| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
B Activation in Tumor-Associated Macrophages1
*
Istituto di Ricerche Farmacologiche "Mario Negri," Milan, Italy;
Department of Biotechnology, University of Brescia, Brescia, Italy; and
Rega Institute for Medical Research, University of Leuven, Leuven, Belgium
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
B activation. TAM produced increased amounts of
the immunosuppressive cytokine IL-10. Abs against IL-10 restored the
defective capacity of TAM to produce IL-12. Our data suggest that
during tumor growth an IL-10-dependent pathway of diversion of
macrophage function can be activated into the tumor microenvironment
and results in the promotion of the IL-10+
IL-12- phenotype of TAM. Blocking IL-10, as well as other
immunosuppressive cytokines present in the tumor microenvironment, such
as TGF-
, may complement therapeutic strategies aimed at activating
type I antitumor immune responses. |
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Macrophages produce high amounts of IL-12, a proinflammatory and
immunoregulatory heterodimeric cytokine composed of two covalently
linked glycosylated chains of 
40 (p40) and 35 (p35) kDa
(13). IL-12 production by macrophages is induced upon cell
activation with a variety of stimuli, including a combination of
IFN-
and LPS (13). In addition to promoting cytokine
production, proliferation, and cytotoxic activity in NK and T cells,
IL-12 plays an essential role in driving differentiation of uncommitted
cells toward a type I CD4+ T helper phenotype
(Th1) and contributes to optimal IFN- production, thus being
critical for promotion of cell-mediated immunity (13). Due
to its biological properties, IL-12 represents an attractive agent for
anticancer therapy (13), and lack of its production may be
a serious impairment for effective antitumor responses. In this study,
we report that TAM have a drastically defective capacity to produce
IL-12 and define the alterations in transcription factors and cytokine
production which underlie this protumor phenotype. Defective IL-12
expression is due to autocrine production of IL-10 and is paralleled by
lack of NF-B activation. Commitment of macrophages to high
production of immunosuppressive cytokines may represent a powerful
strategy used by tumors to escape immune surveillance.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Peritoneal elicited macrophages (PEC) and TAM were incubated in
RPMI 1640 medium containing 10% FCS, 2 mM glutamine, and 100 U/ml
penicillin-streptomycin. For the different treatments (stated in the
text), we used the following concentrations: IFN-, 100 U/ml and LPS,
100 ng/ml.
Preparation of PEC and TAM
Male 8-wk-old C57 black mice were obtained from Charles River Breeding Laboratories (Calco, Italy). Mice were inoculated intramuscularly in the left hind limb with a total of 105 tumor cells. Tumor take was monitored and diameters of growing tumors were measured in centimeters twice a week by caliper. PEC and TAM were obtained 3 wk after tumor cell injection. TAM were isolated as described previously (14): briefly, solid tumors were disaggregated by exposure to 0.3% collagenase (Sigma, St. Louis, MO) for 40 min at 37°C; 150 x 106 cells in 20 ml of RPMI 1640 were seeded in 140-mm petri dishes (Cel Cult; Sterilin, Feltham, U.K.), and, after 2 h of incubation, nonadherent cells were vigorously washed. Adherent cells were >95% macrophages as assessed by morphologic and functional criteria. Contaminating cells were tumor cells, unidentified small mononuclear cells, and polymorphonuclear leukocytes. All culture reagents contained less than 0.125 endotoxin unit/ml as checked by Limulus amebocyte lysate assay (BioWhittaker, Walkersville, MD). Peritoneal exudate cells were obtained from mice injected 4 days previously with 1 ml of 3% thyoglicollate medium (Difco, Detroit, MI) as described previously (14). A total of 60 x 106 macrophages was seeded in 20 ml of RPMI 1640 (BioWhittaker) supplemented with 2 mM glutamine (Seromed, Munich, Germany) and 20 mM HEPES (Merck, Darmstadt, Germany) in 140-mm petri dishes (Cel Cult; Sterilin), and, after 1 h of incubation, nonadherent cells were thoroughly washed off with jets of medium. Monolayers were >95% macrophages as assessed by morphologic and functional criteria.
