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*
Division of Gastroenterology-Hepatology, Department of Internal Medicine, University of Iowa, Iowa City, IA 52242;
Department of Pathology, University of Wisconsin, Madison, WI 53792; and
Children’s Hospital and Department of Medicine, Beth Israel Hospital, Boston, MA 02215
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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and
IgG2a and less IgE. The expression of Th2 cytokines (IL-4/IL-5) and
IgG1 was comparable to the wild-type control. The mouse with targeted
disruption of its SPr had the nonmammalian gene encoding the enzyme
ß-galactosidase inserted in exon 1 of the SPr gene. There was
ß-galactosidase activity in many mononuclear cells scattered
throughout the schistosome granulomas of SPr-/- mice.
Also, a granuloma T cell line derived from this transgenic mouse
produced ß-galactosidase. These results provide further evidence that
in murine schistosomiasis SPr is displayed commonly on granuloma
inflammatory cells and is important for granuloma development and
expression of IFN- circuitry in this natural
infection. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Substance P (SP)3 is a short polypeptide molecule made by nerves, endothelial cells, and cells of the immune system. Evidence suggests that SP can modulate several important immunologic functions (2).
Schistosome granulomas appear to have a SP immunoregulatory circuit.
Schistosome granulomas contain SP (3) and express mRNA for
preprotachykinin (4), which is the precursor polypeptide for SP. These
observations and more suggest that leukocytes within this inflammation
make SP. SP signals through a specific receptor called neurokine 1.
Schistosome granulomas have mRNA for this SP receptor (SPr), which
localizes to granuloma CD4+ T cells (5). It is possible
that other cell types express it also. In murine schistosomiasis, SP
enhances IFN- secretion from Ag-stimulated splenocytes or granuloma
cells through interaction with the SPr (6). SPr antagonists given
orally impede granuloma formation and interfere with IFN--driven
IgG2a expression, further suggesting a role for SP in the inflammation
(7). SP antagonist also hinders the immune response to
Salmonella, decreasing early IFN- expression in vivo (8).
Recently, mice deficient in SPr (SPr-/-) were generated through targeted disruption of the SPr gene (9). These mice were infected with Schistosoma mansoni to determine the importance of SPr for normal granuloma development in this parasitic disease. The results suggest that SPr is vital for aspects of the granulomatous response.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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This study used 129 Sv x C57BL/6 SPr-/- and littermate control (SPr+/+) mice (9). Breeding colonies for the mice were maintained at the University of Iowa. At 7–8 wk of age, mice were infected subcutaneously with 50 cercariae of the Puerto Rican strain of S. mansoni (10).
Dispersal of granuloma cells and splenocytes and cell culture
Livers of mice sacrificed during the eighth week of infection were homogenized for 30 s at low speed in a Waring blender. Granulomas were collected by 1 x g sedimentation and washed three times in RPMI 1640 medium (RPMI). To prepare a single-cell suspension from these granulomas, the intact granulomas were incubated in a shaking water bath at 37°C for 30 min in RPMI containing 0.5% collagenase (type 1 from Clostridium histolyticum; Sigma, St. Louis, MO). The softened granulomas were disrupted further by repeated suction and expulsion through a 1-ml syringe. The dispersed granuloma cell suspensions were passed through a sterile gauze to exclude nondispersed fragments. The cells were collected by centrifugation, washed three times in RPMI, and counted. Cell viability was determined by eosin Y exclusion.
Single-cell suspensions of splenocytes were prepared from individual spleens from 8-wk-infected mice by gentle teasing in RPMI. The cells were briefly resuspended in distilled water to lyse RBC. The splenocytes then were washed three times in a large volume of RPMI.
Cells were cultured for 48 h in 96-well microwell plates (Corning, Cambridge, MA) with 200 µl of medium (about 4 x 107 cells/flask) at 37°C. Supernatants then were collected for cytokine and Ig measurements by ELISA. The culture medium was RPMI containing 10% FCS, 10 mM HEPES buffer, 2 mM L-glutamine, 100 U/ml penicillin, 5 mg/ml gentamicin, and 100 mg/ml streptomycin (all from Sigma). The cells were cultured alone or in the presence of anti-CD3 mAb (0.2 µg/ml) (145.2C11; provided by Jay Bluestone, University of Chicago, Chicago, IL), soluble egg Ag (SEA) (5 µg/ml), anti-IL-10 mAb (1 µg/ml), or rIL-12 (10 ng/ml) (R & D Systems, Minneapolis, MN). The SEA was made as described (10) from ova isolated from the livers of hamsters infected for about 7 wk with 1000 cercariae.
