Dissociation of endotoxin tolerance and differentiation of alternatively activated macrophages

Endotoxin tolerance is a complex phenomenon characterized primarily by decreased production of proinflammatory cytokines, chemokines, and other inflammatory mediators, whereas the expression of other genes are induced or unchanged. Endotoxin tolerance is induced by prior exposure of murine macrophag...

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Bibliographic Details
Published in:The Journal of immunology (1950) 2013-05, Vol.190 (9), p.4763-4772
Main Authors: Rajaiah, Rajesh, Perkins, Darren J, Polumuri, Swamy Kumar, Zhao, Aiping, Keegan, Achsah D, Vogel, Stefanie N
Format: Article
Language:English
Subjects:
Animals
Cell Differentiation - genetics
Cell Differentiation - immunology
Cell Line
Endotoxins - immunology
Endotoxins - metabolism
Immune Tolerance - genetics
Immune Tolerance - immunology
Interleukin-13 - genetics
Interleukin-13 - immunology
Interleukin-13 - metabolism
Lipopolysaccharides - immunology
Macrophages - immunology
Macrophages - metabolism
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Mitogen-Activated Protein Kinase Kinases - genetics
Mitogen-Activated Protein Kinase Kinases - immunology
Mitogen-Activated Protein Kinase Kinases - metabolism
NF-kappa B - genetics
NF-kappa B - immunology
NF-kappa B - metabolism
Receptors, Cell Surface - genetics
Receptors, Cell Surface - immunology
Receptors, Cell Surface - metabolism
Signal Transduction - genetics
Signal Transduction - immunology
STAT6 Transcription Factor - genetics
STAT6 Transcription Factor - immunology
STAT6 Transcription Factor - metabolism
Transcriptome - genetics
Transcriptome - immunology
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Summary:Endotoxin tolerance is a complex phenomenon characterized primarily by decreased production of proinflammatory cytokines, chemokines, and other inflammatory mediators, whereas the expression of other genes are induced or unchanged. Endotoxin tolerance is induced by prior exposure of murine macrophages/human monocytes, experimental animals, or people to TLR ligands. Although recent studies reported a possible relationship between endotoxin tolerance and differentiation of alternatively activated macrophages (AA-MΦs or M2), we show in this study that LPS pretreatment of IL-4Rα(-/-) and STAT6(-/-) macrophages, which fail to develop into AA-MΦs, resulted in tolerance of proinflammatory cytokines, as well as molecules and chemokines previously associated with AA-MΦs (e.g., arginase-1, mannose receptor, CCL2, CCL17, and CCL22). In contrast to LPS, wild-type (WT) MΦs pretreated with IL-4, the prototype inducer of AA-MΦs, did not induce endotoxin tolerance with respect to proinflammatory cytokines, AA-MΦ-associated chemokines, negative regulators, NF-κB binding and subunit composition, and MAPKs; conversely, IL-13(-/-) macrophages were tolerized equivalently to WT MΦs by LPS pretreatment. Further, IL-4Rα deficiency did not affect the reversal of endotoxin tolerance exerted by the histone deacetylase inhibitor trichostatin A. Like WT mice, 100% of LPS-tolerized IL-4Rα-deficient mice survived LPS + d-galactosamine-induced lethal toxicity and exhibited decreased serum levels of proinflammatory cytokines and AA-MΦ-associated chemokines induced by LPS challenge compared with nontolerized mice. These data indicate that the signaling pathways leading to endotoxin tolerance and differentiation of AA-MΦs are dissociable.
ISSN:0022-1767
1550-6606
DOI:10.4049/jimmunol.1202407