| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
B Activity1
*
Institute for Nutrition Research and
Laboratory for Molecular Embryology, University of Oslo, Blindern, Oslo, Norway
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
B, including cancers and numerous inflammatory conditions.
Toward our goal to define mechanisms through which NF-B leads to the
development of disease, we have developed transgenic mice that express
luciferase under the control of NF-B, enabling real-time in vivo
imaging of NF-B activity in intact animals. We show that in the
absence of extrinsic stimulation, strong luminescence is evident in
lymph nodes in the neck region, thymus, and Peyer’s patches. Treating
mice with TNF-
, IL-1, or LPS increased the luminescence in a
tissue-specific manner, with the strongest activity observed in skin,
lungs, spleen, Peyer’s patches, and the wall of the small intestine.
Liver, kidney, heart, muscle, and adipose tissue displayed less intense
activities. Also, exposure of skin to a low dose of UV radiation
increased luminescence in the exposed areas. Furthermore, induction of
chronic inflammation resembling rheumatoid arthritis produced strong
NF-B activity in the affected joints, as revealed by in vivo
imaging. Thus, we have developed a versatile model for monitoring
NF-B activation in vivo. |
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
B
(1), a family of transcription factors present in
virtually every cell type (2). Heterodimers of NF-B are
most often sequestered in the cytoplasm in an inactive form bound to
inhibitors of NF-B (IBs) (2, 3). Upon appropriate
stimulation of cells, IBs are phosphorylated (4) by
specific IB kinases and degraded (5, 6, 7, 8, 9). Subsequently,
the liberated NF-B heterodimer can migrate to the cell nucleus to
exert its action as a transcriptional activator. Many distinct stimuli
activate NF-B, including proinflammatory cytokines, T and B cell
mitogens, bacteria and bacterial LPS, viruses, viral proteins, and
physical and chemical stress (3). Activated NF-B
subsequently alters the transcription of a large number of genes, many
of which participate in immune and inflammatory responses
(3).
A wide range of human disorders involves inappropriate regulation of
NF-B, including cancers (10), neurodegenerative
diseases (11), rheumatoid arthritis (RA)3
(12), asthma (13), inflammatory bowel disease
(14), and atherogenesis (15). As treatments
of such diseases may include selective modulators of NF-B, several
studies have aimed at identifying agents that efficiently inhibit
NF-B activity in vitro (2). It is, however, necessary
to validate these in vitro studies with appropriate animal models.
Until now, NF-B activity have been assessed in sacrificed animals by
band-shift analysis of nuclear extracts, nuclear localization of
NF-B by specific Abs, or analyzing reporter gene activity in
homogenates (16, 17) or sections (18) of
transgenic mice containing a reporter gene controlled by an NF-B
response element. As phosphorylation of NF-B in many cases is a
prerequisite for transcriptional activity, nuclear localization or DNA
binding alone cannot distinguish between transcriptionally active and
inactive NF-B (19). Toward our goal to define
mechanisms through which NF-B leads to the development of disease we
have developed transgenic mice that express a luciferase reporter whose
transcription is dependent upon NF-B. The relative amount of
luminescence can be assayed noninvasively by real-time imaging.
Reporter gene expression in vivo has previously been assessed using optical techniques such as microscopy of green fluorescent protein (20, 21) or near-infrared fluorescence (22), both of which have limited depth penetration. Nuclear imaging techniques using gamma cameras (23), positron emission tomography (24), or single-photon emission computed tomography (25) have satisfactory depth penetration, but they have a lower spatial resolution. Magnetic resonance imaging techniques (26) provide excellent spatial resolutions, but the temporal resolution is limited, and the technique is several orders of magnitude less sensitive than optical and nuclear techniques.
Our detection system was adapted from one described by Contag and
colleagues (27). In their study of mice infected with
recombinant bacteria containing the luciferase gene, the displayed
luminescence was sufficiently intense to be detected externally. They
also showed that HIV long terminal repeat-regulated luciferase
expression was readily assessed in transgenic mice (27).
