Cellular recognition of
herpes simplex virus infection and virus-induced cytokine production.
Melchjorsen
J.
Institute of Medical
Microbiology and
Immunology, The Bartholin Building, University of Aarhus, DK-8000 Arhus C.
jesper@microbiology.au.dk.
The aim of the PhD dissertation was i) to
determine the cytokine expression profile after herpes simplex virus (HSV)
infection, ii) describe cellular mechanisms of viral recognition, and iii)
identify viral proteins that inhibit or enhance cytokine production. The
dissertation includes five papers published and two manuscripts intended
for publication. HSV is a very common virus that clinically may manifest in
gingivostomatitis, herpes labialis,
keratitis, encephalitis, and genital herpes.
Normally the infection is self-limiting but in immuno-compromised
individuals, such as newborn babies, transplantation patients, and AIDS
patients the virus may spread throughout the body and result in
encephalitis, which is associated with high mortality and morbidity. i) The PhD study showed that HSV infection in dendritic cells and macrophages induces a number of
well known proinflammatory cytokines, chemokines, and interferons,
including the recently discovered type III interferons
IL-28 and IL-29. The study also presents the first evidence that IL-29 has
potential antiviral activity against HSV in human cells. Furthermore,
selective production of the chemokine RANTES was
seen in murine macrophages. ii) A group of
recognition receptors, termed Toll-like receptors (TLRs),
were investigated, and it was found that HSV infection was recognised through both TLR-dependent and
TLR-independent mechanisms. Downstream of recognition, HSV-induced
activation of the transcription factors IRF3 and NF-kappa-B was essential
for chemokine and interferon expression.
Furthermore, the kinases IKK-beta, TAK1, MEKK1,
and PKR also play important roles for the virus-induced cytokine
expression. iii) HSV evades the antiviral cytokine response through the viral
protein infected cell protein (ICP) 27. Infection of macrophage cell
cultures with ICP27-defective virus resulted in enhanced production of
antiviral cytokines and an enhanced activation of NF-kappa-B and IRF3.
However, the study also showed that virus replication is essential for
cytokine expression and that viral ICP0 positively affects the expression
of cytokines, such as the chemokine RANTES. In
conclusion, viral gene products both enhance and restrict cytokine
production. The project contributes with new knowledge on the progress of
virus infections and may eventually contribute to better design of
treatments and vaccines.
PMID: 16442008 [PubMed - in process]
IL-2 increased RANTES production and CD25
expression in cultured PBMCs only from
antiretroviral treated HIV-1+ patients with detectable viral loads.
Lozano
JM, Kindelan JM, Cabello A, Gonzalez
R, Solana
R, Pena
J.
Department of Immunology, Hospital "Reina
Sofia", University of Cordoba, Spain; Department of Virology, Pasteur
Institute of Paris, France.
In order to better understand the possible beneficial effects of
intermittent IL-2 treatment as complement of antiretroviral therapy in
HIV-1+ patients, we have measured the levels of RANTES in the supernatants
and the CD25 expression in cultured PBMCs
obtained from HIV-1+ individuals in presence of IL-2. The results showed a
significant increases in RANTES production and in the expression of CD25+
in the cultures with IL-2 of PBMC obtained from HIV-1+ patients with a
detectable viral load in comparison with both, HIV-1+ patients with no
detectable viral loads and with healthy individuals. These results suggest
that therapeutic IL-2 administered in addition to highly active
anti-retroviral therapy (HAART) may contribute to increase the effect of
this therapy by rising both RANTES production and CD25 expression only in
HIV-1+ patients with detectable viral loads.
PMID: 16644491 [PubMed - in process]
Tumor-derived CD4(+)CD25
(+) regulatory T cell suppression of dendritic
cell function involves TGF-beta and IL-10.
Larmonier
N, Marron
M, Zeng
Y, Cantrell
J, Romanoski
A, Sepassi
M, Thompson
S, Chen
X, Andreansky
S, Katsanis
E.
Department of Pediatrics, Steele Children's Research Center, University of
Arizona, 1501 N. Campbell Ave., P.O. Box 245073, Tucson, AZ, 85724-5073,
USA, katsanis@peds.arizona.edu.
