Regulation of CCL20 expression in astrocytes by IL-6 and IL-17.
Astrocytes have an important role in the regulation of inflammation within the central nervous system (CNS). In neuroinflammatory conditions such as multiple sclerosis, numerous cytokines and chemokines are elevated including IL-6, IL-17, and CCL20. IL-17 enhances IL-6 signaling and subsequent IL-6 expression in astrocytes. CCL20 is a CC motif chemokine that functions as a chemoattractant to facilitate the recruitment of CCR6-expressing cells, including Th17 cells. In this study, we examined the role of IL-6 and IL-17 on CCL20 production in primary murine astrocytes. IL-6 in combination with the IL-6 soluble receptor (sIL-6R) stimulated CCL20 expression in part through STAT3 activation, whereas IL-17 alone had no effect. However, the combination of IL-6, sIL-6R, and IL-17 led to a robust increase in CCL20 production. IL-17 increased the activation-associated phosphorylation of NF-κB, and inhibition of the NF-κB pathway significantly inhibited the enhancement of CCL20 expression by IL-17. In addition, chromatin immunoprecipitation revealed that stimulation of primary astrocytes with IL-6 plus the sIL-6R induced STAT3 binding to the CCL20 promoter. Combined stimulation with IL-6, sIL-6R, and IL-17 increased the recruitment of phosphorylated NF-κB to the CCL20 promoter, increased binding of coactivators such as p300 and CBP, and enhanced H3 and H4 histone acetylation, consistent with a transcriptionally active gene. The astrocyte-produced CCL20 increased T cell migration as determined by transwell migration assay. Collectively, these results suggest that astrocytes, in response to IL-6, sIL-6R, and IL-17, may shift chemokine production to that favoring T cell recruitment to the CNS.
Department of Cell Biology, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.
Gordon P
GP
Meares
Xiangyu
X
Ma
Hongwei
H
Qin
Etty N
EN
Benveniste
D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D002465:Cell Movement / Q000276:immunology; D054418:Chemokine CCL20 / Q000096:biosynthesis* / Q000235:genetics; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D020381:Interleukin-17 / Q000502:physiology*; D015850:Interleukin-6 / Q000502:physiology*; D051379:Mice; D061251:Primary Cell Culture; D019947:Receptors, Interleukin-6 / Q000502:physiology
C493447:CCL20 protein, mouse; D054418:Chemokine CCL20; D020381:Interleukin-17; D015850:Interleukin-6; D019947:Receptors, Interleukin-6