Cytokines and Abs
Murine recombinant IFN- was kindly donated by Dr. G. Garotta
(Hoffmann-LaRoche, Basilea, Switzerland). LPS (Escherichia
coli 055:B5) was purchased from Difco. Rat Abs to mouse IL-10
SXC.1 (15), HB10739, and rat Abs to mouse IL-10
JES5-2A5.11 (16), HB10958, were purchased from American
Type Culture Collection (Manassas, VA). Determination of murine IL-12
and murine IL-10 supernatants was conducted by using ELISA kits
purchased from Benfer-Sheller, Keystone Laboratories (Milan, Italy).
Northern blot analysis
Cells were cultured in medium alone or supplemented with the
indicated agents, and total RNA was purified as described
(17). Ten micrograms of total RNA from each sample was
electrophoresed under denaturing conditions, blotted onto Nytran
membranes (Schleicher & Schuell, Keene, NH), and cross-linked by UV
irradiation. Membranes were prehybridized at 42°C in Hybrisol (Oncor,
Gaithersburg, MD) and hybridized overnight with 1 x
106cpm/ml of 32P-labeled
probe. Membranes were then washed three times at room temperature for
10 min in 0.2x SSC [1x SSC: 0.15 M NaCl, and 0.015 M sodium citrate
(pH 7.0)], 0.1% SDS, and twice at 60°C for 20 min in 0.2x SSC and
0.1% SDS before being autoradiographed using Kodak XAR-5 films
(Eastman, Rochester, NY) and intensifier screens at -80°C. cDNAs
were labeled by random priming using a commercial kit (Boehringer
Mannheim, Indianapolis, IN) and
[
-32P]deoxycytidine 5'-triphosphate (3000
Ci/mmol; Amersham, Arlington Heights, IL).
EMSA analysis
For EMSA nuclear proteins were prepared as follows: the cellular
pellet was resuspended in 10–20 times its volume in buffer A (lysis
buffer): 50 mM KCl, 0.5% Nonidet P-40, 25 mM HEPES (pH 7.8), 1 mM
PMSF, 10 µg/ml leupeptin, 20 µg/ml aprotinin, and 100 µM DTT and
subsequently incubated for 5 min in ice. Cells were collected by
centrifugation at 2000 rpm, and the supernatant was decanted. The
nuclei were washed in buffer A without Nonidet P-40, collected at 2000
rpm, and resuspended 5 min in buffer B (extraction buffer): 500 mM KCl,
25 mM HEPES (pH 7.8), 10% glycerol, 1 mM PMSF, 10 µg/ml leupeptin,
20 µg/ml aprotinin, and 100 µM DTT for 5 min in ice. The samples
were subsequently frozen and thawed (twice) by dry ice and a 37°C
water bath, rotated 20 min at 4°C, and centrifuged at 14,000 rpm for
20 min. The clear supernatant was collected and the proteins were
dialyzed for 4 h against buffer C (dialysis buffer): 50 mM KCl, 25
mM HEPES (pH 7.8), 10% glycerol, 1 mM PMSF, 10 µg/ml leupeptin, 20
µg/ml aprotinin, and 100 µM DTT. The nuclear proteins were
incubated with radiolabeled DNA probes in a 20-µl reaction mixture
containing 20 mM Tris (pH 7.5), 60 mM KCl, 2 mM EDTA, 0.5 mM DTT, 1
µg of poly(dI-dC), and 4% Ficoll. Nucleoprotein complexes were
resolved by electrophoresis on 5% nondenaturing polyacrylamide gels in
0.5x Tris-borate-EDTA buffer at 12 V/cm for 2 h at room
temperature. Dried gels were exposed to Kodak XAR-5 film (Eastman) at
-70°C with intensifying screens. Oligonucleotides were purchased
from Life Technologies (Milan, Italy) and were end labeled using Klenow
enzyme and [-32P]deoxycytidine
5'-triphosphate; 1 ng of labeled DNA was used in a standard EMSA
reaction. The following antisera were used in supershift analysis:
1157, raised against the Rel homology domain containing residues
339–357of human p50 and also recognizing the murine p50
(18); 1226, raised against a peptide containing the
C-terminal 14 residues of human and murine p65 (18);
anti-PU.1 (SC-352X) was purchased from Santa Cruz
Biotechnology (Santa Cruz, CA). Double-strand oligonucleotide sequences
used in EMSA are also reported here: 5'- GGAGGGAGGAACTTCTTAAAATT-3'
region A IL-12 p40 (nt -148 to -125);
3'-CTCCCTCCTTGAAGAATTTTAAG-5'; 5'-GTTCCCCCAGAATGTTTT-3' region B
IL-12 p40 (nt -125 to -110); 3'- AAGGGGGTCTTACAAAAG-5'; 5'-
GATCCAGAGGGGACTTTCCGAGAGGC-3' HIV-1 B; and 3'-
GTCTCCCCTGAAAGGCTCTCCGCTAG-5'.
