HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Butcher, B. A. Articles by Denkers, E. Y. Search for Related Content PubMed PubMed Citation Articles by Butcher, B. A. Articles by Denkers, E. Y. Pubmed/NCBI databases Gene GEO Profiles HomoloGene UniGene Compound via MeSH Substance via MeSH

Cutting Edge: IL-10-Independent STAT3 Activation by Toxoplasma gondii Mediates Suppression of IL-12 and TNF- in Host Macrophages¹

Barbara A. Butcher^2,*, Leesun Kim^*, Athanasia D. Panopoulos, Stephanie S. Watowich, Peter J. Murray and Eric Y. Denkers^*

^* Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, Department of Immunology; University of Texas M. D. Anderson Cancer Center, Houston, TX 77030; and Department of Infectious Diseases, St. Jude Children’s Research Hospital, Memphis, TN 38105

	Abstract

Top Abstract Introduction Materials and Methods Results Discussion Disclosures References

 
Infection of mouse macrophages by Toxoplasma gondii renders the cells resistant to proinflammatory effects of LPS triggering. In this study, we show that cell invasion is accompanied by rapid and sustained activation of host STAT3. Activation of STAT3 did not occur with soluble T. gondii extracts or heat-killed tachyzoites, demonstrating a requirement for live parasites. Parasite-induced STAT3 phosphorylation and suppression of LPS-triggered TNF- and IL-12 was intact in IL-10-deficient macrophages, ruling out a role for this anti-inflammatory cytokine in the suppressive effects of T. gondii. Most importantly, Toxoplasma could not effectively suppress LPS-triggered TNF- and IL-12 synthesis in STAT3-deficient macrophages. These results demonstrate that T. gondii exploits host STAT3 to prevent LPS-triggered IL-12 and TNF- production, revealing for the first time a molecular mechanism underlying the parasite’s suppressive effect on macrophage proinflammatory cytokine production.

	Introduction

Top Abstract Introduction Materials and Methods Results Discussion Disclosures References

 
The intracellular protozoan Toxoplasma gondii displays potent down-regulatory effects on IL-12, TNF-, and NO production by infected macrophages (M)³ (1, 2). Subversion of M function likely reflects the need to avoid immunopathology during in vivo infection (3). Although IL-12 release eventually occurs in infected M, production of TNF- remains suppressed (4). Toxoplasma also disrupts intracellular signaling cascades including NF-B/Rel, STAT1, and MAPK transduction pathways that are important in proinflammatory cytokine induction, although for each a molecular mechanism has yet to be defined (1, 5, 6, 7). Furthermore, a link between disabled activation of signaling cascades and suppressed cytokine production during Toxoplasma infection has not been definitively established.

In light of observations that IL-10 and Toxoplasma in parallel mediate suppression of M IL-12 and TNF- production (1, 8), we tested the hypothesis that the parasite exploits an IL-10 signaling pathway to subvert proinflammatory cytokine production. The IL-10 transduction cascade is initiated by cytokine-mediated IL-10R ligation that triggers JAK1 activation and recruitment of STAT3 (9). JAK1 phosphorylates STAT3 on Tyr⁷⁰⁵ and phosphorylated STAT3 forms dimers that translocate to the nucleus. The dimer is then activated for optimal transcriptional regulation by serine phosphorylation of each monomer (10). STAT3 is essential for the immunosuppressive activity of IL-10 (11, 12, 13). Mice lacking STAT3 display an embryonic lethal phenotype, and targeted deletion of STAT3 in M and neutrophils condemns mice to chronic enterocolitis characterized by uncontrolled proinflammatory cytokine production (12).

In this study, we show that M infection by T. gondii induces rapid and sustained STAT3 phosphorylation, independently of host IL-10. We further demonstrate that STAT3 is crucial for effective tachyzoite-mediated suppression of endotoxin-induced IL-12 and TNF- responses. These results define a molecular mechanism underlying the parasite’s ability to sabotage M proinflammatory cytokine production.

	Materials and Methods

Top Abstract Introduction Materials and Methods Results Discussion Disclosures References

 
Mice

Female C57BL/6 mice, 6–8 wk of age, were purchased from Taconic Farms and housed under specific pathogen-free conditions in the Cornell University College of Veterinary Medicine animal facility.

