Haplotype-independent costimulation of IL-10 secretion by SDF-1/CXCL12 proceeds via AP-1 binding to-the human IL-10 promoter

Kimberly N. Kremer, Ashok Kumar, Karen Elaine Hedin

Research output: Contribution to journalArticle

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Abstract

Costimulation by the chemokine, stromal cell-derived factor-1 (SDF-1)/CXCL12, has been shown to increase the amount of IL-10 secreted by TCR-stimulated human T cells; however, the molecular mechanisms of this response are unknown. Knowledge of this signaling pathway may be useful because extensive evidence indicates that deficient IL-10 secretion promotes autoiinmunity. The human IL-10 locus is highly polymorphic. We report in this study that SDF-1 costimulates IL-10 secretion from T cells containing all three of the most common human IL-10 promoter haplotypes that are identified by single-nucleotide polymorphisms at -1082, -819, and -592 bp (numbering is relative to the transcription start site). We further show that SDF-1 primarily costimulates IL-10 secretion by a diverse population of CD45RA- ("memory") phenotype T cells that includes cells expressing the presumed regulatory T cell marker, Foxp3. To address the molecular mechanisms of this response, we showed that SDF-1 costimulates the transcriptional activities in normal human T cells of reporter plasmids containing 1.1 kb of all three of the common IL-10 promoter haplotypes. IL-10 promoter activity was ablated by mutating two nonpolymorphic binding sites for the AP-1 transcription factor, and chromatin immunoprecipitation assays of primary human T cells revealed that SDF-1 costimulation enhances AP-1 binding to both of these sites. Together, these resalts delineate the molecular mechanisms responsible for SDF-1 costimulation of T. cell IL-10 secretion. Because it is preserved among several human haplotypes and in diverse T cell populations including Fosp3+ T cells, this pathway of IL-10 regulation may represent a key mechanism for modulating expression of this important immunoregulatory cytokine.

Original languageEnglish (US)
Pages (from-to)1581-1588
Number of pages8
JournalJournal of Immunology
Volume178
Issue number3
StatePublished - Feb 1 2007

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Chemokine CXCL12
Transcription Factor AP-1
Interleukin-10
Haplotypes
T-Lymphocytes
Chromatin Immunoprecipitation
Transcription Initiation Site
Regulatory T-Lymphocytes
Chemokines
Population
Single Nucleotide Polymorphism
Plasmids
Binding Sites
Cytokines
Phenotype

ASJC Scopus subject areas

  • Immunology

Cite this

Haplotype-independent costimulation of IL-10 secretion by SDF-1/CXCL12 proceeds via AP-1 binding to-the human IL-10 promoter. / Kremer, Kimberly N.; Kumar, Ashok; Hedin, Karen Elaine.

In: Journal of Immunology, Vol. 178, No. 3, 01.02.2007, p. 1581-1588.

Research output: Contribution to journalArticle

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abstract = "Costimulation by the chemokine, stromal cell-derived factor-1 (SDF-1)/CXCL12, has been shown to increase the amount of IL-10 secreted by TCR-stimulated human T cells; however, the molecular mechanisms of this response are unknown. Knowledge of this signaling pathway may be useful because extensive evidence indicates that deficient IL-10 secretion promotes autoiinmunity. The human IL-10 locus is highly polymorphic. We report in this study that SDF-1 costimulates IL-10 secretion from T cells containing all three of the most common human IL-10 promoter haplotypes that are identified by single-nucleotide polymorphisms at -1082, -819, and -592 bp (numbering is relative to the transcription start site). We further show that SDF-1 primarily costimulates IL-10 secretion by a diverse population of CD45RA- ({"}memory{"}) phenotype T cells that includes cells expressing the presumed regulatory T cell marker, Foxp3. To address the molecular mechanisms of this response, we showed that SDF-1 costimulates the transcriptional activities in normal human T cells of reporter plasmids containing 1.1 kb of all three of the common IL-10 promoter haplotypes. IL-10 promoter activity was ablated by mutating two nonpolymorphic binding sites for the AP-1 transcription factor, and chromatin immunoprecipitation assays of primary human T cells revealed that SDF-1 costimulation enhances AP-1 binding to both of these sites. Together, these resalts delineate the molecular mechanisms responsible for SDF-1 costimulation of T. cell IL-10 secretion. Because it is preserved among several human haplotypes and in diverse T cell populations including Fosp3+ T cells, this pathway of IL-10 regulation may represent a key mechanism for modulating expression of this important immunoregulatory cytokine.",
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