Densitometry
Densitometric analysis was performed with a scanning densitometer GS300 (Hoefer Scientific Instruments, San Francisco, CA).
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
We implanted s.c. the 3-methylcolanthrene (MCA)-derived
fibrosarcoma MN/MCA-1 in C57B1/6 mice (1). Three weeks
after tumor implant, TAM and PEC were obtained as described
(14) and cultured for 18 h in the presence or absence
of IFN- (100 U/ml) and LPS (100 ng/ml). Supernatants were collected
and assayed by ELISA for IL-12 production. As shown in Fig. 1
A, supernatants from normal
PEC (NPEC) and PEC from tumor-bearing mice (TPEC) contained high levels
of IL-12 (400 pg/ml). In contrast, IL-12 protein levels
were almost undetectable in supernatants from TAM.
|
B) were strongly induced in NPEC upon
cotreatment with IFN- (100 U/ml) and LPS (100 ng/ml) for 4 h,
its expression was slightly lower in TPEC and virtually absent in TAM.
Similar results were obtained when the IL-12 p35 mRNA levels
were analyzed (Fig. 1C).
Lack of IL-12 NF-B-binding activity in TAM
Transcriptional mechanisms leading to activation of the murine
IL-12 p40 promoter have been studied (19). The NF-B
half site located in the proximal IL-12 p40 promoter region (nt -148
to -125) was described to functionally interact with NF-B proteins
and identified as an essential regulatory element for transcriptional
activity of this promoter gene. To investigate the molecular mechanisms
responsible for the suppression of IL-12 expression, we
performed EMSA studies by using nuclear extracts from TAM and PEC from
both normal and tumor-bearing mice in the presence of a
32P-labeled oligonucleotide (nt -148 to -125)
containing the IL-12p40 NF-B half site (Fig. 2A). In resting cells, similar
levels of a predominant DNA/protein complex b were observed in the
presence of nuclear extracts from NPEC, TPEC, or TAM. Noteworthy, upon
IFN-/LPS cell activation, while formation of complex b did not
undergo significant variations, two inducible DNA/protein complexes (a1
and a2) were expressed at much higher levels in nuclear extracts from
NPEC and TPEC in comparison to TAM. To identify the protein components
of complexes a1 and a2, competition studies and supershift analysis
were performed (Fig. 2B) in the presence of nuclear extracts
from NPEC. Although cold competition with specific (Fig. 2B,
lane 6) and nonspecific (Fig. 2B, B and NS,
lanes 7 and 9) cold oligonucleotides verified the
specificity of this DNA/protein interaction, a cold oligonucleotide
containing the NF-B binding site of the HIV-long terminal repeat
(20) (Fig. 2B, lane 8) was able to
compete complex a1 and a2 formation, suggesting the presence of NF-B
members within these complexes. Supershift analysis with antisera
against the p50 (Fig. 2B, lane 2) and p65 (Fig. 2B, lane 3) NF-B proteins identified p50 as a
component of complex a2 and the p50/p65 NF-B heterodimer as
components of complex a1. The fact that anti-p50 Ab (antiserum1157)
did not supershift but rather competed the DNA/protein complex
formation of complexes a1 and a2 is due to the nature of this Ab which
was raised against the binding domain region of the p50 protein
(18), thus preventing its binding activity. A similar
DNA-binding pattern was obtained by using a
32P-labeled HIV-B oligonucleotide as probe
(Fig. 2C), suggesting that lack of interaction of NF-B
proteins with the IL-12 p40 NF-B site is not selective for this DNA
element, but is likely due to lack of expression of nuclear NF-B.
