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* Department of Cell Biology and
Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294
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-
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.
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 Institutes of Health Grants NS-45290 and NS-36765 (to E.N.B.), National Multiple Sclerosis Society Grant RG 3892-A-12 (to E.N.B.), National Institutes of Health Grants DK-60132, DK-71176, and DK-64400 (to C.O.E and Y.C.), and National Institutes of Health Pilot and Feasibility Grant AR-48311 (to H.Q.). We also acknowledge the support of the University of Alabama at Birmingham Cytometry Core Facility (AM-20614).
2 Address correspondence and reprint requests to Dr. Hongwei Qin, Department of Cell Biology, 1918 University Boulevard, McCallum Building (MCLM) 392, University of Alabama at Birmingham, Birmingham, AL 35294. E-mail address: hqin{at}uab.edu
3 Abbreviations used in this paper: SOCS, suppressor of cytokine signaling; BMDM, bone marrow-derived macrophage; CBP, CREB-binding protein; ChIP, chromatin immunoprecipitation; CHX, cycloheximide; DC, dendritic cell; DN, dominant negative; GAS, IFN- activation sequence; IKK, I
B kinase; Pol II, polymerase II; RPA, RNase protection assay; siRNA, small interfering RNA; RAW-STAT-3i, RAW264.7 cells incubated with STAT-3 siRNA; STAT-3C, constitutively active STAT-3; WT, wild type.
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