T cell line
To establish a T lymphocyte line, 5 x 106
granuloma cells were incubated in a RPMI-pretreated nylon wool column
for 15 min at 37°C. The column was then flushed with RPMI to recover
the nonadherent cells. These were washed three times in RPMI and
cultured in a T25 flask in complete RPMI medium containing 10% FCS and
10% conditioned medium. Conditioned medium was the 48-h culture
supernatant of Con A (10 µg/ml; Sigma)-stimulated spleen cells
isolated from normal mice. The granuloma cells were washed and replated
weekly with the same medium. After 1 mo, the cells grew rapidly, and
aliquots of cells were frozen in liquid nitrogen for future use. These
cultured granuloma cells were >99% CD4+
ß+ T lymphocytes by FACS analysis.
Measurement of granuloma size
Mean granuloma size was determined in stained histologic sections using an optical image splitter. Examined were 20 granulomas with clearly identifiable central ovum from each of eight different mice, and the data were presented as mean cross-sectional area ± SE.
lac Z expression
Liver tissue from schistosome-infected SPr mutant mice and wild-type controls were stained for ß-galactosidase activity, which is the enzyme made by the lac Z gene. Tissues were fixed in fixative containing 0.2% glutaraldehyde, 5 mM EGTA, and 2 mM MgCl2 in phosphate buffer (23 mM sodium phosphate monobasic, 77 mM sodium phosphate dibasic, pH 7.3) for 1 h at room temperature, then washed in PBS for 10 min three times and incubated overnight in PBS containing 30% sucrose. Tissues were frozen in liquid nitrogen, and 5- to 6-µm sections were mounted on glass slides. These were washed in PBS for 5 min, then fixed again for 10 min in the fixative solution mentioned above. After washing in PBS 2 times for 5 min, the sections were incubated in X-gal solution (0.1% x-gal, 0.2% potassium ferrocyanide, 0.16% potassium ferricyanide, 2 mM MgCl2, 0.01% deoxycholate, and 0.02% igepal in phosphate buffer) in a humidity chamber at 37°C overnight. ß-galactosidase activity was indicated by blue staining. In some experiments, the tissue was lightly counterstained with nuclear fast red and eosin Y to allow partial identification of ß-galactosidase-positive cells and to examine their topographic expression.
Dispersed granuloma cells and T cell lines were cytocentrifuged onto glass slides. The cells were fixed for 5 min with the fixative solution mentioned above. Next, slides were washed for 5 min in each of three changes of PBS. Slides then were soaked 30 min in the 30% sucrose solution and washed three more times in PBS. The slides next were exposed to the X-gal solution for 48 h and then washed three times with PBS, dried, and coverslipped.
Cytokine and Ig assays
Cytokine concentrations in supernatants were measured by ELISA.
To measure IFN-, plates were coated with a mAb to IFN- (HB170;
American Type Culture Collection, Manassa, VA) and incubated with
supernatant. IFN- was detected with polyclonal rabbit
anti-IFN- (a gift from Dr. Mary Wilson, Department of Medicine,
University of Iowa) followed by biotinylated goat anti-rabbit IgG
(Accurate Chemical, Westbury, NY), strepavidin-HRP and
2,2'-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) substrate (Zymed,
San Francisco, CA). IL-4 was captured with 11B11 (HB191; DNAX Research
Institute, Palo Alto, CA) and detected with biotinylated BVD6 (provided
by Kevin Moore and John Abrams, DNAX). IL-5 was captured with TRFK5 and
detected with biotinylated TRFK4 (provided by Dr. Robert Coffman, DNAX)
followed by strepavidin-peroxidase conjugate. mAbs were purified from
culture supernatants by ammonium sulfate precipitation. Sensitivities
of the ELISAs were 30 pg/ml for IFN-, 100 pg/ml for IL-4, and 30
pg/ml for IL-5.
IgG2a and IgG1 were assayed by ELISA using commercial Abs following the directions of the manufacturer (Southern Biotechnology Associates, Birmingham, AL). These assays could measure down to 10 ng/ml. The IgE assay used EM95 mAb for coating and a polyclonal goat anti-mouse IgE Ab for detection (Richard Lynch, Department of Pathology, University of Iowa). This assay was sensitive down to 200 ng/ml.