Thus, the identification of alteration in the molecular mechanisms
leading to NF-B activation may be important for the defective
expression of a number of NF-B-dependent genes involved in
inflammation and immunity, in addition to IL-12
(21).
|
IL-10 strongly inhibits IL-12 production by human and murine
monocytes/macrophages in response to activation by LPS
(22). We have therefore evaluated the IL-10 protein and
mRNA expression in TAM and PEC (Fig. 3).
Unlike NPEC and TPEC, unstimulated TAM expressed appreciable levels of
IL-10 protein (Fig. 3A) and mRNA (Fig. 3B)
comparable to those found in LPS-stimulated PEC. LPS-induced IL-10
expression and production (300 pg/ml) in TAM was much greater
(
12-fold) than in PEC. Interestingly, although IFN- (100 U/ml)
inhibited the LPS-induced IL-10 mRNA expression in PEC, TAM were
insensitive to this pathway of negative regulation (Fig. 3B). Because IL-10 inhibits NF-B activation and IL-12
production (13, 23), it was important to address whether
IL-10 production and defective IL-12 induction were causally related in
TAM. As shown in Fig. 3C, two blocking anti-IL-10 mAbs
completely restored the capacity of TAM to produce IL-12 to levels
similar to those of control cells.
|
A, similar to the
MN/MCA1 fibrosarcoma, TAM associated from the MS2, mFS6, and M4 tumors
were committed to high production of IL-10 and lack of
IL-12 p40 mRNAs expression. In partial contrast, TAM
associated with the B16 melanoma did not express either
IL-12 or IL-10, whereas TPEC B16 expressed lower
levels of IL-12 mRNA and significant levels of
IL-10 mRNA. Of interest, in contrast with sarcoma cells, B16
melanoma cells secreted high amounts of IL-10 (data not shown),
suggesting that melanoma-derived IL-10 may be responsible for defective
activation of macrophages associated with this tumor. Next, to
ascertain the possible relevance of this mechanism in human tumors, TAM
were isolated from solid tissue of human ovarian carcinoma (e.g., see
Refs. 1 and 6). Cells were cultured in vitro
for 24 h, and the supernatants were tested for IL-12 and IL-10.
Results show (Fig. 4B), in three separate experiments, IL-12
levels in supernatants from resting and stimulated TAM were very low
(undetectable and 5 ± 3 pg/ml, respectively). In contrast, TAM
constitutively secreted high amounts of IL-10 (37 ± 9 pg/ml)
further increased upon activation (95 ± 15 pg/ml). In contrast,
activated human monocytes secreted high levels of IL-12 (132 ± 35
pg/ml) and low levels of IL-10 (36 ± 8 pg/ml).
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
IL-10, which was first identified as a factor produced by Th2 cells,
inhibits cytokine production by Th1 cells (26) and
contributes to the inhibition of accessory function of macrophages and
dendritic cells (27). Along with TGF-, IL-10 is
spontaneously produced by a variety of tumors and is believed to play a
major role in the induction of immunosuppression during tumor growth
(28). IL-10-immunosuppressive activities may be at least
in part ascribed to its capability to inhibit NF-B activity
(23). NF-B plays a central role in the control of
inflammation and immunity (21) and represents an ideal
target for tumors to disrupt immune responses. In our experiments,
suppression of the NF-B-dependent IL-12 p40 gene
expression (19) correlated with lack of NF-B-binding
activity in nuclear extracts from TAM, whereas two different
anti-IL-10 mAbs fully restored IL-12 production. This molecular
pathway most likely underlies other alterations of TAM functions
dependent on NF-B activation, such as defective inducible NO
synthase activation (9, 21), and represents a severe
impairment for inflammatory and immune responses. In support of
this, IL-10 knockout mice demonstrated prolonged survival and
increased capacity to reject tumors as compared with control mice
(29).
