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1
Institutes of
*
Microbiology and Genetics, and
Molecular Pathology, Vienna Biocenter, Vienna, Austria; and
DNAX Research Institute, Palo Alto, CA 94304
The goal of this study was to investigate how bacterial LPS affects
macrophage responsiveness to the activating factor IFN-
.
Pretreatment of macrophages with LPS for <2 h increased the
transcriptional response to IFN-. In contrast, simultaneous
stimulation with IFN- and LPS, or pretreatment with LPS for >4 h,
suppressed Stat1 tyrosine 701 phosphorylation, dimerization, and
transcriptional activity in response to IFN-. Consistently, the
induction of MHCII protein by IFN- was antagonized by LPS
pretreatment. Neutralizing Abs to IL-10 were without effect on
LPS-mediated suppression of Stat1 activation. Decreased IFN- signal
transduction after LPS treatment corresponded to a direct induction of
suppressor of cytokine signaling3 (SOCS3) mRNA and protein. Under the
same conditions socs1, socs2, and
cis genes were not transcribed. In transfection assays,
SOCS3 was found to suppress the transcriptional response of macrophages
to IFN-. A causal link of decreased IFN- signaling to SOCS3
induction was also suggested by the LPS-dependent reduction of
IFN--mediated Janus kinase 1 (JAK1) activation. Further consistent
with inhibitory activity of SOCS3, LPS also inhibited the
JAK2-dependent activation of Stat5 by GM-CSF. Our results thus link the
deactivating effect of chronic LPS exposure on macrophages with its
ability to induce SOCS3.
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P. S. Grutkoski, Y. Chen, C. S. Chung, and A. Ayala Sepsis-induced SOCS-3 expression is immunologically restricted to phagocytes J. Leukoc. Biol., November 1, 2003; 74(5): 916 - 922. [Abstract] [Full Text] [PDF]
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R. K. Pai, M. Convery, T. A. Hamilton, W. H. Boom, and C. V. Harding Inhibition of IFN-{gamma}-Induced Class II Transactivator Expression by a 19-kDa Lipoprotein from Mycobacterium tuberculosis: A Potential Mechanism for Immune Evasion J. Immunol., July 1, 2003; 171(1): 175 - 184. [Abstract] [Full Text] [PDF]
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J. G. Bode, J. Schweigart, J. Kehrmann, C. Ehlting, F. Schaper, P. C. Heinrich, and D. Haussinger TNF-{alpha} Induces Tyrosine Phosphorylation and Recruitment of the Src Homology Protein-Tyrosine Phosphatase 2 to the gp130 Signal-Transducing Subunit of the IL-6 Receptor Complex J. Immunol., July 1, 2003; 171(1): 257 - 266. [Abstract] [Full Text] [PDF]
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S. Bertholet, H. L. Dickensheets, F. Sheikh, A. A. Gam, R. P. Donnelly, and R. T. Kenney Leishmania donovani-Induced Expression of Suppressor of Cytokine Signaling 3 in Human Macrophages: a Novel Mechanism for Intracellular Parasite Suppression of Activation Infect. Immun., April 1, 2003; 71(4): 2095 - 2101. [Abstract] [Full Text]
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C. Niemand, A. Nimmesgern, S. Haan, P. Fischer, F. Schaper, R. Rossaint, P. C. Heinrich, and G. Muller-Newen Activation of STAT3 by IL-6 and IL-10 in Primary Human Macrophages Is Differentially Modulated by Suppressor of Cytokine Signaling 3 J. Immunol., March 15, 2003; 170(6): 3263 - 3272. [Abstract] [Full Text] [PDF]
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P. J. M. Ceponis, D. M. McKay, J. C. Y. Ching, P. Pereira, and P. M. Sherman Enterohemorrhagic Escherichia coli O157:H7 Disrupts Stat1-Mediated Gamma Interferon Signal Transduction in Epithelial Cells Infect. Immun., March 1, 2003; 71(3): 1396 - 1404. [Abstract] [Full Text] [PDF]
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 A. H. Dalpke and K. Heeg Synergistic and antagonistic interactions between LPS and superantigens Innate Immunity, February 1, 2003; 9(1): 51 - 54. [Abstract] [PDF]
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R. Lang, D. Patel, J. J. Morris, R. L. Rutschman, and P. J. Murray Shaping Gene Expression in Activated and Resting Primary Macrophages by IL-10 J. Immunol., September 1, 2002; 169(5): 2253 - 2263. [Abstract] [Full Text] [PDF]
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T. Hayashi, T. Kaneda, Y. Toyama, M. Kumegawa, and Y. Hakeda Regulation of Receptor Activator of NF-kappa B Ligand-induced Osteoclastogenesis by Endogenous Interferon-beta (INF-beta ) and Suppressors of Cytokine Signaling (SOCS). THE POSSIBLE COUNTERACTING ROLE OF SOCSs IN IFN-beta -INHIBITED OSTEOCLAST FORMATION J. Biol. Chem., July 26, 2002; 277(31): 27880 - 27886. [Abstract] [Full Text] [PDF]
