Regulation of the CCL2 Gene in Pancreatic β-Cells by IL-1β and Glucocorticoids

Role of MKP-1

Susan J. Burke, Matthew R. Goff, Barrett L. Updegraff, Danhong Lu, Patricia L. Brown, Steven C. Minkin, John P. Biggerstaff, Ling Zhao, Michael Karlstad, J. Jason Collier

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

Release of pro-inflammatory cytokines from both resident and invading leukocytes within the pancreatic islets impacts the development of Type 1 diabetes mellitus. Synthesis and secretion of the chemokine CCL2 from pancreatic β-cells in response to pro-inflammatory signaling pathways influences immune cell recruitment into the pancreatic islets. Therefore, we investigated the positive and negative regulatory components controlling expression of the CCL2 gene using isolated rat islets and INS-1-derived β-cell lines. We discovered that activation of the CCL2 gene by IL-1β required the p65 subunit of NF-κB and was dependent on genomic response elements located in the -3.6 kb region of the proximal gene promoter. CCL2 gene transcription in response to IL-1β was blocked by pharmacological inhibition of the IKKβ and p38 MAPK pathways. The IL-1β-mediated increase in CCL2 secretion was also impaired by p38 MAPK inhibition and by glucocorticoids. Moreover, multiple synthetic glucocorticoids inhibited the IL-1β-stimulated induction of the CCL2 gene. Induction of the MAP Kinase Phosphatase-1 (MKP-1) gene by glucocorticoids or by adenoviral-mediated overexpression decreased p38 MAPK phosphorylation, which diminished CCL2 gene expression, promoter activity, and release of CCL2 protein. We conclude that glucocorticoid-mediated repression of IL-1β-induced CCL2 gene transcription and protein secretion occurs in part through the upregulation of the MKP-1 gene and subsequent deactivation of the p38 MAPK. Furthermore, the anti-inflammatory actions observed with MKP-1 overexpression were obtained without suppressing glucose-stimulated insulin secretion. Thus, MKP-1 is a possible target for anti-inflammatory therapeutic intervention with preservation of β-cell function.

Original languageEnglish (US)
Article numbere46986
JournalPLoS One
Volume7
Issue number10
DOIs
StatePublished - Oct 9 2012

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Dual Specificity Phosphatase 1
interleukin-1
glucocorticoids
Interleukin-1
mitogen-activated protein kinase
Glucocorticoids
p38 Mitogen-Activated Protein Kinases
Phosphotransferases
Genes
Islets of Langerhans
genes
cells
Anti-Inflammatory Agents
islets of Langerhans
IKappaB kinase
Transcription
Gene Expression
Chemokine CCL2
Response Elements
Type 1 Diabetes Mellitus

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Burke, S. J., Goff, M. R., Updegraff, B. L., Lu, D., Brown, P. L., Minkin, S. C., ... Collier, J. J. (2012). Regulation of the CCL2 Gene in Pancreatic β-Cells by IL-1β and Glucocorticoids: Role of MKP-1. PLoS One, 7(10), [e46986]. https://doi.org/10.1371/journal.pone.0046986

Regulation of the CCL2 Gene in Pancreatic β-Cells by IL-1β and Glucocorticoids : Role of MKP-1. / Burke, Susan J.; Goff, Matthew R.; Updegraff, Barrett L.; Lu, Danhong; Brown, Patricia L.; Minkin, Steven C.; Biggerstaff, John P.; Zhao, Ling; Karlstad, Michael; Collier, J. Jason.

In: PLoS One, Vol. 7, No. 10, e46986, 09.10.2012.

Research output: Contribution to journalArticle

Burke, SJ, Goff, MR, Updegraff, BL, Lu, D, Brown, PL, Minkin, SC, Biggerstaff, JP, Zhao, L, Karlstad, M & Collier, JJ 2012, 'Regulation of the CCL2 Gene in Pancreatic β-Cells by IL-1β and Glucocorticoids: Role of MKP-1', PLoS One, vol. 7, no. 10, e46986. https://doi.org/10.1371/journal.pone.0046986
Burke, Susan J. ; Goff, Matthew R. ; Updegraff, Barrett L. ; Lu, Danhong ; Brown, Patricia L. ; Minkin, Steven C. ; Biggerstaff, John P. ; Zhao, Ling ; Karlstad, Michael ; Collier, J. Jason. / Regulation of the CCL2 Gene in Pancreatic β-Cells by IL-1β and Glucocorticoids : Role of MKP-1. In: PLoS One. 2012 ; Vol. 7, No. 10.
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