Our transgenic mice express luciferase driven by three NF-B response
elements (i.e., sites identical with the B site from the Ig light
chain promoter (16)). The results presented here
demonstrate that NF-B activation can be assessed in living animals
using luciferase as a reporter. The luciferase-derived luminescence is
strongly regulated in response to classical inducers and modulators of
NF-B. Also, UVB radiation and chronic inflammation give strong
NF-B-dependent luminescence in the affected regions. As NF-B is
involved in a number of diseases, our model offers a valuable tool for
studying NF-B regulation in conditions where NF-B is a key
player.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
The DNA construct containing three NF-B sites from the Ig
light chain promoter coupled to the gene encoding firefly luciferase
(3x-B-luc) was tested in U937 and COS-1 cells before the
generation of transgenic mice, thus verifying the integrity of the
3x-B-luc construct. Stable transfection of U937 was
accomplished by electroporation of cells by the 3x-B-luc
plasmid and pMEP4 (Invitrogen, Carlsbad, CA) containing a hygromycin
resistance gene. U937 cells or transiently transfected COS-1 cells
(28) were incubated with TNF- (5 ng/ml; R&D Systems,
Minneapolis, MN), LPS (7–10 µg/ml; Sigma, St. Louis, MO), or PMA (50
ng/ml; Sigma) for 3–4 h. Cells were then harvested and assayed for
luciferase enzyme activity as described by the manufacturer (Promega,
Madison, WI). Generation of transgenic founder lines was subsequently
accomplished using standard techniques of microinjection
(29)
Generating transgenic mice
Generation of transgenic mice following microinjection was
largely based on standard techniques described by Hogan and colleagues
(29). Briefly, (C57 BL/6J x
CBA/J)F1 females were superovulated and mated
overnight with F1 males to yield fertilized
zygotes. Pronuclei of zygotes were injected with the
3x-B-luc plasmid linearized with HindIII and
BglI (giving a product of 
4.5 kb). Surviving zygotes were
transferred to pseudopregnant CD-1 recipients. Of 45 offspring
(F0), seven tested positive for
3x-B-luc by PCR genotyping. The F1
generation was subsequently analyzed for transgene expression. The
founder, named tgH24, was chosen for further studies and was crossed
with wild-type F1 mice. All subsequent transgenic
offspring were crossed with wild-type F1 to yield
only 3x-B-luc heterozygous mice with the (C57BL/6J x
CBA/J) genetic background.
Animal experiments
The following compounds were used to induce NF-B activity by
i.v. injection in the tail vein: mouse TNF- (4–8 µg/kg; R&D
Systems), mouse IL-1 (4 µg/kg; R&D Systems), LPS
(Escherichia coli serotype 055:B5, 2 mg/kg; Sigma).
UVB-induced NF-B activity was obtained with a transgenic mouse
treated with depilatory cream (Veet, London, U.K.) on the ventral side.
The skin was treated with cream two or three times for 3–4 min until
fur was removed from the desired area. Aluminum foil with three small
holes covered the skin, permitting localized exposure to UVB light from
a lamp fitted with a filter permeant to radiation in the UVB range (296
nm, 1-min exposure at 6 W/m2). Chronic
inflammation was induced by injecting Abs against collagen type II (4
mg/kg; Stratagene, La Jolla, CA) i.v. into transgenic mice on day 0,
followed by injection of LPS (50 µg; Sigma) i.v. on day 3. Criteria
for the presence of inflammation in the paws were redness, stiffness,
and swelling.
All animal experiments were performed according to national guidelines for animal welfare.
Imaging and luciferase measurements
Imaging of transgenic mice was performed with an ultrasensitive camera consisting of an image intensifier coupled to a CCD camera (C2400-47 Hamamatsu, Stockholm, Sweden) fitted with a 25-mm macro lens (Schneideroptics, Hauppauge, NY). Before imaging mice were anesthetized (Hypnorm/Dormicum; Janssen, Beerse, Belgium; Roche, Basel, Switzerland) and either treated with depilatory cream on the ventral side (Veet) or the skin and abdominal muscle was removed to expose internal organs. D-Luciferin (120 mg/kg; Biothema, Dalarö, Sweden) dissolved in 200 µl PBS, pH 7.8, was injected i.v. in the tail vein. Immediately afterward the mice were placed in a light-sealed chamber connected to the ultrasensitive camera as described. Gray scale images were obtained before luminescence imaging for reference. Luminescence emitted from the mouse was integrated for 10 min starting 2 min after the injection of luciferin. Individual organs to be imaged were excised from the mice 3 min following i.v. injection of D-luciferin (120 mg/kg). Organs were then placed in a culture dish and immediately imaged as described. Relative photon counts from intact organs were related to the weight of the organ, whereas luciferase enzyme activities in homogenates were related to protein concentration (milligrams per milliliter; Bio-Rad, Hercules, CA) in the sample extracts. The luciferase activity in homogenates was assessed according to the manufacturer’s protocol (Promega). The pseudocolored images represent light intensity (white is the strongest, and blue is the weakest). All images were processed with the software Image-Pro Plus 4.0 (Media Cybernetics, Silver Spring, MD) integrated with the HPD-LIS module developed by Hamamatsu.