Flow cytometric analysis
Spleen and liver granuloma cells were washed twice and adjusted
to 2 x 107 cells/ml in FACS buffer (HBSS containing
10% BCS and 0.02% sodium azide). The cell suspensions then were
dispensed into microcentrifuge tubes each containing 1 x
106 cells in 50 µl FACS buffer. Each tube also received 1
µg 2.4G2 Ab (anti-FcR) (American Type Culture Collection) to
block nonspecific binding of conjugated Abs to FcR. Cells were stained
with saturating amounts of conjugated Abs for 30 min at 4°C. The
following mAbs were used for staining: anti-CD4-Cy5 (GK1.5),
anti-CD8a-PE, anti-Thy 1.2-FITC, DX5-FITC, and B220-FITC (all
from PharMingen, San Diego, CA). Following staining, cells were washed
twice and resuspended in 300 µl FACS buffer. Stained cells were
analyzed on a four-decade Becton Dickinson FACS 440 flow cytometer
(Mountain View, CA). Forward angle light scatter and three simultaneous
immunofluorescence parameters were collected on 30,000 cells. The data
were analyzed using FACS/DESK software.
RNA extraction and PCR assay for SPr mRNA
Each experiment used RNA from splenocytes or granuloma cells pooled from three to four separate mice. Total cellular RNA was extracted from cell suspensions by homogenization in guanidinium/acid-phenol as previously described (11). Cellular RNA (5 µg) was reverse transcribed with Moloney-monkey leukemia virus (400 U) using an 18-mer oligo-dT (0.5 µg) as primer. The first strand cDNA was diluted to 250 µl, and 15 µl (0.3 µg RNA) was added to PCR buffer containing 2 U Taq DNA polymerase, 1.4 mM Mg Cl2, 50 mM KCl, and 100 mM Tris, pH 8.3, in a total volume of 50 µl. The sense primer to amplify SPr was 5'-CCA ACA CCT CCA CCA AGA CTT CTG-3', and the antisense primer was 5'-GCC ACA GCT GTC ATG GAG TAG AT-3'. The PCR consisted of 40 cycles at 93°C for 1.1 min, 63°C for 1.36 min, and 72°C for 1.14 min. Products of RT-PCR amplification were analyzed by agarose gel electrophoresis using 1.7% Nusieve GTG agarose (FMC Bioproducts, Rockland, ME) in 0.5x TBE buffer (90 mM Tris, 64.6 mM boric acid, 2.5 mM EDTA, pH 8.3). The authenticity of the 338-bp fragment was confirmed by sequencing.
Total RNA preparations contained equivalent 18 and 28S RNA bands. RNA extracts were quantified spectrophotometrically. In most experiments, samples were compared for content of actin to further confirm equivalent mRNA content and reverse transcription.
Statistical analysis
Data are means ± SD or SE of multiple determinations. Difference between two groups was compared using Student’s t test. Values of p < 0.05 were considered significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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SPr-/- mice and littermate control animals were
infected with S. mansoni. Both groups of animals formed
granulomas in response to schistosome ova deposited in the liver.
Freshly isolated, dispersed granuloma cells and splenocytes from
SPr-/- mice expressed no SPr mRNA as determined by a
sensitive RT-PCR assay. However, cells from SPr+/+ animals
constitutively expressed SPr mRNA strongly as determined by PCR
amplification of the predicted 338-bp fragment from splenic and
granuloma cDNA (Fig. 1
). The
authenticity of the 338-bp fragment also was confirmed by
sequencing (data not shown).
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Transgenic mice devoid of SPr were made by gene targeting. Most of exon 1 was deleted and replaced with the genes for neomycin resistance and lac Z (9). The latter encodes for the nonmammalian enzyme ß-galactosidase. It was expected that cells from this mouse with an activated SPr promoter would produce ß-galactosidase.
We evaluated granulomas for lac Z gene expression using
histochemical methods on tissue sections. Fig. 2 shows that SPr-/- mice
infected with schistosomiasis form granulomas that contain inflammatory
cells expressing ß-galactosidase. ß-galactosidase-positive cells
were evident throughout the granuloma, but most numerous near the outer
rim of these inflammatory lesions. No ß-galactosidase activity was
visible in granulomas from wild-type control animals. The
ß-galactosidase activity was vulnerable to prolonged fixation.
Also, the sections were difficult to counterstain, because this
frequently obscured the blue ß-galactosidase-positive cells.