CD4(+)CD25(+) regulatory T cells have been characterized as a critical
population of immunosuppressive cells. They play a crucial role in cancer
progression by inhibiting the effector function
of CD4(+) or CD8(+) T lymphocytes. However,
whether regulatory T lymphocytes that expand during tumor progression can
modulate dendritic cell function is unclear. To
address this issue, we have evaluated the inhibitory potential of CD4(+)CD25(+) regulatory T cells from mice bearing a
BCR-ABL(+) leukemia on bone marrow-derived dendritic
cells. We present data demonstrating that CD4(+)CD25(+)FoxP3(+)
regulatory T cells from tumor-bearing animals impede dendritic
cell function by down-regulating the activation of the transcription factor
NF-kappaB. The expression of the co-stimulatory
molecules CD80, CD86 and CD40, the production of TNF-alpha, IL-12, and
CCL5/RANTES by the suppressed DC is strongly down-regulated. The
suppression mechanism requires TGF-beta and IL-10 and is associated with
induction of the Smad signaling pathway and
activation of the STAT3 transcription factor.
PMID: 16612596 [PubMed - as supplied by
publisher]
Rat peritoneal mast cells release
regulated upon activation normal T cell expressed and secreted (RANTES)
after TNF-alpha activation.
Kempuraj D, Petrarca C, Frydas S, Riccioni G, Conti
P, Tete S, Vecchiet J.
Pharmacology Department, Medical School, Tufts University, Boston, MA, USA.
Chemokines are a family consisting of at least
ten distinct novel 8-10 kD
cytokines. The cysteine-cysteine (C-C) chemokines are chemoattractant
and activators for monocytes, T cells and mast
cells. RANTES is the prototype of the C-C chemokine
subfamily, purified from different sources with chemoattractant
and activator properties. In this study we found that supernatants derived
from TNF-alpha (scalar concentrations)-activated rat peritoneal mast cell
cultures (5 x 10(5)/mL), incubated overnight,
produced high levels of RANTES. This data describes an additional mode of
generation of RANTES. Moreover, RANTES mRNA was not significantly produced
in untreated cells, while it was dramatically increased by calcium ionophore A23187, LPS and TNF-alpha compared with the
controls. These results underscore the importance of the presence of mast
cells for the production of RANTES in the inflammatory process and
contribute to an understanding of the mechanism by which RANTES profoundly
affects inflammatory responses in vivo.
PMID: 16602627 [PubMed - in process]
Interleukin 5, IL6, IL12, IFN-gamma, RANTES and Fractalkine in human nasal polyps, turbinate mucosa and
serum.
Danielsen A, Tynning T, Brokstad KA, Olofsson J, Davidsson A.
Department of Otorhinolaryngology,
Axess Medical Hospital, Oslo, Norway.
Polyps are considered to develop as an end result of an inflammatory
process. Cytokines and chemokines in the
respiratory mucosa may be a key to polyp pathophysiology.
The main objective was to identify IL-5, IL-6, IL-12, RANTES, IFN-gamma and
Fractalkine in humans on the protein level in
nasal polyps and mucosa from the inferior turbinate (IT). Furthermore, the
cytokines and chemokines RANTES and Fractalkine were analyzed in plasma. Tissue homogenates
and plasma from 13 patients were analyzed by the ELISA technique. All the
patients had longstanding nasal/paranasal polyposis. Fractalkine was
detected in polyps and IT in two different patients. IL-5 was expressed in
polyps and IT. IL-6 was expressed in all patients with a higher level in
polyps than IT. IL-12 was present in plasma, polyps and IT, though at an
increased level in polyps. RANTES was present at a higher level in plasma
than in polyps and IT. IFN-gamma was detectable in polyps and IT. Fractalkine is detected in nasal polyps, which is a new
observation. The overall results indicate a mixed T(H)1/T(H)2
cytokine profile in nasal polyps. RANTES and IL-12 are strongly present in
plasma, suggesting an ongoing inflammatory "drive". IL-6 and
IL-12 are up-regulated in polyps versus the IT. Up-regulation of IL-6 may
be explained by increased fibroblast activity dependant on an ongoing local
inflammation possibly initiated by an infection. IL-5, RANTES and IFN-gamma
are equally represented in polyps and IT, indicating equilibrium between
the nasal polyps and surrounding tissue, and that an up-regulation of
cytokines in the polyp indicates a potential for polyp growth.
Relation of p53, Bcl-2,
Ki-67 and E-cadherin expressions in early
invasive breast cancers with comedonecrosis (CN)
as an accelerated apoptosis.
Hosaka
N, Ryu
T, Cui W, Li Q, Nishida A,
Miyake T, Inaba
M, Ikehara
S.
Kansai Medical University, Japan.
AIMS: To study the relationship between comedonecrosis
(CN) formation and morphology, apoptosis, and p53, Bcl-2, Ki-67 index and E-cadherin expression in early invasive breast cancer.