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I. Woldman, L. Varinou, K. Ramsauer, B. Rapp, and T. Decker The Stat1 Binding Motif of the Interferon-gamma Receptor Is Sufficient to Mediate Stat5 Activation and Its Repression by SOCS3 J. Biol. Chem., November 30, 2001; 276(49): 45722 - 45728. [Abstract] [Full Text] [PDF]
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G. Z. Tau, S. N. Cowan, J. Weisburg, N. S. Braunstein, and P. B. Rothman2 Regulation of IFN-{gamma} Signaling Is Essential for the Cytotoxic Activity of CD8+ T Cells J. Immunol., November 15, 2001; 167(10): 5574 - 5582. [Abstract] [Full Text] [PDF]
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L. Terstegen, P. Gatsios, S. Ludwig, S. Pleschka, W. Jahnen-Dechent, P. C. Heinrich, and L. Graeve The Vesicular Stomatitis Virus Matrix Protein Inhibits Glycoprotein 130-Dependent STAT Activation J. Immunol., November 1, 2001; 167(9): 5209 - 5216. [Abstract] [Full Text] [PDF]
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C. J. Greenhalgh and D. J. Hilton Negative regulation of cytokine signaling J. Leukoc. Biol., September 1, 2001; 70(3): 348 - 356. [Abstract] [Full Text] [PDF]
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 N. Sekine, S. Fukumoto, T. Ishikawa, T. Okazaki, and T. Fujita GH Inhibits Interferon-{gamma}-Induced Signal Transducer and Activator of Transcription-1 Activation and Expression of the Inducible Isoform of Nitric Oxide Synthase in INS-1 Cells Endocrinology, September 1, 2001; 142(9): 3909 - 3916. [Abstract] [Full Text] [PDF]
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 D. L. Krebs and D. J. Hilton SOCS Proteins: Negative Regulators of Cytokine Signaling Stem Cells, September 1, 2001; 19(5): 378 - 387. [Abstract] [Full Text] [PDF]
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J. G. Bode, R. Fischer, D. Haussinger, L. Graeve, P. C. Heinrich, and F. Schaper The Inhibitory Effect of IL-1{beta} on IL-6-Induced {alpha}2-Macroglobulin Expression Is Due to Activation of NF-{kappa}B J. Immunol., August 1, 2001; 167(3): 1469 - 1481. [Abstract] [Full Text] [PDF]
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A. H. Dalpke, S. Opper, S. Zimmermann, and K. Heeg Suppressors of Cytokine Signaling (SOCS)-1 and SOCS-3 Are Induced by CpG-DNA and Modulate Cytokine Responses in APCs J. Immunol., June 15, 2001; 166(12): 7082 - 7089. [Abstract] [Full Text] [PDF]
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 M. P. Gil, E. Bohn, A. K. O'Guin, C. V. Ramana, B. Levine, G. R. Stark, H. W. Virgin, and R. D. Schreiber Biologic consequences of Stat1-independent IFN signaling PNAS, June 5, 2001; 98(12): 6680 - 6685. [Abstract] [Full Text] [PDF]
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M. Takahashi, M. Takahashi, F. Shinohara, H. Takada, and H. Rikiishi Effects of Superantigen and Lipopolysaccharide on Induction of CD80 through Apoptosis of Human Monocytes Infect. Immun., June 1, 2001; 69(6): 3652 - 3657. [Abstract] [Full Text] [PDF]
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C. Brender, M. Nielsen, K. Kaltoft, G. Mikkelsen, Q. Zhang, M. Wasik, N. Billestrup, and N. Odum STAT3-mediated constitutive expression of SOCS-3 in cutaneous T-cell lymphoma Blood, February 15, 2001; 97(4): 1056 - 1062. [Abstract] [Full Text] [PDF]
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D. Stoiber, S. Stockinger, P. Steinlein, J. Kovarik, and T. Decker Listeria monocytogenes Modulates Macrophage Cytokine Responses Through STAT Serine Phosphorylation and the Induction of Suppressor of Cytokine Signaling 3 J. Immunol., January 1, 2001; 166(1): 466 - 472. [Abstract] [Full Text] [PDF]
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S. T. Ahmed and L. B. Ivashkiv Inhibition of IL-6 and IL-10 Signaling and Stat Activation by Inflammatory and Stress Pathways J. Immunol., November 1, 2000; 165(9): 5227 - 5237. [Abstract] [Full Text] [PDF]
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M. Delgado and D. Ganea Inhibition of IFN-{gamma}-Induced Janus Kinase-1-STAT1 Activation in Macrophages by Vasoactive Intestinal Peptide and Pituitary Adenylate Cyclase-Activating Polypeptide J. Immunol., September 15, 2000; 165(6): 3051 - 3057. [Abstract] [Full Text] [PDF]
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 D. Krebs and D. Hilton SOCS: physiological suppressors of cytokine signaling J. Cell Sci., January 8, 2000; 113(16): 2813 - 2819. [Abstract] [PDF]
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A. Stephanou, T. M. Scarabelli, B. K. Brar, Y. Nakanishi, M. Matsumura, R. A. Knight, and D. S. Latchman Induction of Apoptosis and Fas Receptor/Fas Ligand Expression by Ischemia/Reperfusion in Cardiac Myocytes Requires Serine 727 of the STAT-1 Transcription Factor but Not Tyrosine 701 J. Biol. Chem., July 20, 2001; 276(30): 28340 - 28347. [Abstract] [Full Text] [PDF]
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