Our data suggest that during tumor growth, an IL-10-dependent pathway
of diversion of macrophage function can be activated into the tumor
microenvironment. Although it remains to be determined which
tumor-dependent signals are involved in promoting the
IL-10+ IL-12- phenotype of
TAM, blocking IL-10, as well as other immunosuppressive cytokines
present in the tumor microenvironment, such as TGF-, may complement
therapeutic strategies aimed at activating type I antitumor immune
responses.
|
Acknowledgments |
|---|
. |
Footnotes |
|---|
2 Address correspondence and reprint requests to Dr. Antonio Sica, Istituto di Ricerche Farmacologiche "Mario Negri," via Eritrea 62, 20157 Milan, Italy. E-mail address:
3 Abbreviations used in this paper: TAM, tumor-associated macrophages; PEC, peritoneal-elicited macrophages; MCA, 3-methylcolanthrene; NPEC, normal PEC; TPEC, tumor-bearing PEC.
Received for publication June 7, 1999. Accepted for publication November 4, 1999.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
B p50 has IB-like functions. Cell 71:243.[Medline]
B half-site. Mol. Cell. Biol. 15:5258.[Abstract]
B) that activates transcription from a human immunodeficiency virus type 1 promoter in vivo. Proc. Natl. Acad. Sci. USA 85:4700.
B in the immune system. Annu. Rev. Immunol. 12:141.[Medline]
B (NF-B) activation in human monocytes: IL-10 and IL-4 suppress cytokine synthesis by different mechanisms. J. Biol. Chem. 270:9558.This article has been cited by other articles:
|
|
 |
|
  T. Hagemann, S. K. Biswas, T. Lawrence, A. Sica, and C. E. Lewis Regulation of macrophage function in tumors: the multifaceted role of NF-{kappa}B Blood, April 2, 2009; 113(14): 3139 - 3146. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Eriksson, P. Tsagozis, K. Lundberg, R. Parsa, S. M. Mangsbo, M. A. A. Persson, R. A. Harris, and P. Pisa Tumor-Specific Bacteriophages Induce Tumor Destruction through Activation of Tumor-Associated Macrophages J. Immunol., March 1, 2009; 182(5): 3105 - 3111. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. P. Edwards, X. Zhang, and D. M. Mosser The Expression of Heparin-Binding Epidermal Growth Factor-Like Growth Factor by Regulatory Macrophages J. Immunol., February 15, 2009; 182(4): 1929 - 1939. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. R. Sierra, S. Corso, L. Caione, V. Cepero, P. Conrotto, A. Cignetti, W. Piacibello, A. Kumanogoh, H. Kikutani, P. M. Comoglio, et al. Tumor angiogenesis and progression are enhanced by Sema4D produced by tumor-associated macrophages J. Exp. Med., July 7, 2008; 205(7): 1673 - 1685. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Guruvayoorappan Tumor Versus Tumor-Associated Macrophages: How Hot is the Link? Integr Cancer Ther, June 1, 2008; 7(2): 90 - 95. [Abstract] [PDF]
|
|
|
|
|
|
S. K. Biswas, A. Sica, and C. E. Lewis Plasticity of Macrophage Function during Tumor Progression: Regulation by Distinct Molecular Mechanisms J. Immunol., February 15, 2008; 180(4): 2011 - 2017. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. M. Tiemessen, A. L. Jagger, H. G. Evans, M. J. C. van Herwijnen, S. John, and L. S. Taams CD4+CD25+Foxp3+ regulatory T cells induce alternative activation of human monocytes/macrophages PNAS, December 4, 2007; 104(49): 19446 - 19451. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Zeni, L. Mazzetti, D. Miotto, N. Lo Cascio, P. Maestrelli, P. Querzoli, M. Pedriali, E. De Rosa, L. M. Fabbri, C. E. Mapp, et al. Macrophage expression of interleukin-10 is a prognostic factor in nonsmall cell lung cancer Eur. Respir. J., October 1, 2007; 30(4): 627 - 632. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Weigert, N. Tzieply, A. von Knethen, A. M. Johann, H. Schmidt, G. Geisslinger, and B. Brune Tumor Cell Apoptosis Polarizes Macrophages Role of Sphingosine-1-Phosphate Mol. Biol. Cell, October 1, 2007; 18(10): 3810 - 3819. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D.-M. Kuang, Y. Wu, N. Chen, J. Cheng, S.-M. Zhuang, and L. Zheng Tumor-derived hyaluronan induces formation of immunosuppressive macrophages through transient early activation of monocytes Blood, July 15, 2007; 110(2): 587 - 595. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. J. Fleetwood, T. Lawrence, J. A. Hamilton, and A. D. Cook Granulocyte-Macrophage Colony-Stimulating Factor (CSF) and Macrophage CSF-Dependent Macrophage Phenotypes Display Differences in Cytokine Profiles and Transcription Factor Activities: Implications for CSF Blockade in Inflammation J. Immunol., April 15, 2007; 178(8): 5245 - 5252. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Rafei, J. H. Wu, B. Annabi, L. Lejeune, M. Francois, and J. Galipeau A GMCSF and IL-15 fusokine leads to paradoxical immunosuppression in vivo via asymmetrical JAK/STAT signaling through the IL-15 receptor complex Blood, March 1, 2007; 109(5): 2234 - 2242. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Saccani, T. Schioppa, C. Porta, S. K. Biswas, M. Nebuloni, L. Vago, B. Bottazzi, M. P. Colombo, A. Mantovani, and A. Sica p50 Nuclear Factor-{kappa}B Overexpression in Tumor-Associated Macrophages Inhibits M1 Inflammatory Responses and Antitumor Resistance Cancer Res., December 1, 2006; 66(23): 11432 - 11440. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. K. Biswas, L. Gangi, S. Paul, T. Schioppa, A. Saccani, M. Sironi, B. Bottazzi, A. Doni, B. Vincenzo, F. Pasqualini, et al. A distinct and unique transcriptional program expressed by tumor-associated macrophages (defective NF-{kappa}B and enhanced IRF-3/STAT1 activation) Blood, March 1, 2006; 107(5): 2112 - 2122. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Torroella-Kouri, X. Ma, G. Perry, M. Ivanova, P. J. Cejas, J. L. Owen, V. Iragavarapu-Charyulu, and D. M. Lopez Diminished Expression of Transcription Factors Nuclear Factor {kappa}B and CCAAT/Enhancer Binding Protein Underlies a Novel Tumor Evasion Mechanism Affecting Macrophages of Mammary Tumor-Bearing Mice Cancer Res., November 15, 2005; 65(22): 10578 - 10584. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Schutyser, A. Richmond, and J. Van Damme Involvement of CC chemokine ligand 18 (CCL18) in normal and pathological processes J. Leukoc. Biol., July 1, 2005; 78(1): 14 - 26. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Liu, X. Bi, S. Xu, and J. Xiang Tumor-Infiltrating Dendritic Cell Subsets of Progressive or Regressive Tumors Induce Suppressive or Protective Immune Responses Cancer Res., June 1, 2005; 65(11): 4955 - 4962. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Cao, J. Liu, L. Song, and X. Ma The Protooncogene c-Maf Is an Essential Transcription Factor for IL-10 Gene Expression in Macrophages J. Immunol., March 15, 2005; 174(6): 3484 - 3492. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. A. Ogden, J. D. Pound, B. K. Batth, S. Owens, I. Johannessen, K. Wood, and C. D. Gregory Enhanced Apoptotic Cell Clearance Capacity and B Cell Survival Factor Production by IL-10-Activated Macrophages: Implications for Burkitt's Lymphoma J. Immunol., March 1, 2005; 174(5): 3015 - 3023. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. del Fresno, K. Otero, L. Gomez-Garcia, M. C. Gonzalez-Leon, L. Soler-Ranger, P. Fuentes-Prior, P. Escoll, R. Baos, L. Caveda, F. Garcia, et al. Tumor Cells Deactivate Human Monocytes by Up-Regulating IL-1 Receptor Associated Kinase-M Expression via CD44 and TLR4 J. Immunol., March 1, 2005; 174(5): 3032 - 3040. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C.