Therefore, to partially identify cells with lac Z
expression, granulomas were isolated from the liver and dispersed
with collagenase to form single-cell suspensions. Some of the dispersed
granuloma cells from SPr-/- mice also produced
ß-galactosidase. The activity rested exclusively in mononuclear cells
(data not shown).
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). Dispersed granuloma cells and
granuloma T cell lines from SPr+/+ animals did not express
the lac Z gene. Thus, it appeared that some granuloma
mononuclear cells and a T cell line from the SPr transgenic mouse had
an activated SPr promoter.
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Although the number of liver granulomas was similar, mean
granuloma size was smaller in the SPr-/- mouse (Fig. 4). The mean granuloma cross-sectional
area, as measured in stained histological liver sections, was
101,225 ± 2,772 µm2 (±SE) for the
SPr+/+ control and 61,826 ± 4,581 µm2
for the SPr-/- animal (p <
0.05). The granulomas of SPr-/- mice also appeared
somewhat more cellular.
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).
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). Analysis of splenocytes yielded similar results
(data not shown). Measurement of cytokine production
Mice infected with schistosomiasis normally develop strong
Th2-type granulomas that produce large amounts of IL-4 and IL-5 and
small quantities of IFN-. SP stimulates IFN- secretion in murine
schistosomiasis (6). To further explore the relevance of SP in IFN-
production, we infected SPr-/- animals with
schistosomiasis to learn if the resulting inflammation displayed
alternations in cytokine secretion. Dispersed splenocytes or granuloma
cells from SPr+/+ or SPr-/- animals were
cultured in vitro for 48 h in the presence or absence of SEA as a
source of specific Ag or anti-CD3 mAb. Some wells also received
anti-IL-10 mAb or rIL-12, which are factors that enhance IFN-
release. Then, culture supernatants were assayed for IFN-, IL-4, and
IL-5 content.
The data, presented in Fig. 5, indicate
that granuloma cells of SPr+/+ mice released no detectable
IFN- constitutively and secreted only small amounts after SEA
stimulation. Anti-CD3 mAb, anti-IL-10 mAb, and rIL-12 all
stimulated IFN- production.
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either constitutively or after SEA stimulation.
(Fig. 5). Also, these cells were notably less responsive to
anti-CD3, anti-IL-10, and rIL-12, making less IFN- compared
with the control animals.
There was no constitutive IFN- secretion from splenocytes of either
SPr+/+ or SPr-/- animals. However, the
SPr-/- splenocytes were less capable of producing IFN-
in response to Ag, anti-CD3, anti-IL-10, or rIL-12 (Fig. 5).
Thus, the data outlined above show that both granuloma and splenic
IFN- production were partly SPr dependent.
Granuloma cells released IL-4 and IL-5 constitutively, whereas
splenocytes only produced small detectable amounts of IL-5
constitutively. Granuloma cells and splenocytes from SPr+/+
or SPr-/- animals produced comparable quantities of these
cytokines even after SEA or anti-CD3 stimulation (Table II).
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B cells within schistosome granulomas normally make several Ig
isotypes. IgG2a secretion is contingent on IFN- (7). IgE and IgG1
production is strongly dependent on IL-4 (12). Because
SPr-/- animals with schistosomiasis produce less IFN-
than the littermate controls, we determined if granulomas from
SPr-/- animals exhibited a corresponding alteration in Ig
secretion. Dispersed granuloma cells or splenocytes were cultured for
48 h in vitro. The culture supernatants then were assayed for
IgG2a, IgG1, and IgE content. Table II shows that both the granuloma
cells and splenocytes of control and SPr-/- mice
constitutively released IgG2a and IgG1. However, in the
SPr-/- state, the spleen and granuloma cells released
substantially less IgG2a (about 2 and 4% of expected value,
respectively) but normal amounts of IgG1. These data show that in
animals with schistosomiasis IgG2a production is SPr dependent. Also,
SPr-/- mice made less IgE, although the difference
between the SPr-/- and SPr+/+ animals was
less profound.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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circuitry both in the granulomas and spleens. This is in
agreement with our previous report showing that mice infected with
schistosomiasis and treated with SPr antagonist form smaller granulomas
that produce less IFN- (7). Also, in vitro experiments suggest that
SP functions to stimulate IFN- secretion in the spleens and
granulomas (6). All together, the above findings support the contention
that SP is important for maintaining the low-grade IFN- response
within the strong Th2-type inflammation of murine schistosomiasis.
