCG infection in major organs, BCG
infection is progressive in severe combined immunodeficient (SCID) mice
and is even more progressive in SCID mice that are treated with
hydrocortisone (HC). Because it was also shown that BCG infection in
SCID mice is confined to macrophages in granulomas, it was suggested
(13) that HC treatment causes exacerbation of infection in
SCID mice by virtue of its ability to suppress the expression of
macrophage-based, innate defense mechanisms capable of slowing the
intracellular growth of mycobacteria. It is known (3, 20),
in support of this interpretation, that glucocorticoids, by way of
inhibiting activation of NF-
B, can prevent macrophages from
synthesizing and secreting tumor necrosis factor alpha and other
proinflammatory cytokines considered essential for the expression of
innate and acquired defenses at sites of infection. It seemed
reasonable to suspect that if BCG possessed the potential to infect
parenchymal cells, this potential would be realized in SCID mice
treated with HC. The purpose of this study is to show that this is the
case in the liver.
| |
MATERIALS AND METHODS |
Mice and BCG infection.
Wild-type (WT) CB17 and CB17 SCID
mice 8 to 10 weeks of age were obtained from the Trudeau Institute
Animal Breeding Facility (Saranac Lake, N.Y.). BCG Pasteur (TMC 1101)
was grown as a dispersed culture in Proskauer and Beck medium
containing 0.01% Tween 80, harvested in log phase, dispensed in 1-ml
vials, and stored at 
70°C. To infect mice a vial was thawed, and
the culture was subjected to 5 s of ultrasound to break up clumps
and diluted appropriately in saline containing 0.01% Tween. The mice
were inoculated intravenously with 105 BCG CFU in a volume
of 0.2 ml. BCG CFU were enumerated in the lungs, liver, and spleen on
day 30 of infection by plating 10-fold serial dilutions of whole-organ
homogenates on enriched Middlebrook 7H11 agar and counting colonies
after 3 weeks of incubation at 37°C. Differences between means of CFU
per organ were determined by Student's t test.
Histology.
A small piece of the left dorsal lobe of each of
the livers used for enumerating bacteria was removed and fixed in 10%
neutral buffered fomaldehyde for 24 h and then washed in running
tap water. The pieces were dehydrated in graded ethanol solutions and
embedded in paraffin by standard methods or in glycol methacrylate
(JB-4 embedding kit; Polysciences, Inc., Warrington, Pa.) according to
the manufacturer's instructions. Paraffin sections were cut on a
rotary microtome and after dewaxing were stained for acid-fast bacteria
with a modified acid-fast stain (4) and counterstained with methylene blue. Sections of glycol methacrylate-embedded liver
were cut with glass knives and stained with 2% crystal violet. Photomicrography was performed with a Nikon Microphot-Fx microscope.
For electron microscopy two infected mice were killed by
CO2 asphyxiation and quickly perfused via the left
ventricle with 5 ml of heparinized phosphate-buffered saline (PBS) and
then with PBS containing 2% glutaraldehyde. Pieces of perfused liver
were removed, diced into 1-mm2 pieces, and fixed for 2 h in
the glutaraldehyde solution. The pieces were then washed in PBS and
postfixed for 1 h in 1% osmium tetroxide and then for 1 h in
1% uranyl acetate. Dehydration was in 70 and 100% ethanol, and
embedding was in Epon. Thin sections were stained with lead acetate and
viewed and photographed with a JEOL 1200EX electron microscope.
HC.
HC was obtained in emulsion form from United Research
Laboratories (Philadelphia, P.). It was given subcutaneously in a dose of 1.25 mg on days 15, 17, 20, and 23 of infection.
| |
RESULTS |
Growth of BCG in WT and SCID mice.
