Molecular mechanism of lipopolysaccharide-induced SOCS-3 gene expression in macrophages and microglia

Hongwei Qin, Kevin L. Roberts, Sandrine A. Niyongere, Yingzi Cong, Charles O. Elson, Etty N. Benveniste

Research output: Contribution to journalArticle

109 Citations (Scopus)

Abstract

Immunological activation of macrophages/microglia within the CNS leads to the production of cytokines and chemokines that ultimately impact on glial and neuronal function. Suppressor of cytokine signaling (SOCS) proteins are negative regulators of adaptive and innate immune responses. Our previous studies demonstrated that SOCS-3 attenuates macrophage/microglial activation in vitro, suggesting that SOCS-3 may exert beneficial effects for immune-mediated CNS diseases in vivo. In this study, we describe LPS as a potent inducer of SOCS-3 transcription and expression in macrophages/microglia. An analysis of the SOCS-3 promoter indicates that AP-1 and IFN-γ activation sequence (GAS) elements are involved in LPS-induced SOCS-3 transcription. LPS-induced SOCS-3 expression was diminished in IL-10-deficient macrophages at later time points, indicating the involvement of endogenous IL-10 in this response. Blocking STAT-3 expression and activation using STAT-3 small interfering RNA reduced LPS-induced SOCS-3 gene expression. LPS activated the MAPK-ERK1/2, JNK, and p38 pathways that, in addition to STAT-3, were also involved in LPS-induced SOCS-3 expression. LPS treatment of cells led to the acetylation of histones H3 and H4 on the SOCS-3 promoter and the recruitment of STAT-3, c-Jun, c-Fos, CREB-binding protein, p300, and RNA polymerase II to the endogenous SOCS-3 promoter in a time-dependent manner. These results indicate that LPS-induced MAPK activation, the production of endogenous IL-10, and STAT-3 activation play critical roles in SOCS-3 expression, which provides for feedback attenuation of cytokine-induced immune and inflammatory responses in macrophages and microglia.

Original languageEnglish (US)
Pages (from-to)5966-5976
Number of pages11
JournalJournal of Immunology
Volume179
Issue number9
StatePublished - Nov 1 2007
Externally publishedYes

Fingerprint

Microglia
Lipopolysaccharides
Macrophages
Cytokines
Gene Expression
Interleukin-10
Macrophage Activation
Histones
Suppressor of Cytokine Signaling Proteins
CREB-Binding Protein
MAP Kinase Signaling System
RNA Polymerase II
Central Nervous System Diseases
Transcription Factor AP-1
Adaptive Immunity
Acetylation
Chemokines
Innate Immunity
Neuroglia
Small Interfering RNA

ASJC Scopus subject areas

  • Immunology

Cite this

Qin, H., Roberts, K. L., Niyongere, S. A., Cong, Y., Elson, C. O., & Benveniste, E. N. (2007). Molecular mechanism of lipopolysaccharide-induced SOCS-3 gene expression in macrophages and microglia. Journal of Immunology, 179(9), 5966-5976.

Molecular mechanism of lipopolysaccharide-induced SOCS-3 gene expression in macrophages and microglia. / Qin, Hongwei; Roberts, Kevin L.; Niyongere, Sandrine A.; Cong, Yingzi; Elson, Charles O.; Benveniste, Etty N.

In: Journal of Immunology, Vol. 179, No. 9, 01.11.2007, p. 5966-5976.

Research output: Contribution to journalArticle

Qin, H, Roberts, KL, Niyongere, SA, Cong, Y, Elson, CO & Benveniste, EN 2007, 'Molecular mechanism of lipopolysaccharide-induced SOCS-3 gene expression in macrophages and microglia', Journal of Immunology, vol. 179, no. 9, pp. 5966-5976.
Qin H, Roberts KL, Niyongere SA, Cong Y, Elson CO, Benveniste EN. Molecular mechanism of lipopolysaccharide-induced SOCS-3 gene expression in macrophages and microglia. Journal of Immunology. 2007 Nov 1;179(9):5966-5976.
Qin, Hongwei ; Roberts, Kevin L. ; Niyongere, Sandrine A. ; Cong, Yingzi ; Elson, Charles O. ; Benveniste, Etty N. / Molecular mechanism of lipopolysaccharide-induced SOCS-3 gene expression in macrophages and microglia. In: Journal of Immunology. 2007 ; Vol. 179, No. 9. pp. 5966-5976.
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