The lysM/cre STAT3-deficient mice that lack neutrophil and M STAT3 expression were generated as described (11, 12). Mice that lack STAT3 expression in the bone marrow were derived by breeding STAT3^flox/flox mice with a transgenic strain that expresses cre recombinase in hemopoietic and endothelial precursors (TIE2/cre mice) (14, 15). Age- and gender-matched littermates containing the wild-type (WT) STAT3 allele were used as controls. Bone marrow was collected from mice at 4.0–4.5 wk of age.

Parasites

RH88 tachyzoites were maintained as described (1) and tested every 4–6 wk for Mycoplasma contamination using a commercial PCR-ELISA kit (Roche Applied Science). Soluble tachyzoite Ag (STAg) was prepared as described (16).

Bone marrow-derived M preparation

M were derived from bone marrow by 5-day culture in L929-containing supernatants as previously described (7).

Cell culture

Tachyzoites were added to cell cultures (3:1 ratio, parasites:M) unless otherwise indicated in text. Plates were briefly centrifuged to synchronize tachyzoites and M contact. For endotoxin triggering studies, LPS (100 ng/ml; Salmonella minnesota, ultrapure; List Biologicals) was added 60 min after infection, and cells were collected at times indicated for analysis. In some experiments, blocking anti-IL-10R or isotype control Ab (kindly provided by D. Sacks, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, MD) was included. Cytokine ELISAs were performed on supernatants collected 6 h after LPS addition.

Cytokine ELISA

IL-12(p40) was measured by ELISA as described (1) and TNF- was measured using a commercial kit according to the manufacturer’s instructions (R&D Systems).

Immunoblot analysis

Cells (2 x 10⁶/sample) were lysed in reducing SDS sample buffer and immunoblot analysis was performed as described (7).

Immunofluorescence microscopy

Coverslips bearing infected M monolayers were fixed and permeabilized with ice-cold methanol and incubated (1 h, room temperature) with anti-STAT3 Ab (Cell Signaling Technologies) and FITC-tagged anti-p30 (Argene) to detect intracellular parasites. Anti-STAT3 Ab was detected with Alexa Fluor 594 secondary Ab (Molecular Probes).

Cytoplasmic and nuclear extracts

Cytoplasmic and nuclear extracts from 10⁷ M were prepared using the NE-PER extraction kit (Pierce) according to the manufacturer’s protocol.

	Results

Top Abstract Introduction Materials and Methods Results Discussion Disclosures References

 
T. gondii infection induces rapid M STAT3 phosphorylation

Bone marrow-derived M were infected with RH strain tachyzoites and STAT3 activation was assessed relative to that induced by LPS. Fig. 1A shows that Toxoplasma induces strong STAT3 Tyr⁷⁰⁵ phosphorylation as early as 2 min after addition of parasites and that phosphorylation of the transcription factor is sustained for at least 22 h. Importantly, the response was distinct from LPS-induced STAT3 phosphorylation, inasmuch as the latter occurred only after 2 h, and activation decreased after 6 h. We compared STAT3 Tyr⁷⁰⁵ phosphorylation mediated by STAg and heat-killed parasites relative to infection with live parasites. As shown in Fig. 1B, while live parasite infection induced strong STAT3 phosphorylation, neither STAg nor heat-killed parasites activated this signaling intermediate. We also found that STAT3 underwent subsequent Ser⁷²⁷ phosphorylation, an event occurring after nuclear translocation that is required for full transcriptional activity (Fig. 1C).

View larger version (61K): [in this window] [in a new window]   FIGURE 1. Tachyzoites induce rapid M STAT3 phosphorylation. A, M were infected with T. gondii tachyzoites (Tg) (3:1, Tg:M) or LPS (100 ng/ml). Cells were lysed at the indicated times with SDS-PAGE reducing buffer for Western blot analysis of phospho-Tyr705-STAT3 and total STAT3. B, M were infected with live T. gondii (Tg), incubated with the same number of heat-killed (HK) tachyzoites, or incubated with STAg (25 µg/ml). Lysates were prepared at the indicated minute postinfection and analyzed for phospho-Tyr705-STAT3 and total STAT3 expression. C, Lysates from infected M were assessed for phospho-Ser727 and total STAT3 at the indicated minute after infection. M, Cells in medium alone. These experiments were repeated three times with similar results.