Table
1 shows that by day 30 of infection BCG
had grown to much higher numbers in the organs of SCID mice than in the
organs of WT mice and that infection in both types of mice was
exacerbated by treatment with HC given between days 15 and 23. Differences in the mean CFU per organ between any two groups of mice
shown in Table 1 were highly significant (P < 0.001)
according to Student's t test. The results are in agreement
with those of more detailed previously published studies (13,
14), which showed that while BCG infection is slowly resolved in
WT mice, it is progressive in SCID mice and is much more progressive in
HC-treated SCID mice. The results indicate that mice posses a
glucocorticoid-sensitive defense mechanism capable of retarding the
growth of BCG in the lungs, liver, and spleen in the absence of
T-cell-mediated immunity. They also indicate that this mechanism
probably operates in WT mice in the presence of specific immunity.
Histologic consequences of higher levels of BCG infection.
The
liver was chosen as the organ in which to look for infection of
parenchymal cells because of the ease of distinguishing parenchymal
cells (hepatocytes) from other cells on the basis of size, morphology,
and staining characteristics. The intravenous route of inoculation was
chosen because it ensured that the liver would contain an adequate
number of sites of infection to examine histologically. Day 30 was
chosen as the time to study the liver because at this stage of
infection bacterial numbers were considered high enough in HC-treated
SCID mice to result in infection of parenchymal cells, if, in fact,
parenchymal cells were capable of becoming infected.
A microscopic examination of sections of wax-embedded livers (not
shown) from the same mice used to obtain the results in Table 1
revealed that acid-fast bacilli were confined to granulomas scattered
throughout the liver. Granulomas in the livers of HC-treated SCID mice
were much larger, more numerous, and more heavily infected than those
in the livers of untreated SCID mice. Again, liver granulomas in
untreated SCID mice were larger and more numerous and contained more
acid-fast bacilli than those in HC-treated WT and untreated WT mice.
Sections of plastic-embedded livers revealed much more detail about the
types of cells infected with BCG. In agreement with the results of
previous histology studies (13, 14) it was found (Fig.
1) that BCG bacilli in liver granulomas of WT and SCID mice were confined to the cytoplasm of macrophages. However, the macrophages in granulomas of SCID mice were more numerous and contained more acid-fast bacilli than those in WT mice.
Closer examination showed, moreover, that in livers of SCID mice
occasional hepatocytes were infected with BCG at the margins of
granulomas (Fig. 1). Infected cells at the margins of granulomas were easily identified as hepatocytes on the basis of being the same
large size and morphology as the cells that made up the bulk of liver
parenchyma.
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FIG. 1.
Crystal violet-stained, 2-µm-thick plastic section of
a liver granuloma. The granuloma in the WT mouse (a) is compact and
comprised predominantly of concentrically arranged macrophages, whereas
the granuloma in the HC-treated WT mouse (b) is comprised of a loose
collection of macrophages containing large numbers of BCG bacilli. The
granuloma in the SCID mouse (c) is also comprised predominantly of
macrophages that are heavily infected with BCG. The higher power
micrograph of the edge of a granuloma in a SCID mouse (d) shows a
hepatocyte at the margin of the granuloma (arrow) heavily
infected with BCG. Bars represent 20 µm. Magnifications: ×1,060 (a),
×1,280 (b), ×1020 (c), and ×1,280 (d).
|
|
Infection of hepatocytes was much more extensive at the margins of
liver granulomas in HC-treated SCID mice. This is illustrated in Fig.
2, where it can be seen that liver
granulomas in these mice were larger and the number of bacilli per
granuloma was much higher than in untreated SCID mice. Indeed, in
granulomas in HC-treated SCID mice BCG bacilli formed large compact
aggregates in the cytoplasm of macrophages. The cytoplasm of
hepatocytes at the margins of these granulomas was also replete with
BCG bacilli, and in some cases hepatocytes beyond the margins of
granulomas were heavily infected with BCG. The overall histological
interpretations given are based on an examination of six or more
sections cut at intervals along a block of embedded liver from each of
the five mice in the groups shown in Table 1. All sections of
granulomas from HC-treated SCID mice displayed at least two heavily
infected hepatocytes at their margins. In contrast, infected
hepatocytes were only occasionally seen at the edge of granulomas in
liver sections of untreated SCID mice.
