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Signal Transducer and Activator of Transcription 3 Is the Dominant Mediator of the Anti-Inflammatory Effects of IL-10 in Human Macrophages

The Journal of immunology (1950), 2004-01, Vol.172 (1), p.567-576 [Peer Reviewed Journal]

ISSN: 0022-1767 ;EISSN: 1550-6606 ;DOI: 10.4049/jimmunol.172.1.567 ;PMID: 14688368

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Title:
Signal Transducer and Activator of Transcription 3 Is the Dominant Mediator of the Anti-Inflammatory Effects of IL-10 in Human Macrophages
Author: Williams, Lynn ; Bradley, Laura ; Smith, Alexandra ; Foxwell, Brian
Subjects: Adenoviruses, Human - genetics ; Antigens, CD - biosynthesis ; Antigens, CD - metabolism ; Cells, Cultured ; DNA - antagonists & inhibitors ; DNA - metabolism ; DNA-Binding Proteins - antagonists & inhibitors ; DNA-Binding Proteins - biosynthesis ; DNA-Binding Proteins - genetics ; DNA-Binding Proteins - physiology ; Down-Regulation - genetics ; Down-Regulation - immunology ; Genetic Vectors ; Glycoproteins - antagonists & inhibitors ; Glycoproteins - biosynthesis ; Glycoproteins - genetics ; Histocompatibility Antigens Class II - biosynthesis ; Humans ; Immune Sera - pharmacology ; Immunoglobulins - biosynthesis ; Immunoglobulins - genetics ; Inflammation Mediators - antagonists & inhibitors ; Inflammation Mediators - immunology ; Inflammation Mediators - physiology ; Interleukin-10 - antagonists & inhibitors ; Interleukin-10 - immunology ; Interleukin-10 - physiology ; Interleukin-6 - antagonists & inhibitors ; Interleukin-6 - biosynthesis ; Lipopolysaccharides - antagonists & inhibitors ; Lipopolysaccharides - pharmacology ; Macrophages - immunology ; Macrophages - metabolism ; Phosphorylation ; Protein Binding - genetics ; Protein Biosynthesis ; Protein Tyrosine Phosphatase, Non-Receptor Type 2 ; Protein Tyrosine Phosphatases - antagonists & inhibitors ; Protein Tyrosine Phosphatases - biosynthesis ; Protein Tyrosine Phosphatases - genetics ; Proteins - physiology ; Receptors, Cell Surface ; Receptors, IgG - antagonists & inhibitors ; Receptors, IgG - biosynthesis ; Receptors, Tumor Necrosis Factor - antagonists & inhibitors ; Receptors, Tumor Necrosis Factor - biosynthesis ; Receptors, Tumor Necrosis Factor - metabolism ; Receptors, Tumor Necrosis Factor, Type II ; Repressor Proteins - antagonists & inhibitors ; Repressor Proteins - biosynthesis ; RNA, Messenger - antagonists & inhibitors ; RNA, Messenger - biosynthesis ; RNA, Messenger - metabolism ; Signal Transduction - genetics ; Signal Transduction - immunology ; Signaling Lymphocytic Activation Molecule Family Member 1 ; SOCS-3 protein ; STAT3 Transcription Factor ; Suppressor of Cytokine Signaling 3 Protein ; Suppressor of Cytokine Signaling Proteins ; Tissue Inhibitor of Metalloproteinase-1 - antagonists & inhibitors ; Tissue Inhibitor of Metalloproteinase-1 - biosynthesis ; Tissue Inhibitor of Metalloproteinase-1 - metabolism ; Trans-Activators - antagonists & inhibitors ; Trans-Activators - biosynthesis ; Trans-Activators - genetics ; Trans-Activators - physiology ; Transcription Factors - antagonists & inhibitors ; Transcription Factors - biosynthesis ; Tumor Necrosis Factor-alpha - antagonists & inhibitors ; Tumor Necrosis Factor-alpha - biosynthesis ; Tumor Necrosis Factor-alpha - genetics ; Up-Regulation - genetics ; Up-Regulation - immunology
Is Part Of: The Journal of immunology (1950), 2004-01, Vol.172 (1), p.567-576
Description: The signaling mechanism by which the anti-inflammatory cytokine IL-10 mediates suppression of proinflammatory cytokine synthesis remains largely unknown. Macrophage-specific STAT3-null mice have demonstrated that STAT3 plays a critical role in the suppression of LPS-induced TNF-alpha release, although the mechanism by which STAT3 mediates this inhibition is still not clear. Using an adenoviral system, we have expressed a dominant negative (DN) STAT3 in human macrophages to broaden the investigation to determine the role of STAT3 in IL-10-mediated anti-inflammatory signaling and gene expression. Overexpression of STAT3 DN completely inhibited IL-10-induced suppressor of cytokine signaling 3, tissue inhibitor of MMP-1, TNF receptor expression, and the recently identified IL-10-inducible genes, T cell protein tyrosine phosphatase and signaling lymphocyte activation molecule. STAT3 DN also blocked IL-10-mediated inhibition of MHC class II and COX2 expression. In agreement with the studies in STAT3-null mice, overexpression of the STAT3 DN completely reversed the ability of IL-10 to inhibit LPS-mediated TNF-alpha and IL-6 production. However, real-time PCR analysis showed that STAT3 DN expression did not affect immediate suppression of TNF-alpha mRNA, but did reverse the suppression observed at later time points, suggesting a biphasic regulation of TNF-alpha mRNA levels by IL-10. In conclusion, although STAT3 does appear to be the dominant mediator of the majority of IL-10 functions, there are elements of its anti-inflammatory activity that are STAT3 independent.
Publisher: United States: Am Assoc Immnol
Language: English
Identifier: ISSN: 0022-1767
EISSN: 1550-6606
DOI: 10.4049/jimmunol.172.1.567
PMID: 14688368
Source: GFMER Free Medical Journals
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Signal Transducer and Activator of Transcription 3 Is the Dominant Mediator of the Anti-Inflammatory Effects of IL-10 in Human Macrophages

ISSN: 0022-1767 ;EISSN: 1550-6606 ;DOI: 10.4049/jimmunol.172.1.567 ;PMID: 14688368

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