Experimental design: We first divided early invasive breast cancers into
two groups according to the presence (CN+ tumors) or absence (CN- tumors)
of CN. Next, we examined the histological grade, apoptosis, and expressions
of E-cadherin, Ki-67, p53 and Bcl-2 in the cancer
area as well as in normal ducts (ND) from the specimen. RESULTS: CN+ tumors
showed less tubule and gland formation than CN- tumors, although the
histological grade was no different between the groups. Cells during early
CN undergo apoptosis and subsequent necrosis. Whereas p53 was higher in CN+
tumors than in CN- tumors and ND, Bcl-2 was lower in CN+ tumors than in CN-
tumors and ND. Ki-67 in both tumors were higher
than in ND, but there was no difference between the tumors. E-cadherin in CN+ tumors was slightly higher than in CN-
tumors, but lower than in ND. The level of CN was positively correlated
with p53, but inversely correlated with Bcl-2 in all tumors, and p53and
Bcl-2 were inversely correlated with each other.
Furthermore, CN and p53 were correlated with Ki-67 in CN+ tumors, and Bcl-2
was correlated with Ki-67 in CN- tumors. CONCLUSION: CN may be actively
regulated via an apoptotic procedure in massive cancers for their survival and
progression, and the above proteins may be involved cooperatively in this
process. CN+ and CN- tumors may have opposite proliferative
systems under the p53-Bcl-2 pathway.
PMID: 16473926 [PubMed - as supplied by
publisher]
Estrogen receptor-alpha binds p53 tumor
suppressor protein directly and represses its function.
Liu W, Konduri
SD, Bansal
S, Nayak
BK, Rajasekaran
SA, Karuppayil
SM, Rajasekaran
AK, Das
GM.
Pharmacology & Therapeutics, Roswell Park Cancer Institute, Buffalo, NY
14263.
Estrogen receptor-alpha (ERalpha) promotes cell
proliferation of breast cancer cells whereas tumor suppressor protein p53
impedes proliferation of cells with genomic damage. Whether there is a
direct link between these two antagonistic pathways has remained unclear.
Here we report that ERalpha binds directly to p53
and negatively regulates its function. The activation function-2 (AF-2)
domain of ERalpha and the C-terminal regulatory
domain of p53 are necessary for the interaction. Knocking down p53 and ERalpha by small interfering RNA (siRNA)
elicits opposite effects on p53-target gene expression and cell cycle
progression. Remarkably, ionizing radiation that causes genomic damage
disrupts the interaction between ERalpha and p53.
Ionizing radiation together with ERa knock down
results in an additive effect on transcription of endogenous p53-target
gene p21 (CDKN1) in human breast cancer cells. Our findings reveal a novel
mechanism for regulating p53 and suggest that suppressing p53 function is
an important component in the pro-proliferative
role of ERalpha.
PMID: 16469747 [PubMed - as supplied by
publisher]
Relation of p53, Bcl-2, Ki-67 and E-cadherin expressions in early invasive breast cancers
with comedonecrosis (CN) as an accelerated
apoptosis.
Hosaka
N, Ryu
T, Cui W, Li Q, Nishida A,
Miyake T, Inaba
M, Ikehara
S.
Kansai Medical University, Japan.
AIMS: To study the relationship between comedonecrosis
(CN) formation and morphology, apoptosis, and p53, Bcl-2, Ki-67 index and
E-cadherin expression in early invasive breast
cancer. Experimental design: We first divided early invasive breast cancers
into two groups according to the presence (CN+ tumors) or absence (CN-
tumors) of CN. Next, we examined the histological grade, apoptosis, and
expressions of E-cadherin, Ki-67, p53 and Bcl-2
in the cancer area as well as in normal ducts (ND) from the specimen.
RESULTS: CN+ tumors showed less tubule and gland formation than CN- tumors,
although the histological grade was no different between the groups. Cells
during early CN undergo apoptosis and subsequent necrosis. Whereas p53 was
higher in CN+ tumors than in CN- tumors and ND, Bcl-2 was lower in CN+
tumors than in CN- tumors and ND. Ki-67 in both tumors were
higher than in ND, but there was no difference between the tumors. E-cadherin in CN+ tumors was slightly higher than in CN-
tumors, but lower than in ND. The level of CN was positively correlated
with p53, but inversely correlated with Bcl-2 in all tumors, and p53and
Bcl-2 were inversely correlated with each other.
Furthermore, CN and p53 were correlated with Ki-67 in CN+ tumors, and Bcl-2
was correlated with Ki-67 in CN- tumors. CONCLUSION: CN may be actively regulated
via an apoptotic procedure in massive cancers for their survival and
progression, and the above proteins may be involved cooperatively in this
process. CN+ and CN- tumors may have opposite proliferative
systems under the p53-Bcl-2 pathway.
PMID: 16473926 [PubMed - as supplied by
publisher]
Hiv