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FIG. 2.
Crystal violet-stained, 2-µm-thick plastic sections of
liver granulomas in SCID mice treated with HC. The micrograph of a
whole granuloma (a) shows very heavily infected macrophages containing
dense rafts of BCG and a heavily infected hepatocyte (arrow) at the
margin of the granuloma. Note that the infected hepatocyte is the same
large size as the uninfected hepatocyte below it and is much lager than
macrophages in the granuloma. Each of the other two micrographs (b and
c) was selected to show heavily infected hepatocytes (arrows) at the
margins of granulomas. Bars represent 20 µm. Magnifications: ×1,360
(a) and ×1,190 (b and c).
|
|
Electron microscopy of HC-treated SCID livers provided additional
evidence that BCG caused extensive infection of hepatocytes. This is
illustrated in Fig. 3, which shows part
of a heavily infected hepatocyte that was situated at the edge of a
granuloma on one side, and can be seen to be adjacent to a liver
sinusoid on the other. BCG bacilli can be seen to be numerous in its
cytoplasm and to be confined to phagocytic vesicles. There was no
evidence that BCG bacilli were present free in the cytosol. Given that the cell shown in Fig. 3 is large, is situated external to a sinusoid on the parenchymal side of sinusoid endothelium, and has the same ultrastructure as parenchymal cells that were seen elsewhere in the
section, there can be no doubt that it is a hepatocyte. Also, the fact
that it contains glycogen deposits as well as mitochondria rich in
cristae and with an electron-dense matrix typical of those described
for hepatocytes (2) makes it difficult to identify it as
any cell other than a hepatocyte. Macrophages in granulomas viewed by electron microscopy (not shown) contained smaller
mitochondria with fewer cristae and were devoid of glycogen
granules.
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FIG. 3.
Electron micrograph of an infected hepatocyte in an
HC-treated SCID mouse. The hepatocyte was situated at the edge of a
granuloma (out of view at the top) and next to a sinusoid (S)
marginated by typical endothelium (E). The hepatocyte is heavily
infected with BCG bacilli (arrows) that are enclosed in phagosomes.
Mitochondria and glycogen deposits (G) typical of hepatocytes are
clearly visible. Bars, 2 µm.
|
|
In contrast to its effect on SCID mice, HC treatment did not result in
infection of hepatocytes in WT mice but resulted, instead, in atypical
granuloma development (Fig. 1). Thus, whereas liver infection in WT
mice was confined to compact granulomas consisting of
concentrically arranged macrophages, liver infection in HC-treated WT
mice was confined to loose collections of heavily infected macrophages.
| |
DISCUSSION |
It was shown in previous publications (13,
14) that whereas WT mice acquire the capacity to slowly resolve
BCG infection, SCID mice allow progressive BCG growth. It was also
shown (13) that treatment with HC causes exacerbation of
infection in both types of mice but that infection in SCID mice reaches
much higher levels. The results of the day 30 CFU counts presented here
confirm these previously published findings. They serve to show that
SCID mice posses an HC-sensitive, T-cell-independent mechanism(s) that functions to retard the growth of BCG at sites of infection. Since the
control of BCG growth occurs in the cytoplasm of macrophages, it seems
likely that the HC-sensitive defense mechanism that is ultimately
responsible for retarding BCG growth is located in the cytoplasm of
these cells. In this connection, it has been shown in the in vitro
setting (16) that human and mouse macrophages posses
innate, HC-sensitive antimicrobial mechanisms that are independent of
those activated by gamma interferon and therefore by T-cell-mediated
immunity. It has also been shown (17) that glucocorticoids
can suppress the baseline antimicrobial action of macrophages against
microbial pathogens. Presumably, HC is able to inhibit the expression
of innate antimycobacterial mechanisms of macrophages in vitro partly
by virtue of its ability to inhibit NF-B-dependent transcriptional
activation of macrophage genes involved in upregulation of
antimycobacterial defense (1, 3, 20).