View larger version (45K): [in this window] [in a new window]   FIGURE 2. Toxoplasma infection induces appearance of phospho-STAT3 in infected cell nuclei. A, M were infected and collected at the indicated time points. Cytoplasmic (C) and nuclear (N) extracts prepared for immunoblot analysis of phospho-Tyr705-STAT3. M, Cells in medium alone. B, A total of 60 min after infection, cells were stained with Ab specific for tachyzoites (green) and phospho-STAT3 (red). Nuclei were counterstained with DAPI (blue). Activated nuclear STAT3 is revealed by pink-staining nuclei (superimposition of blue and red). White arrow, Infected cell; yellow arrow, uninfected cell. These experiments were repeated twice with the same result.

Both IL-10 and IL-6 are potent STAT3 activators, although whereas IL-10-mediated STAT3 has an anti-inflammatory effect, IL-6 has a suppressor of cytokine signaling (SOCS)-3 dependent proinflammatory outcome (17, 18, 19). To address the role of these cytokines in Toxoplasma anti-inflammatory effects, we determined whether parasite-induced STAT3 phosphorylation and cytokine inhibition was dependent upon autocrine activity of these cytokines using M from IL-10 and IL-6 knockout (KO) mice. As shown in Fig. 3A, lack of either cytokine had no effect on tachyzoite-induced STAT3 phosphorylation. To determine whether parasite-mediated suppression of LPS-induced cytokine release was independent of endogenous IL-10 and IL-6, we preinfected gene-deleted and WT M then subjected the cells to LPS stimulation. As shown in Fig. 3B, the parasite was able to suppress both IL-12 and TNF- production in the absence of these cytokines. The combined data show that STAT3 activation is not due to autocrine IL-10 or IL-6, and that parasite-mediated cytokine suppression occurs independently of these cytokines.

View larger version (40K): [in this window] [in a new window]   FIGURE 3. Neither IL-10 nor IL-6 are involved in Toxoplasma-induced M cytokine suppression or STAT3 activation. A, WT, IL-10 KO, and IL-6 KO M were infected with T. gondii (3:1, Tg:M) or WT and IL-10 KO M were treated with rIL-10 (100 u/ml), and phospho-Tyr705-STAT3 and total STAT3 was assessed by immunoblot analysis at the indicated minute postinfection. B, M from WT, IL-10 KO and IL-6 KO mice were infected with tachyzoites at the ratios indicated, 60 min later LPS (100 ng/ml) was added, then 6 h later supernatants were harvested for cytokine ELISA. These experiments were repeated twice with the same results.

View larger version (58K): [in this window] [in a new window]   FIGURE 4. Ab blocking of the IL-10R does not prevent Toxoplasma-induced STAT3 activation. WT or IL-10 KO M were preincubated with medium alone, anti-IL-10R blocking Ab, or an isotype control before addition of parasites (Tg) or IL-10. After 1-h incubation, lysates were subjected to Western blotting and detection of phospho-Tyr705-STAT3 and total STAT3. These experiments were repeated twice with similar results.

Because STAT3 deletion yields an embryonic lethal phenotype in mice, we used bone marrow-derived M from both lysM/cre and TIE2/cre generated mutant animals that exhibit myeloid lineage-specific or hemopoietic and endothelial precursor-specific STAT3 deletion, respectively. To confirm STAT3 deletion in individual mice, we infected M and performed Western blot analysis for both total and phospho-STAT3. As shown in Fig. 5A, three lysM/cre putative KOs (1.2, 1.4, and 1.7) displayed significantly less total STAT3 than their transgenic control counterparts (1.8, 2.2, and 2.3). More significantly, phosphorylation of residual STAT3 in the conditional mutants was greatly diminished. Fig. 5A also shows Western blot analysis of two STAT3-deficient (S1 and S2) mice generated by TIE2/cre targeting and two nondeleted littermates (W1 and W2). STAT3-positive and STAT3-deleted M were next infected with Toxoplasma followed by LPS stimulation, and supernatants were harvested 6 h later for cytokine ELISA. Fig. 5B shows a dramatic alleviation in T. gondii-mediated IL-12 and TNF- suppression in each of the gene-deleted animals. In the absence of functional STAT3, tachyzoites cannot mediate effective suppression of either TNF- or IL-12. We conclude that Toxoplasma-triggered STAT3 activation plays a major role in the immunosuppressive effects of the parasite on LPS-induced cytokine production.

