Expression and functional significance of SOCS-1 and SOCS-3 in astrocytes.
Astrocytes play a number of important physiological roles in CNS homeostasis. Inflammation stimulates astrocytes to secrete cytokines and chemokines that guide macrophages/microglia and T cells to sites of injury/inflammation. Herein, we describe how these processes are controlled by the suppressor of cytokine signaling (SOCS) proteins, a family of proteins that negatively regulate adaptive and innate immune responses. In this study, we describe that the immunomodulatory cytokine IFN-beta induces SOCS-1 and SOCS-3 expression in primary astrocytes at the transcriptional level. SOCS-1 and SOCS-3 transcriptional activity is induced by IFN-beta through IFN-gamma activation site (GAS) elements within their promoters. Studies in STAT-1alpha-deficient astrocytes indicate that STAT-1alpha is required for IFN-beta-induced SOCS-1 expression, while STAT-3 small interfering RNA studies demonstrate that IFN-beta-induced SOCS-3 expression relies on STAT-3 activation. Specific small interfering RNA inhibition of IFN-beta-inducible SOCS-1 and SOCS-3 in astrocytes enhances their proinflammatory responses to IFN-beta stimulation, such as heightened expression of the chemokines CCL2 (MCP-1), CCL3 (MIP-1alpha), CCL4 (MIP-1beta), CCL5 (RANTES), and CXCL10 (IP-10), and promoting chemotaxis of macrophages and CD4(+) T cells. These results indicate that IFN-beta induces SOCS-1 and SOCS-3 in primary astrocytes to attenuate its own chemokine-related inflammation in the CNS.
Qin
Hongwei
H
Department of Cell Biology, University of Alabama at Birmingham, Birmingham, AL 35294, USA. hqin@uab.edu
Niyongere
Sandrine A
SA
Lee
Sun Jung
SJ
Baker
Brandi J
BJ
Benveniste
Etty N
EN
D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology; D002478:Cells, Cultured; D018925:Chemokines / Q000235:genetics; D002633:Chemotaxis; D005786:Gene Expression Regulation; D016899:Interferon-beta / Q000502:physiology; D008264:Macrophages / Q000502:physiology; D051379:Mice; D050794:STAT1 Transcription Factor / Q000502:physiology*; D050796:STAT3 Transcription Factor / Q000502:physiology*; D000071222:Suppressor of Cytokine Signaling 1 Protein; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics*; D014158:Transcription, Genetic
D018925:Chemokines; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; C491590:Socs1 protein, mouse; C491411:Socs3 protein, mouse; C494080:Stat1 protein, mouse; C494087:Stat3 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D016899:Interferon-beta