p65/RelA binding assay
p65/RelA-DNA binding was assessed according to the manufacturer
(Active Motif, Carlsbad, CA). Briefly, tissues were gently homogenized
in lysis buffer (50 mg tissue/150 µl) and centrifuged (15,000
x g) to give a clear lysate. Tissue lysate (40–60 µg
protein/ml) was added to wells in microplates coated with
oligonucleotides containing binding sites for NF-B and incubated for
1 h. Ab against p65/RelA was then added, followed by addition of
secondary p65/RelA Ab-antibody conjugated with HRP to give a color
reaction. The degree of p65/RelA DNA binding was quantified by
spectrophotometry, reading absorbance at 450 nm. Lysis buffer was used
as a negative control.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
B-dependent luminescence in untreated transgenic mice
To monitor constitutive NF-B activity D-luciferin
was injected i.v., and the mice were placed on their back in a
light-sealed chamber and imaged as described (Fig. 1
A). Strong luminescence was
detected in two small areas in the neck, and an intense signal was
often emitted from one or several small spots in the abdominal area
(Fig. 1B). In addition, there were weaker and more diffuse
signals observed in the thoracic and abdominal regions. When internal
organs were exposed before imaging, it was evident that the strong
luminescence in the neck was associated with lymph nodes, the thoracic
signal originated from thymus, and the abdominal high activities were
located in structures identified as Peyer’s patches along the small
intestine (Fig. 1C).
|
Treating mice with TNF-, IL-1, and LPS, all known activators
of NF-B signaling (3), increased the luminescence in a
time- and region-specific manner (Fig. 2). When luminescence from whole animal
and selected regions was quantified, we observed that the thoracic
region displayed the highest induction.
|
A). In untreated mice thymus
displayed strong luminescence. Peyer’s patches also displayed distinct
luminescence. Following induction by LPS (2 mg/kg), luminescence from
the other organs was highly increased. The largest activities were
observed in skin, lungs, spleen, and the small intestine (i.e., both
Peyer’s patches and the intestinal wall), while liver, kidney, heart,
muscle, and adipose tissue displayed a less intense activity. The high
activity measured in noninduced thymus was largely unchanged following
LPS treatment.
|
) and mice treated with TNF- (4
µg/kg), IL-1 (4 µg/kg), or LPS (2 mg/kg; Fig. 3
B),
and the luciferase activity was quantified with a conventional enzyme
assay. In untreated mice thymus was by far the most active organ
(luciferase activity expressed per weight unit of protein), followed by
spleen, small intestine (i.e., intestinal wall with Peyer’s patches),
and skin (Table I and Fig. 3A). In accordance with the
results from noninvasive imaging, all treatments induced luciferase
activity in several organs. For all treatments the greatest induction
was observed in liver and lungs, with a maximum of about 200-fold
induction in both organs with LPS. Strong induction of NF-B activity
was also observed in kidney by all treatments and in heart, skin, and
muscle by IL-1 treatment. Luciferase activity in the thymus was not
affected by any of the treatments (data not shown).
|
C). In lungs, lymph nodes, heart, kidney, muscle, and
liver the luminescence imaged with the camera correlated highly with
the luciferase enzyme activity (correlation coefficient r
ranged in these organs from 0.877 in liver to 0.99 in lungs). In spleen
(r = 0.68), skin (r = 0.68), and thymus
(r = 0.56) a less clear correlation was observed, while
in intestine no correlation could be observed between the imaged
luminescence and the actual luciferase activities. We also observed that luciferase activity determined by whole organ luminescence apparently was quenched more in "dark" organs such as liver, kidney, spleen, and heart compared with more translucent organs such as lungs. This is in accordance with the observation that hemoglobin is the major absorber of visible light, including the light emitted from luciferase (i.e., 520–570 nm) (30). In addition, organs with a nonuniform distribution of cells expressing luciferase, such as the small intestine and lymph nodes, would be expected to deviate between whole organ imaging and homogenate assay.