View larger version (31K): [in this window] [in a new window]   FIGURE 5. STAT3 mediates T. gondii-induced suppression of LPS-triggered M cytokine synthesis. A, M from STAT3-sufficient (1.8, 2.2, 2.3, W1, W2) and STAT3-deficient (1.2, 1.4, 1.7, S1, S2) mice were infected with Toxoplasma, and 60 min later, total and phospho-Tyr705-STAT3 and total STAT3 expression were analyzed by immunoblot analysis. Each lane represents a single mouse. B, The same populations of M shown in A were subjected to LPS triggering 60 min after infection, then 6 h later supernatants were collected for IL-12(p40) and TNF- ELISA. The results show parasite dose-response curves for cells from individual STAT3-positive and STAT3-negative mice. The graph depicts percent of the cytokine response relative to the same cell population stimulated with LPS in the absence of T. gondii (defined as 100% response). These experiments were repeated twice with virtually identical results.

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion Disclosures References

We do not yet know how T. gondii activates STAT3. The ability of the parasite to induce STAT3 phosphorylation in the presence of blocking anti-IL-10R Ab argues against triggering through this receptor. The IL-10R complex itself induces STAT3 phosphorylation by mediating activation of Jak1 and Tyk2, and it is possible that Toxoplasma triggers activation of these intermediates. The tyrosine kinase c-src also possesses STAT3-activating capability and therefore is also a candidate for parasite-triggered STAT3 phosphorylation (21, 22). Alternatively, we do not discount the possibility that cell invasion by Toxoplasma, during which parasite apical organelles are discharged and a unique parasitophorous vacuole is formed (23, 24, 25), provides a signal for direct STAT3 phosphorylation in the absence of upstream host kinase activation.

How IL-10-triggered STAT3 activation mediates anti-inflammatory effects is currently not clear, although de novo protein synthesis is known to be required (26). The SOCS-3 gene is a target for STAT3, and it has been suggested that SOCS-3 is an essential component of anti-inflammatory signaling (17). More recent evidence demonstrates that the effects of IL-10 are independent of this suppressor molecule, and suggest instead that STAT3/SOCS-3 signaling is more important in modulation of IL-6 activity (18, 19, 27).

Other studies suggest that STAT3 may interfere with the NF-B signaling pathway, either by stabilizing cytoplasmic IB-, thereby preventing NF-B nuclear translocation (28), or by blocking the activity of IB kinase whose enzymatic activity is required for IB- activation (29). We, and others, have found transient inhibition of NF-B signaling in infected cells, but nonetheless the pathway leading to IB- phosphorylation, ubiquitination, and degradation is intact (1, 5). The latter argues for parasite-mediated manipulation of NF-B nuclear import per se rather than STAT3-dependent blockade in IB- degradation. Interference with NF-B nuclear translocation also appears to be a transient phenomenon (4, 7), in contrast to parasite-mediated STAT3 phosphorylation that is stable for up to 22 h postinfection (Fig. 1).

Our data show involvement of STAT3 in T. gondii-induced suppression of LPS-triggered cytokine responses. Nevertheless, low level parasite-induced IL-12 synthesis was not affected by STAT3 deletion, and the parasite failed to induce TNF- in the presence or absence of STAT3 (data not shown). These findings suggest that parasite-induced STAT3 activation may not affect pathways of cytokine production triggered by the parasite itself.