IFN- is a B cell switch factor that induces activation of the
constant heavy gene of IgG2a and functions to increase the amount of
IgG2a secreted from IgG2a-committed B cells (13). IFN- is important
for IgG2a expression in murine schistosomiasis (6). It was shown
previously that SP can stimulate splenic IgG2a production in vitro
through enhancement of IFN- secretion. Also, mice treated with SPr
antagonist produce schistosome granulomas that make substantially less
IgG2a. Thus, the appreciable impairment in IgG2a expression by
splenocytes and granuloma cells in SPr-/- mice is further
evidence that SP is important for IFN- expression in murine
schistosomiasis.
IFN- is not essential for most other aspects of the granulomatous
response in murine schistosomiasis. IFN- receptor knockout (KO) mice
infected with schistosomiasis accept the infection normally and form
Th2-type granulomas in the liver that have normal histologic
characteristics (14). Also, splenocytes stimulated with SEA produce the
expected amount of IL-4 and IL-5. Thus, it was not surprising that the
IFN- impairment in the SPr mutant animal lead to no major changes in
granuloma cell composition or Th2 (IL-4, IL-5) cytokine secretion.
However, SPr-/- mice formed liver granulomas smaller in
size than those of the wild-type control animals. The splenocytes and
granuloma cells also made less IgE. This may signify that SP has
functions in murine schistosomiasis beyond IFN- regulation,
because IFN- receptor mutant animals develop normal size
liver granulomas and the splenocytes secrete normal amounts of IgE
(14).
SP and its receptor are widely distributed and implicated in the regulation of a wide range of cellular functions. Reports suggest that SP effects many aspects of immune responses (2, 15). SP also influences vascular endothelial cells, increasing adhesion molecule expression, and vascular permeability (16, 17, 18). It has been shown to act on fibroblasts as well (19). Thus, in schistosomiasis, it remains possible that SP affects several cell types and immunoregulatory circuits.
Various leukocyte subsets like T cells, B cells, and macrophages may
display SPr (2, 20). We previously showed that schistosome granulomas
from normal mice contain SPr mRNA (5), which was confirmed in this
investigation. One source is the granuloma CD4+ lymphocyte,
which displays a functional SPr that can regulate IFN- production.
Granuloma and splenic macrophages make somatostatin (21). SP
down-modulates somatostatin production in splenocytes and granulomas of
mice infected with schistosomiasis (22). SPr antagonists block this
regulation, which is evident even in Rag 1 mice, which lack
T and B cells. This suggests that granuloma and splenic immune cell
types other than T cells also express a functional SPr.
To gain further insight into which granuloma cells possibly are targeted for SP action, lac Z was used as a reporter gene to identify cells within the granuloma with an activated SPr promotor. The transgenic mouse used in this study had most of exon 1 of the SPr gene deleted and replaced with lac Z (9), a nonmammalian gene encoding the enzyme ß-galactosidase. There was ß-galactosidase activity expressed in many mononuclear cells scattered throughout the granuloma, but this activity was most evident within cells of the granuloma outer rim. Also, a granuloma T cell line derived from this transgenic mouse produced ß-galactosidase. These observations afford further evidence that granuloma mononuclear cells like T lymphocytes normally express SPr. However, granuloma eosinophils, which comprise about 50% of the cellular content of schistosome granulomas, displayed no evidence of lac Z expression.
In summary, the SPr-/- mouse showed that the SPr
contributes to IFN- expression, IgG2a production, and possibly other
aspects of immunoregulation in the granulomatous response of murine
schistosomiasis. Also, the expression of the lac Z reporter
gene further suggests that some granuloma cell types prominently
exhibit SPr.
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Joel V. Weinstock, Department of Medicine, 4607 JCP, University of Iowa, 200 Hawkins Drive, Iowa City, IA 52242. E-mail:
3 Abbreviations used in this paper: SP, substance P; RPMI, RPMI 1640 medium; SPr, SP receptor; SPr-/-, SPr (neurokinin 1) knockout mouse; SEA, soluble egg Ag; KO, knockout.
Received for publication November 12, 1998. Accepted for publication March 1, 1999.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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immunoregulatory circuit. Ann. NY Acad. Sci. 840:532.[Medline]
production in murine schistosomiasis mansoni. J. Immunol. 151:225.[Abstract]
. Annu. Rev. Immunol. 15:749.[Medline]
interferon-deficient mice chronically infected with Schistosoma mansoni. Infect. Immun. 65:2583.[Abstract]
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