To verify the model further we compared TNF--induced luciferase
expression with induction of p65/RelA DNA binding. One and a half hours
after TNF- i.v. injection (8 µg/kg) of three mice, DNA binding of
p65/RelA was assayed in tissue homogenates (pooled from three mice).
p65/RelA binding in liver, spleen, lung, and thymus of TNF--treated
mice was 612, 206, 247, and 98% of that in untreated mice,
respectively. Thus, up-regulation of p65/RelA DNA binding and induction
of reporter activity are demonstrated in liver, spleen, and lung, but
not in thymus, as expected.
Effect of dexamethasone on NF-B-regulated luminescence
To further demonstrate the modulation of NF-B activity in
the transgenic mice by the in vivo imaging technique, LPS-induced
transgenic mice were pretreated with dexamethasone (0.45 or 4.5 mg/kg),
a well-known suppressor of NF-B activity (2, 31, 32).
As demonstrated in Fig. 4, whole body
imaging of living mice revealed that 0.45 and 4.5 mg dexamethasone/kg
reduced the total luminescence from the animal by 15 and 45% (mean of
three mice in each group), respectively.
|
NF-B has been implicated in development of UV-induced skin
inflammation and cancer (33, 34). Assessment of NF-B in
the skin as a function of UV radiation is therefore of great interest.
To test whether UVB light (296 nm, 1 min exposure at 6
W/m2) induced NF-B activity in skin of
transgenic mice, we exposed defined regions of the mice to a dose of
UVB defined to be the lowest dose able to induce redness of human skin
(minimal erythema dose, 360 J/cm2). As shown in
Fig. 5, UVB strongly induce the
NF-B-driven luciferase activity in the exposed areas. The
UVB-mediated increase was first observed after 3.5 h. After
6.5 h the activity had increased 6-fold relative to background.
After 24 h the activity reached a maximum (34-fold induction)
while declining significantly after 48 h. Significant induction of
NF-B was observed in regions exposed to doses as low as 100
J/cm2 (data not shown). This is in agreement with
earlier in vitro observations of increased NF-B binding to DNA in
EMSAs (35).
|
B regulated luminescence in arthritis affected joints
During chronic inflammations such as RA NF-B mediates
TNF--induced expression of a number of cytokines (e.g., IL-8 and
IL-6) (12). A number of studies have also shown an
increased activity of NF-B in cultured synoviocytes from patients
with RA (36), and that NF-B has an increased DNA
binding activity in synovial membranes of RA patients
(37). Furthermore, recent studies indicate that reduction
of NF-B activity by overexpression of the inhibitory subunit
IB in rheumatoid synovial tissue inhibits the inflammatory
process and mechanisms of tissue destruction (38). To test
whether NF-B-driven luciferase activity in transgenic mice also
responds during inflammatory processes, we induced chronic inflammation
in the mouse at particular sites, mimicking development of RA, by
injecting Abs against collagen type II and LPS as described by Terato
et al. (39). The right front paw of the injected mouse
developed redness and pronounced swelling typical for arthritic joints.
Video imaging of the affected joint exhibited increased luminescence
after induction of arthritis (Fig. 6).
Quantification of the signal demonstrated a 7-fold induction of NF-B
activity in the arthritic joint compared with the paw in an animal
treated only with LPS.
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
B activity in living animals as a function of cytokines,
endotoxin, physical agent, and state of disease. While previous in vivo
imaging studies of gene expression have studied the constitutive
activity of complete promoters (i.e., the transferrin receptor
(26) and the viral promoters HIV long terminal repeat and
CMV (20, 27, 40)) we have demonstrated the dynamic
activity of a single response element.
