Inflammatory cytokines stimulate the chemokines CCL2/MCP-1 and CCL7/MCP-7 through NFκB and MAPK dependent pathways in rat astrocytes

Wendy L. Thompson, Linda J. Van Eldik

Research output: Contribution to journalArticlepeer-review

168 Scopus citations

Abstract

The chemokines CCL2 and CCL7 are upregulated in the brain during several neurodegenerative and acute diseases associated with infiltration of peripheral leukocytes. Astrocytes can respond to inflammatory cytokines like IL-1β and TNF-α by producing chemokines. This study aims to test the ability of IL-1β and TNF-α to stimulate CCL2 and CCL7 protein production in rat astrocyte cultures, and to elucidate signaling pathways involved in the cytokine-stimulated chemokine upregulation. Astrocytes were stimulated with IL-1β or TNF-α, and CCL2 and CCL7 levels determined by ELISA. Our results show that IL-1β and TNF-α each stimulate production of the chemokines CCL2 and CCL7 in astrocytes in a concentration- and time-dependent manner, with CCL2 showing a more rapid and robust response to the cytokine treatment than CCL7. As a first step to determine the signaling pathways involved in CCL2 and CCL7 upregulation, we stimulated astrocytes with IL-1β or TNF-α in the presence of selective inhibitors of MAPK pathways (SB203580 and SB202190 for p38, SP600125 for JNK, and U0126 for ERK) or NFκB pathways (MG-132 and SC-514). We found that NFκB pathways are important for the cytokine-stimulated CCL2 and CCL7 production, whereas MAPK pathways involving p38 and JNK, but not ERK, may also contribute but to a lesser extent. These data document for the first time that CCL7 protein production can be stimulated in astrocytes by cytokines, and that the upregulation may involve NFκB- and p38/JNK-regulated pathways. In addition, our results suggest that CCL2 and CCL7 share similarities in the signaling pathways necessary for their upregulation.

Original languageEnglish
Pages (from-to)47-57
Number of pages11
JournalBrain Research
Volume1287
DOIs
StatePublished - Sep 1 2009

Bibliographical note

Funding Information:
These studies were supported in part by NIH grant R37 AG013939 (LVE). WT was a predoctoral trainee on NIH T32 AG000260 and is currently supported by NIH F31 NS055471 predoctoral fellowship. We thank Dr. Lucia de Almeida for preparation of the primary glial cultures.

Keywords

  • Astrocyte
  • CCL2
  • CCL7
  • Signal transduction

ASJC Scopus subject areas

  • General Neuroscience
  • Molecular Biology
  • Clinical Neurology
  • Developmental Biology

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