-R. Yang, S.-L. Hsieh, F.-M. Ho, and W.-W. Lin Decoy Receptor 3 Increases Monocyte Adhesion to Endothelial Cells via NF-{kappa}B-Dependent Up-Regulation of Intercellular Adhesion Molecule-1, VCAM-1, and IL-8 Expression J. Immunol., February 1, 2005; 174(3): 1647 - 1656. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Bhattacharyya, P. Sen, M. Wallet, B. Long, A. S. Baldwin Jr, and R. Tisch Immunoregulation of dendritic cells by IL-10 is mediated through suppression of the PI3K/Akt pathway and of I{kappa}B kinase activity Blood, August 15, 2004; 104(4): 1100 - 1109. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Mitsuhashi, J. Liu, S. Cao, X. Shi, and X. Ma Regulation of interleukin-12 gene expression and its anti-tumor activities by prostaglandin E2 derived from mammary carcinomas J. Leukoc. Biol., August 1, 2004; 76(2): 322 - 332. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Mytar, M. Woloszyn, R. Szatanek, M. Baj-Krzyworzeka, M. Siedlar, I. Ruggiero, J. Wieckiewicz, and M. Zembala Tumor cell-induced deactivation of human monocytes J. Leukoc. Biol., December 1, 2003; 74(6): 1094 - 1101. [Abstract] [Full Text]
|
|
|
|
|
|
J. Yang, S. M. Bernier, T. E. Ichim, M. Li, X. Xia, D. Zhou, X. Huang, G. H. Strejan, D. J. White, R. Zhong, et al. LF15-0195 generates tolerogenic dendritic cells by suppression of NF-{kappa}B signaling through inhibition of IKK activity J. Leukoc. Biol., September 1, 2003; 74(3): 438 - 447. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Berrebi, S. Bruscoli, N. Cohen, A. Foussat, G. Migliorati, L. Bouchet-Delbos, M.-C. Maillot, A. Portier, J. Couderc, P. Galanaud, et al. Synthesis of glucocorticoid-induced leucine zipper (GILZ) by macrophages: an anti-inflammatory and immunosuppressive mechanism shared by glucocorticoids and IL-10 Blood, January 15, 2003; 101(2): 729 - 738. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. P. Vicari, C. Chiodoni, C. Vaure, S. Ait-Yahia, C. Dercamp, F. Matsos, O. Reynard, C. Taverne, P. Merle, M. P. Colombo, et al. Reversal of Tumor-induced Dendritic Cell Paralysis by CpG Immunostimulatory Oligonucleotide and Anti-Interleukin 10 Receptor Antibody J. Exp. Med., August 19, 2002; 196(4): 541 - 549. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Mazzoni, V. Bronte, A. Visintin, J. H. Spitzer, E. Apolloni, P. Serafini, P. Zanovello, and D. M. Segal Myeloid Suppressor Lines Inhibit T Cell Responses by an NO-Dependent Mechanism J. Immunol., January 15, 2002; 168(2): 689 - 695. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Ibe, Z. Qin, T. Schuler, S. Preiss, and T. Blankenstein Tumor Rejection by Disturbing Tumor Stroma Cell Interactions J. Exp. Med., November 26, 2001; 194(11): 1549 - 1560. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Yamada, S. Mizuno, M. Reza-Gholizadeh, and I. Sugawara Relative Importance of NF-kappa B p50 in Mycobacterial Infection Infect. Immun., November 1, 2001; 69(11): 7100 - 7105. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Corinti, C. Albanesi, A. la Sala, S. Pastore, and G. Girolomoni Regulatory Activity of Autocrine IL-10 on Dendritic Cell Functions J. Immunol., April 1, 2001; 166(7): 4312 - 4318. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Connelly, M. Palacios-Callender, C. Ameixa, S. Moncada, and A. J. Hobbs Biphasic Regulation of NF-{{kappa}}B Activity Underlies the Pro- and Anti-Inflammatory Actions of Nitric Oxide J. Immunol., March 15, 2001; 166(6): 3873 - 3881. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Mantovani, P. A. Gray, J. Van Damme, and S. Sozzani Macrophage-derived chemokine (MDC) J. Leukoc. Biol., September 1, 2000; 68(3): 400 - 404. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