The experiments are in agreement with earlier in vitro observations of
increased NF-B binding to DNA in EMSAs and nuclear
immunolocalization of NF-B following TNF-, IL-1, and LPS
treatment as well as UVB treatment and also increased activity in
affected joints in the RA model. Most importantly, our experiments
demonstrate modulation of trans-activation, which is not
always a consequence of DNA binding or nuclear localization
(19). Additionally, the model circumvents limitations in
analyses of reporter activity in sections and homogenates as required
in other transgenic animal models (16, 18). It also to
some extent provides sensitivity, and spatial and temporal resolution
compared with tomography imaging techniques (24, 25) and
magnetic resonance imaging (26). Although activity from
thymus, lymph nodes, and intestine can be clearly distinguished through
the skin as illustrated in Fig. 1B, the model may be most
useful for imaging NF-B activity in structures in close proximity to
the surface such as skin and joints in extremities (Figs. 5 and 6). The
relatively short half-life (t1/2, 2–3 h) and
the lack of post-translational modifications of expressed luciferase
reporter also provide the necessary dynamics to monitor NF-B
regulation close to real-time.
Drugs modulating NF-B is needed for treatment in a number of
diseases. Our transgenic mouse model enabling in vivo imaging of
luciferase reporter may be useful for screening potential candidate
drugs for the treatment of inflammatory conditions associated with
aberrant NF-B activation. We propose that similar transgenic models
using other response elements or complete promoters may serve as a
general model to monitor gene expression in vivo and to screen
exogenous factors, such as nutrients, pharmaceuticals, and pollutants,
for modulation of gene expression.
|
Acknowledgments |
|---|
B-luc plasmid, R. A. Davis for valuable
comments on the manuscript, K. Holte and L. Andersen for
technical assistance, and K. Hollung and I. Brude for
providing the stably transfected U937 cells. |
Footnotes |
|---|
2 Address correspondence and reprint requests to Dr. R. Blomhoff, Institute for Nutrition Research, University of Oslo, P.O. Box 1046, Blindern, 0316 Oslo, Norway. E-mail address: rune.blomhoff{at}basalmed.uio.no
3 Abbreviation used in this paper: RA, rheumatoid arthritis.
Received for publication April 27, 2001. Accepted for publication November 15, 2001.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
B and IB proteins: new discoveries and insights. Annu. Rev. Immunol. 14:649.[Medline]
B. Annu. Rev. Cell Biol. 10:405.
B- proteolysis by site-specific, signal-induced phosphorylation. Science 267:1485.B kinase-
: NF-B activation and complex formation with IB kinase- and NIK. Science 278:866.B kinase complex (IKK) contains two kinase subunits, IKK and IKK, necessary for IB phosphorylation and NF-B activation. Cell 91:243.[Medline]
B-kinase. Cell 90:373.[Medline]
B kinases essential for NF-B activation. Science 278:860.B kinase that activates the transcription factor NF-B. Nature 388:548.[Medline]
B/IB proteins and cancer. Oncogene 13:1367.[Medline]
B: a crucial transcription factor for glial and neuronal cell function. Trends Neurosci. 20:252.[Medline]
B in immune and inflammatory responses in the gut. Gut 43:856.B in atherogenesis. Exp. Physiol. 82:297.[Abstract]
B/Rel transcription factors are responsible for tissue-specific and inducible gene activation. Nature 365:767.[Medline]
B activation in a transgenic mouse model of systemic inflammation. Am. J. Respir. Crit. Care Med. 162:1095.B activity in transgenic mice: developmental regulation and tissue specificity. Development 122:2117.[Abstract]
B p65/RelA subunit. Mol. Cell. Biol. 19:4798.B by sodium salicylate and aspirin. Science 265:956.)B kinase-. Nature 396:77.[Medline]
B and constitutive activation of NF-B transcription factors during mouse skin carcinogenesis. Oncogene 18:7423.[Medline]