In addition to preventing production of LPS-induced IL-12 and TNF-, Toxoplasma has recently been reported to manipulate other host responses. These include blocks in LPS-induced MAPK signaling and IFN--induced STAT1 nuclear translocation in mouse M (6, 7). In mouse dendritic cells, infection inhibits proinflammatory cytokine production and expression of costimulatory molecules (30). It has also been found that T. gondii infection renders cells resistant to inducers of apoptosis (31, 32). Whether some, or all, of these effects are mediated through STAT3 has yet to be determined.

	Disclosures

Top Abstract Introduction Materials and Methods Results Discussion Disclosures References

 
The authors have no financial conflict of interest.

	Acknowledgments

 
We thank Dr. D. Sacks for advice and the gift of anti-IL-10R Ab, Dr. A. Sher for valuable discussion and critical review of the manuscript, and R. Rutschman for breeding the STAT3^flox/flox, lysM/cre mice used in this study.

	Footnotes

 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institute of Allergy and Infectious Diseases Grants AI50617 (to E.Y.D.) and AI062921 (to P.J.M.), and American Heart Association, Texas Affiliate 0455143 (to S.S.W.).

² Address correspondence and reprint requests to Dr. Barbara A. Butcher, Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853. E-mail address: bab26{at}cornell.edu

³ Abbreviations used in this paper: M, macrophage; KO, knockout; STAg, soluble tachyzoite Ag; SOCS, suppressor of cytokine signaling; WT, wild type.

Received for publication December 13, 2004. Accepted for publication January 21, 2005.

	References

Top Abstract Introduction Materials and Methods Results Discussion Disclosures References

 