Because HC treatment also caused exacerbation of infection in WT mice,
albeit to a lesser extent, it is apparent that the same innate defense
mechanism might contribute to the control of BCG growth in mice with
acquired specific immunity. However, interpreting the suppressive
effect of HC on BCG infection in immunocompetent mice is much more
difficult because of the contribution that T cells make to immunity in
these mice by secreting gamma interferon and other cytokines capable of
activating the antimycobacterial functions of macrophages. It is known
(13) that glucocorticoids have a suppressive effect on
numerous components of host immunity, including T cells and
macrophages, as well as on the inflammatory response that results in
the extravasation of these cells from blood into sites of infection. It
is also known (13) that glucocorticoids can suppress the
in vivo function of lymphocytes and phagocytic cells by inhibiting
their ability to synthesize the numerous cytokines and chemokines
necessary for the mediation and expression of acquired T-cell-mediated
immunity. Moreover, there is evidence (6, 15) that these
compounds are more suppressive of Th1 than Th2 responses. Even so, the
way that they suppress resistance to infection in vivo is not well
understood. The possibility that HC caused exacerbation of BCG
infection in the present study because of a growth-enhancing effect on
BCG is unlikely, given published evidence (7) that, if
anything, glucocorticoids over a range of concentrations have a modest
inhibitory effect on mycobacterial growth in culture.
Regardless of how HC exacerbates infection, the fact that it reduces
the ability of macrophages at sites of infection to restrict the
intracellular growth of BCG allowed it to be used as a tool to
determine whether liver parenchymal cells can become infected with BCG
if the ability of macrophages to contain infection is sufficiently
compromised. In HC-treated SCID mice unrestricted BCG growth apparently
resulted in the death of infected macrophages and the liberation of BCG
bacilli into the extracellular space, where they were available for
ingestion by neighboring parenchymal cells. Given that infection of
cells by BCG can only occur as a result of active engulfment of BCG
bacilli via plasma membrane invagination, it was not surprising to find
that BCG bacilli were enclosed in phagocytic vacuoles of liver
parenchymal cells. There is no reason to believe at this time that BCG
and other mycobacteria are equipped with mechanisms that enable them to
escape the phagocytic vacuole and enter the cytosol.
It is not suggested here, however, that BCG infection of hepatocytes
can only occur in HC-treated SCID mice. On the contrary, it was evident
that infection of parenchymal cells was occurring in SCID mice without
the influence of HC, albeit at a much lower level. Whether more
extensive hepatocyte infection would have occurred if infection had
been allowed to proceed in SCID mice beyond 30 days is not known. This
presumably would depend on the bacterial load in macrophages of SCID
mice becoming large enough to cause these cells to die and liberate BCG
bacilli into the extracellular environment. Even if liberation of BCG
bacilli from individual macrophages were to occur, significant
infection of hepatocytes would not be expected to take place, unless
SCID mice were unable to generate enough monocytes to replace
macrophages lost to infection at infectious foci. This may well have
been the case in SCID mice, but not in HC-treated SCID mice, given that
glucocorticoids have been shown to reduce the rate at which recently
formed monocytes are released from bone marrow into the circulation
(21).
Additional evidence that infection of hepatocytes was much more
extensive in HC-treated SCID mice than in untreated SCID mice is seen
in the demonstration that the granulomas in HC-treated SCID mice were
much larger. Since the space occupied by liver granulomas in all groups
of mice represents space originally occupied by parenchymal cells, it
follows that the larger the granulomas are the greater the loss of
parenchymal cells to infection is at these sites. Indeed, it is obvious
that since the granulomas in WT mice extend beyond the boundry of
sinusoids, these granulomas also occupy space originally occupied by
parenchymal cells. This indicates that infection of hepatocytes might
have occurred to a small extent in WT mice, presumably before specific
immunity was acquired.