B signaling. Cancer Res. 59:3299.B and CBF1. Am. J. Pathol. 152:793.[Abstract]
B in synovial membranes of patients with rheumatoid arthritis. Biochem. Mol. Biol. Int. 37:827.[Medline]
B inhibits both inflammatory and destructive mechanisms in rheumatoid synovium but spares anti-inflammatory mediators. Proc. Natl. Acad. Sci. USA 96:5668.This article has been cited by other articles:
|
|
 |
|
  C. O'Mahony, H. van der Kleij, J. Bienenstock, F. Shanahan, and L. O'Mahony Loss of vagal anti-inflammatory effect: in vivo visualization and adoptive transfer Am J Physiol Regulatory Integrative Comp Physiol, October 1, 2009; 297(4): R1118 - R1126. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S.-L. Wu, J.-C. Chen, C.-C. Li, H.-Y. Lo, T.-Y. Ho, and C.-Y. Hsiang Vanillin Improves and Prevents Trinitrobenzene Sulfonic Acid-Induced Colitis in Mice J. Pharmacol. Exp. Ther., August 1, 2009; 330(2): 370 - 376. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Zangani, H. Carlsen, A. Kielland, A. Os, H. Hauglin, R. Blomhoff, L. A. Munthe, and B. Bogen Tracking Early Autoimmune Disease by Bioluminescent Imaging of NF-{kappa}B Activation Reveals Pathology in Multiple Organ Systems Am. J. Pathol., April 1, 2009; 174(4): 1358 - 1367. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. E. Simmonds and B. M. Foxwell Signalling, inflammation and arthritis: NF-{kappa}B and its relevance to arthritis and inflammation Rheumatology, May 1, 2008; 47(5): 584 - 590. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Haugen and C. A. Drevon Activation of Nuclear Factor-{kappa}B by High Molecular Weight and Globular Adiponectin Endocrinology, November 1, 2007; 148(11): 5478 - 5486. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Partridge, H. Carlsen, K. Enesa, H. Chaudhury, M. Zakkar, L. Luong, A. Kinderlerer, M. Johns, R. Blomhoff, J. C. Mason, et al. Laminar shear stress acts as a switch to regulate divergent functions of NF-{kappa}B in endothelial cells FASEB J, November 1, 2007; 21(13): 3553 - 3561. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Q. Li, Y. Guo, W. Tan, Q. Ou, W.-J. Wu, D. Sturza, B. Dawn, G. Hunt, C. Cui, and R. Bolli Cardioprotection Afforded by Inducible Nitric Oxide Synthase Gene Therapy Is Mediated by Cyclooxygenase-2 via a Nuclear Factor-{kappa}B Dependent Pathway Circulation, October 2, 2007; 116(14): 1577 - 1584. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Karlsen, L. Retterstol, P. Laake, I. Paur, S. Kjolsrud-Bohn, L. Sandvik, and R. Blomhoff Anthocyanins Inhibit Nuclear Factor-{kappa}B Activation in Monocytes and Reduce Plasma Concentrations of Pro-Inflammatory Mediators in Healthy Adults J. Nutr., August 1, 2007; 137(8): 1951 - 1954. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. M. Houten, D. H. Volle, C. L. Cummins, D. J. Mangelsdorf, and J. Auwerx In Vivo Imaging of Farnesoid X Receptor Activity Reveals the Ileum as the Primary Bile Acid Signaling Tissue Mol. Endocrinol., June 1, 2007; 21(6): 1312 - 1323. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Ying and T. M. Monticello Modern Imaging Technologies in Toxicologic Pathology: An Overview Toxicol Pathol, December 1, 2006; 34(7): 815 - 826. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Luo, A. H. Lin, E. Masliah, and T. Wyss-Coray Bioluminescence imaging of Smad signaling in living mice shows correlation with excitotoxic neurodegeneration PNAS, November 28, 2006; 103(48): 18326 - 18331. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Groeneweg, E. Kanters, M. N. Vergouwe, H. Duerink, G. Kraal, M. H. Hofker, and M. P. J. de Winther Lipopolysaccharide-induced gene expression in murine macrophages is enhanced by prior exposure to oxLDL J. Lipid Res., October 1, 2006; 47(10): 2259 - 2267. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J.-M. Cavaillon and D. Annane Invited review: Compartmentalization of the inflammatory response in sepsis and SIRS Innate Immunity, June 1, 2006; 12(3): 151 - 170. [Abstract] [PDF]