1. Butcher, B. A., L. Kim, P. F. Johnson, E. Y. Denkers. 2001. Toxoplasma gondii tachyzoites inhibit proinflammatory cytokine induction in infected macrophages by preventing nuclear translocation of the transcription factor NFB. J. Immunol. 167:2193.[Abstract/Free Full Text]
2. Luder, C. G. K., M. Algner, C. Lang, N. Bleicher, U. Gross. 2003. Reduced expression of the inducible nitric oxide synthase after infection with Toxoplasma gondii facilitates parasite replication in activated murine macrophages. Int. J. Parasitol. 33:833.[Medline]
3. Denkers, E. Y., L. Kim, B. A. Butcher. 2003. In the belly of the beast: subversion of macrophage proinflammatory signaling cascades during Toxoplasma gondii infection. Cell. Microbiol. 5:75.[Medline]
4. Butcher, B. A., E. Y. Denkers. 2002. Mechanism of entry determines ability of Toxoplasma gondii to inhibit macrophage proinflammatory cytokine production. Infect. Immun. 70:5216.[Abstract/Free Full Text]
5. Shapira, S. S., K. Speirs, A. Gerstein, J. Caamano, C. A. Hunter. 2002. Suppression of NF-B activation by infection with Toxoplasma gondii. J. Infect. Dis. 185:S66.
6. Luder, C. G. K., W. Walter, B. Beuerle, M. J. Maeurer, U. Gross. 2001. Toxoplasma gondii down-regulates MHC class II gene expression and antigen presentation by murine macrophages via interference with nuclear translocation of STAT1. Eur. J. Immunol. 31:1475.[Medline]
7. Kim, L., B. A. Butcher, E. Y. Denkers. 2004. Toxoplasma gondii interferes with lipopolysaccharide-induced mitogen-activated protein kinase activation by mechanisms distinct from endotoxin tolerance. J. Immunol. 172:3003.[Abstract/Free Full Text]
8. Donnelly, R. P., H. Dickensheets, D. S. Finbloom. 1999. The interleukin-10 signal transduction pathway and regulation of gene expression in mononuclear phagocytes. J. Interferon Cytokine Res. 19:563.[Medline]
9. Moore, K. A., R. de Waal Malefyt, R. L. Coffman, A. O’Garra. 2001. Interleukin-10 and the interleukin-10 receptor. Annu. Rev. Immunol. 19:683.[Medline]
10. Shen, Y., K. Schlessinger, X. Zhu, E. Meffre, F. Quimby, D. E. Levy, J. E. Darnell. 2004. Essential role of STAT3 in postnatal survival and growth revealed by mice lacking STAT3 serine 727 phosphorylation. Mol. Cell. Biol. 24:407.[Abstract/Free Full Text]
11. Lang, R., D. Patel, J. J. Morris, R. L. Rutschman, P. J. Murray. 2002. Shaping gene expression in activated and resting primary macrophages by IL-10. J. Immunol. 169:2253.[Abstract/Free Full Text]
12. Takeda, K., B. E. Clausen, T. Kaisho, T. Tsujimura, N. Terada, I. Forster, S. Akira. 1999. Enhanced Th1 activity and development of chronic enterocolitis in mice devoid of stat3 in macrophages and neutrophils. Immunity 10:39.[Medline]
13. Williams, L., L. Bradley, A. Smith, B. Foxwell. 2004. Signal transducer and activator of transcription 3 is the dominant mediator of the anti-inflammatory effects of IL-10 in human macrophages. J. Immunol. 172:567.[Abstract/Free Full Text]
14. Koni, P. A., S. K. Joshi, U.-A. Temann, D. Olson, L. Burkly, R. A. Flavell. 2001. Conditional vascular cell adhesion molecule 1 deletion in mice: impaired lymphocyte migration to bone marrow. J. Exp. Med. 193:741.[Abstract/Free Full Text]
15. Takeda, K., T. Kaisho, N. Yoshida, J. Takeda, T. Kishimoto, S. Akira. 1998. Stat3 activation is responsible for IL-6-dependent T cell proliferation through preventing apoptosis: generation and characterization of T cell-specific Stat3-deficient mice. J. Immunol. 161:4652.[Abstract/Free Full Text]
16. Del Rio, L., B. A. Butcher, S. Bennouna, S. Hieny, A. Sher, E. Y. Denkers. 2004. Toxoplasma gondii triggers MyD88-dependent and CCL2(MCP-1) responses using distinct parasite molecules and host receptors. J. Immunol. 172:6954.[Abstract/Free Full Text]
17. Berlato, C., M. A. Cassatella, I. Kinjyo, L. Gatto, A. Yoshimura, F. Bazzoni. 2002. Involvement of suppressor of cytokine synthesis signaling-3 as a mediator of the inhibitory effects of IL-10 on lipopolysaccharide-induced macrophage activation. J. Immunol. 168:6404.[Abstract/Free Full Text]
18. Croker, B. A., D. L. Krebs, J.-G. Zhang, S. Wormald, T. A. Willson, E. G. Stanley, L. Robb, C. J. Greenhalgh, I. Forster, B. E. Clausen, et al 2003. SOCS3 negatively regulates IL-6 signaling in vivo. Nat. Immunol. 4:540.[Medline]
19. Lang, R., A.-L. Pauleau, E. Parganas, Y. Takahashi, J. Mages, J. N. Ihle, R. Rutschman, P. J. Murray. 2003. SOCS regulates the plasticity of gp130 signaling. Nat. Immunol. 4:546.[Medline]
20. Petska, S., C. D. Krause, D. Sarkar, M. R. Walter, Y. Shi, P. B. Fisher. 2004. Interleukin-10 and related cytokines and receptors. Annu. Rev. Immunol. 22:929.[Medline]
21. Cirri, P., P. Chiarugi, F. Marra, G. Raugei, G. Camichi, G. Manao, G. Ramponi. 1997. c-Src activates both STAT1 and STAT3 in PDGF-stimulated NIH3T3 cells. Biochem. Biophys. Res. Commmun. 239:493.[Medline]
22. Yu, C. L., D. J. Meyer, G. S. Campbell, A. C. Larner, C. Carter-Su, J. Schwartz, R. Jove. 1995. Enhanced DNA-binding activity of a Stat3-related protein in cells transformed by the Src oncoprotein. Science 269:81.[Abstract/Free Full Text]
23. Ma, X., J. M. Chow, G. Gri, G. Carra, F. Gerosa, S. F. Wolf, R. Dzialo, G. Trinchieri. 1996. The interleukin-12 p40 promoter is primed by interferon- in monocytic cells. J. Exp. Med. 183:147.[Abstract/Free Full Text]
24. Mordue, D. G., L. D. Sibley. 1997. Intracellular fate of vacuoles containing Toxoplasma gondii is determined at the time of formation and depends upon the mechanism of entry. J. Immunol. 159:4452.[Abstract]
25. Carruthers, V. B., L. D. Sibley. 1997. Sequential protein secretion from three distinct organelles of Toxoplasma gondii accompanies invasion of human fibroblasts. Eur. J. Cell Biol. 73:114.[Medline]
26. Aste-Amezaga, M., X. Ma, A. Sartori, G. Trinchieri. 1998. Molecular mechanisms of the induction of IL-12 and its inhibition by IL-10. J. Immunol. 160:5936.[Abstract/Free Full Text]
27. Yasukawa, H., M. Ohishi, H. Mori, M. Murakami, T. Chinen, D. Aki, T. Hanada, K. Takeda, S. Akira, M. Hoshijima, et al 2003. IL-6 induces an anti-inflammatory response in the absence of SOCS3 in macrophages. Nat. Immunol. 4:551.[Medline]
28. Shames, B. D., C. H. Selzman, D. R. Meldrum, E. J. Pulido, H. A. Barton, X. Meng, A. H. Harken, R. C. McIntyre. 1998. Interleukin-10 stabilizes inhibitory B- in human monocytes. Shock 10:389.[Medline]
29. Schottelius, A. J., M. W. Mayo, R. B. Sartor, A. S. Baldwin. 1999. Interleukin-10 signaling blocks inhibitor of B kinase activity and nuclear factor B DNA binding. J. Biol. Chem. 274:31868.[Abstract/Free Full Text]
30. McKee, A. S., F. Dzierszinski, M. Boes, D. S. Roos, E. J. Pearce. 2004. Functional inactivation of immature dendritic cells by the intracellular protozoan Toxoplasma gondii. J. Immunol. 173:2632.[Abstract/Free Full Text]
31. Goebel, S., U. Gross, C. G. K. Luder. 2001. Inhibition of host cell apoptosis by Toxoplasma gondii is accompanied by reduced activation of the caspase cascade and alterations of poly(ADP-ribose) polymerase expression. J. Cell Sci. 114:3495.[Abstract/Free Full Text]
32. Nash, P. B., M. B. Purner, R. P. Leon, P. Clarke, R. C. Duke, T. J. Curiel. 1998. Toxoplasma gondii-infected cells are resistant to multiple inducers of apoptosis. J. Immunol. 160:1824.[Abstract/Free Full Text]