As for the possibility that BCG is capable of parasitizing parenchymal
cells in other organs in SCID and HC-treated SCID mice, it was not
investigated in this study, although it will be the subject of a study
soon to be initiated in this laboratory. In light of knowledge
(9-12, 18) that a variety of cell types are capable of
ingesting and supporting the growth of M. tuberculosis in
vitro, it seems reasonable to suspect that parenchymal cell infection
in other organs would occur under the conditions described here. This
is an important possibility to investigate given the significant
contribution made by CD8 T cells to the expression of anti-M.
tuberculosis immunity in mice and humans (5, 8, 19).
Indeed, it is possible that a key role of CD8 T cells in the expression
of anti-M. tuberculosis immunity might be the recognition and lysis of infected parenchymal cells rather than macrophages. The
results shown here with BCG serve to draw attention to this possibility. Moreover, since BCG is an attenuated organism with a
limited ability to cause disease, it may not be necessary to render
mice as severely immunodeficient as done in this study to show that
virulent strains of M. tuberculosis and M. bovis are capable of infecting parenchymal cells.
| |
ACKNOWLEDGMENTS |
Grant AI-37844 from the National Institute of Allergy and
Infectious Diseases and grant HL-64565 from the National Heart Lung Blood Institute supported this work.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Trudeau
Institute, 100 Algonquin Ave., Saranac Lake, NY 12983. Phone: (518)
891-3080. Fax: (518) 891-5126. E-mail: rjnorth{at}northnet.org
Present address: Paul Smith's College of Arts and Sciences, Paul
Smiths, NY 12970.
Editor:
E. I. Tuomanen
| |
REFERENCES |
| 1.
|
Ashwell, J. D.,
F. W. M. Lu, and M. S. Vacchio.
2000.
Glucocorticoids in T cell development and function.
Annu. Rev. Immunol.
18:309-345[CrossRef][Medline].
|
| 2.
|
Cross, C. C., and K. L. Mercer.
1993.
Cell and tissue ultrastructure. A functional perspective. W. H.
Freeman and Company, Oxford, England.
|
| 3.
|
Drouet, C.,
A. N. Shakhov, and C. V. Jongeneel.
1991.
Enhancers and transcription factors controlling the inducibility of tumor necrosis factor-alpha promoter in primary macrophages.
J. Immunol.
147:1694-1670[Abstract].
|
| 4.
|
Ellis, R. S., and L. A. Zabrowany.
1993.
Safer staining method for acid fast bacilli.
J. Clin. Pathol.
46:559-560[Abstract/Free Full Text].
|
| 5.
|
Flynn, J. L.,
M. M. Goldstein,
K. J. Treibold,
B. Koller, and B. R. Bloom.
1992.
Major histocompatibility complex class I-restricted T cells are required for resistance to Mycobacterium tuberculosis infection.
Proc. Natl. Acad. Sci. USA
89:12013-12017[Abstract/Free Full Text].
|
| 6.
|
Franchimont, D.,
D. Galon,
M. Gadina,
R. Visconti,
Y.-J. Zhou,
M. Aringer,
D. M. Frucht,
G. P. Chrousos, and J. J. O'Shea.
2000.
Inhibition of Th1 immune response by glucocorticoids: dexamethasone selectively inhibits IL-12-induced Stat4 phosphorylation in T lymphocytes.
J. Immunol.
164:1768-1774[Abstract/Free Full Text].
|
| 7.
|
Hennes, A. R.,
H. G. Muchmore,
H. G. McClure, and J. F. Hammersten.
1959.
In vitro inhibition of growth of M. tuberculosis by certain 11-oxygenated steroids.
Proc. Soc. Exp. Biol.