|
|
|
|
 |
|
 K. Nagashima, V. G. Sasseville, D. Wen, A. Bielecki, H. Yang, C. Simpson, E. Grant, M. Hepperle, G. Harriman, B. Jaffee, et al. Rapid TNFR1-dependent lymphocyte depletion in vivo with a selective chemical inhibitor of IKKbeta Blood, June 1, 2006; 107(11): 4266 - 4273. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. T. Sadikot and T. S. Blackwell Bioluminescence Imaging Proceedings of the ATS, December 1, 2005; 2(6): 537 - 540. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Wunder, R. H. Straub, S. Gay, J. Funk, and U. Muller-Ladner Molecular imaging: novel tools in visualizing rheumatoid arthritis Rheumatology, November 1, 2005; 44(11): 1341 - 1349. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. H. Lin, J. Luo, L. H. Mondshein, P. ten Dijke, D. Vivien, C. H. Contag, and T. Wyss-Coray Global Analysis of Smad2/3-Dependent TGF-{beta} Signaling in Living Mice Reveals Prominent Tissue-Specific Responses to Injury J. Immunol., July 1, 2005; 175(1): 547 - 554. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. O Moskaug, H. Carlsen, M. C. Myhrstad, and R. Blomhoff Polyphenols and glutathione synthesis regulation Am. J. Clinical Nutrition, January 1, 2005; 81(1): 277S - 283S. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. T. Magness, H. Jijon, N. Van Houten Fisher, N. E. Sharpless, D. A. Brenner, and C. Jobin In Vivo Pattern of Lipopolysaccharide and Anti-CD3-Induced NF-{kappa}B Activation Using a Novel Gene-Targeted Enhanced GFP Reporter Gene Mouse J. Immunol., August 1, 2004; 173(3): 1561 - 1570. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Didierlaurent, I. Ferrero, L. A. Otten, B. Dubois, M. Reinhardt, H. Carlsen, R. Blomhoff, S. Akira, J.-P. Kraehenbuhl, and J.-C. Sirard Flagellin Promotes Myeloid Differentiation Factor 88-Dependent Development of Th2-Type Response J. Immunol., June 1, 2004; 172(11): 6922 - 6930. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Xie, Z. Luo, K. M. Slawin, and D. M. Spencer The EZC-Prostate Model: Noninvasive Prostate Imaging in Living Mice Mol. Endocrinol., March 1, 2004; 18(3): 722 - 732. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Carlsen, M. C. W. Myhrstad, M. Thoresen, J. O. Moskaug, and R. Blomhoff Berry Intake Increases the Activity of the {gamma}-Glutamylcysteine Synthetase Promoter in Transgenic Reporter Mice J. Nutr., July 1, 2003; 133(7): 2137 - 2140. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. E. Yull, W. Han, E. D. Jansen, M. B. Everhart, R. T. Sadikot, J. W. Christman, and T. S. Blackwell Bioluminescent Detection of Endotoxin Effects on HIV-1 LTR-driven Transcription in Vivo J. Histochem. Cytochem., June 1, 2003; 51(6): 741 - 749. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Alexander, H. Carlsen, and R. Blomhoff Strong In Vivo Activation of NF-{kappa}B in Mouse Lenses by Classic Stressors Invest. Ophthalmol. Vis. Sci., June 1, 2003; 44(6): 2683 - 2688. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Dragland, H. Senoo, K. Wake, K. Holte, and R. Blomhoff Several Culinary and Medicinal Herbs Are Important Sources of Dietary Antioxidants J. Nutr., May 1, 2003; 133(5): 1286 - 1290. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. F. Massoud and S. S. Gambhir Molecular imaging in living subjects: seeing fundamental biological processes in a new light Genes & Dev., March 1, 2003; 17(5): 545 - 580. [Full Text] [PDF]
|
|
|
|
 |
|
 H.-R. Zhou, Z. Islam, and J. J. Pestka Rapid, Sequential Activation of Mitogen-Activated Protein Kinases and Transcription Factors Precedes Proinflammatory Cytokine mRNA Expression in Spleens of Mice Exposed to the Trichothecene Vomitoxin Toxicol. Sci., March 1, 2003; 72(1): 130 - 142. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D A Mann The NF{kappa}B luciferase mouse: a new tool for real time measurement of NF{kappa}B activation in the whole animal Gut, December 1, 2002; 51(6): 769 - 770. [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