This article has been cited by other articles:

				M. Yamamoto, D. M. Standley, S. Takashima, H. Saiga, M. Okuyama, H. Kayama, E. Kubo, H. Ito, M. Takaura, T. Matsuda, et al. A single polymorphic amino acid on Toxoplasma gondii kinase ROP16 determines the direct and strain-specific activation of Stat3 J. Exp. Med., November 23, 2009; 206(12): 2747 - 2760. [Abstract] [Full Text] [PDF]

				Y. Zhao, D. J. P. Ferguson, D. C. Wilson, J. C. Howard, L. D. Sibley, and G. S. Yap Virulent Toxoplasma gondii Evade Immunity-Related GTPase-Mediated Parasite Vacuole Disruption within Primed Macrophages J. Immunol., March 15, 2009; 182(6): 3775 - 3781. [Abstract] [Full Text] [PDF]

				J. Leng, B. A. Butcher, C. E. Egan, D. S. Abi Abdallah, and E. Y. Denkers Toxoplasma gondii Prevents Chromatin Remodeling Initiated by TLR-Triggered Macrophage Activation J. Immunol., January 1, 2009; 182(1): 489 - 497. [Abstract] [Full Text] [PDF]

				A. L. Bierly, W. J. Shufesky, W. Sukhumavasi, A. E. Morelli, and E. Y. Denkers Dendritic Cells Expressing Plasmacytoid Marker PDCA-1 Are Trojan Horses during Toxoplasma gondii Infection J. Immunol., December 15, 2008; 181(12): 8485 - 8491. [Abstract] [Full Text] [PDF]