101:145-147.
|
| 8.
|
Lewinsohn, D. M.,
L. Zhu,
V. J. Madison,
D. C. Dillon,
S. P. Fling,
S. G. Reed,
K. H. Grabstein, and M. R. Alderson.
2001.
Classically restricted human CD8 T lymphocytes derived from Mycobacterium tuberculosis-infected cells: definition of antigen specificity.
J. Immunol.
166:439-446[Abstract/Free Full Text].
|
| 9.
|
Mapother, U., and J. G. Sanger.
1984.
In vitro interaction of Mycobacterium avium with intestinal epithelial cells.
Infect. Immun.
45:67-73[Abstract/Free Full Text].
|
| 10.
|
McDonough, K. A., and Y. Kress.
1995.
Cytotoxicity for lung epithelial cells is a virulence-associated phenotype of Mycobacterium tuberculosis.
Infect. Immun.
63:4802-4811[Abstract].
|
| 11.
|
Mehta, P. K.,
C. H. King,
E. H. White,
J. J. Murtagh, and F. D. Quinn.
1996.
Comparison of in vitro models of Mycobacterium tuberculosis invasion and intracellular replication.
Infect. Immun.
64:2673-2679[Abstract].
|
| 12.
|
Mermudez, L. E., and J. Goodman.
1996.
Mycobacterium tuberculosis invades and replicates in type II epithelial cells.
Infect. Immun.
64:1400-1406[Abstract].
|
| 13.
|
North, R. J., and A. Izzo.
1993.
Mycobacterial virulence. Virulent strains of Mycobacterium tuberculosis have faster in vivo doubling times and are better equipped to resist growth-inhibiting functions of macrophages in the presence and absence of specific immunity.
J. Exp. Med.
177:1723-1733[Abstract/Free Full Text].
|
| 14.
|
North, R. J., and A. A. Izzo.
1993.
Granuloma formation in severe combined immunodeficient (SCID) mice in response to progressive BCG infection.
Am. J. Pathol.
142:1959-1966[Abstract].
|
| 15.
|
Ramirez, F.
1998.
Glucocorticoids induce a Th2 response in vitro.
Dev. Immunol.
6:233-243[Medline].
|
| 16.
|
Rook, G. A.,
J. Steele,
M. Ainsworth, and C. Leveton.
1987.
A direct effect of glucocorticoid hormones on the ability of human and mouse macrophages to control growth of M. tuberculosis.
Eur. J. Respir. Dis.
71:286-291[Medline].
|
| 17.
|
Schaffner, A., and T. Schaffner.
1987.
Glucocorticoid-induced impairment of macrophage antimcrobial activity: mechanisms and dependence on the state of activation.
Rev. Infect. Dis.
9(Suppl. 5):620-629.
|
| 18.
|
Shepard, C. C.
1958.
A comparison of selected mycobacteria in HeLa, monkey kindey, and human amnion cells in tissue culture.
J. Exp. Med.
107:237-245[Abstract].
|
| 19.
|
Smith, S. M., and H. M. Dockrell.
2000.
Role of CD8 T cells in mycobacterial infections.
Immunol. Cell Biol.
78:325-333[CrossRef][Medline].
|
| 20.
|
Steer, J. H.,
K. M. Kroeger,
L. J. Abraham, and D. A. Joyce.
2000.
Glucocorticoids suppress tumor necrosis factor-alpha by human monocytic THP-1 cells by suppressing transactivation through adjacent NF-kappa B and c-Jun-activating transcription factor-2 binding sites in the promoter.
J. Biol. Chem.
16:18432-18440.
|
| 21.
|
Thompson, J., and R. van Furth.
1973.
The effect of glucocorticosteroids on the proliferation and kinetics of promonocyes and monocytes of the bone marrow.
J. Exp. Med.
137:10-21[Abstract].
|
Infection and Immunity, May 2001, p. 3175-3180, Vol. 69, No. 5
0019-9567/01/$04.00+0 DOI: 10.1128/IAI.69.5.3175-3180.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
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Abstract
Introduction