				E. D. Phelps, K. R. Sweeney, and I. J. Blader Toxoplasma gondii Rhoptry Discharge Correlates with Activation of the Early Growth Response 2 Host Cell Transcription Factor Infect. Immun., October 1, 2008; 76(10): 4703 - 4712. [Abstract] [Full Text] [PDF]

				K. N. Couper, D. G. Blount, and E. M. Riley IL-10: The Master Regulator of Immunity to Infection J. Immunol., May 1, 2008; 180(9): 5771 - 5777. [Abstract] [Full Text] [PDF]

				H. Nishinakamura, Y. Minoda, K. Saeki, K. Koga, G. Takaesu, M. Onodera, A. Yoshimura, and T. Kobayashi An RNA-binding protein {alpha}CP-1 is involved in the STAT3-mediated suppression of NF-{kappa}B transcriptional activity Int. Immunol., May 1, 2007; 19(5): 609 - 619. [Abstract] [Full Text] [PDF]

				R. Rigano, B. Buttari, E. Profumo, E. Ortona, F. Delunardo, P. Margutti, V. Mattei, A. Teggi, M. Sorice, and A. Siracusano Echinococcus granulosus Antigen B Impairs Human Dendritic Cell Differentiation and Polarizes Immature Dendritic Cell Maturation towards a Th2 Cell Response Infect. Immun., April 1, 2007; 75(4): 1667 - 1678. [Abstract] [Full Text] [PDF]

				K. C. El Kasmi, J. Holst, M. Coffre, L. Mielke, A. de Pauw, N. Lhocine, A. M. Smith, R. Rutschman, D. Kaushal, Y. Shen, et al. General Nature of the STAT3-Activated Anti-Inflammatory Response J. Immunol., December 1, 2006; 177(11): 7880 - 7888. [Abstract] [Full Text] [PDF]

				K. S. Masek, J. Fiore, M. Leitges, S.-F. Yan, B. D. Freedman, and C. A. Hunter Host cell Ca2+ and protein kinase C regulate innate recognition of Toxoplasma gondii J. Cell Sci., November 1, 2006; 119(21): 4565 - 4573. [Abstract] [Full Text] [PDF]

				L. Kim, B. A. Butcher, C. W. Lee, S. Uematsu, S. Akira, and E. Y. Denkers Toxoplasma gondii Genotype Determines MyD88-Dependent Signaling in Infected Macrophages J. Immunol., August 15, 2006; 177(4): 2584 - 2591. [Abstract] [Full Text] [PDF]

				S. Bennouna, W. Sukhumavasi, and E. Y. Denkers Toxoplasma gondii Inhibits Toll-Like Receptor 4 Ligand-Induced Mobilization of Intracellular Tumor Necrosis Factor Alpha to the Surface of Mouse Peritoneal Neutrophils Infect. Immun., July 1, 2006; 74(7): 4274 - 4281. [Abstract] [Full Text] [PDF]

				Yimin and M. Kohanawa A Regulatory Effect of the Balance between TNF-{alpha} and IL-6 in the Granulomatous and Inflammatory Response to Rhodococcus aurantiacus Infection in Mice J. Immunol., July 1, 2006; 177(1): 642 - 650. [Abstract] [Full Text] [PDF]

				C. W. Lee, S. Bennouna, and E. Y. Denkers Screening for Toxoplasma gondii-Regulated Transcriptional Responses in Lipopolysaccharide-Activated Macrophages Infect. Immun., March 1, 2006; 74(3): 1916 - 1923. [Abstract] [Full Text] [PDF]

				S. Zimmermann, P. J. Murray, K. Heeg, and A. H. Dalpke Induction of Suppressor of Cytokine Signaling-1 by Toxoplasma gondii Contributes to Immune Evasion in Macrophages by Blocking IFN-{gamma} Signaling J. Immunol., February 1, 2006; 176(3): 1840 - 1847. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Butcher, B. A. Articles by Denkers, E. Y. Search for Related Content PubMed PubMed Citation Articles by Butcher, B. A. Articles by Denkers, E. Y. Pubmed/NCBI databases Gene GEO Profiles HomoloGene UniGene Compound via MeSH Substance via MeSH