The transcription factor CREB enhances interleukin-17A production and inflammation in a mouse model of atherosclerosis

Sivareddy Kotla, Nikhlesh Singh, Mark R. Heckle, Gabor Tigyi, Rao Gadiparthi

Research output: Contribution to journalArticle

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Abstract

The enzyme 15-lipoxygenase (15-LO) plays a role in atherogenesis (also known as atherosclerosis), but the underlying mechanisms are unclear. We found that 15(S)-hydroxyeicosatetraenoic acid [15(S)-HETE], the major 15-LO - dependent metabolite of arachidonic acid, stimulated the production of reactive oxygen species (ROS) by monocytes through the xanthine oxidase - mediated activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. ROS production led to the Syk-, Pyk2-, and mitogen-activated protein kinase (MAPK) - dependent production of the proinflammatory cytokine interleukin-17A (IL-17A) in a manner that required the transcription factor CREB (cyclic adenosine monophosphate response element - binding protein). In addition, this pathway was required for the 15(S)-HETE - dependent migration and adhesion of monocytes to endothelial cells. Consistent with these observations, we found that peritoneal macrophages from apolipoprotein E - deficient (ApoE-/-) mice fed a high-fat diet (a mouse model of atherosclerosis) exhibited increased xanthine oxidase and NADPH oxidase activities; ROS production; phosphorylation of Syk, Pyk2, MAPK, and CREB; and IL-17A production compared to those from similarly fed ApoE-/-:12/15-LO-/- mice. These events correlated with increased lipid deposits and numbers of monocytes andmacrophages in the aortic arches of ApoE-/- mice, which resulted in atherosclerotic plaque formation. Together, these observations suggest that 15(S)-HETE exacerbates atherogenesis by enhancing CREB-dependent IL-17A production and inflammation.

Original languageEnglish (US)
Article numberra83
JournalScience Signaling
Volume6
Issue number293
DOIs
StatePublished - Sep 17 2013

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Interleukin-17
Hydroxyeicosatetraenoic Acids
Atherosclerosis
Apolipoproteins E
Transcription Factors
Arachidonate 15-Lipoxygenase
Inflammation
Monocytes
Reactive Oxygen Species
Xanthine Oxidase
Mitogen-Activated Protein Kinases
NADP
Oxidoreductases
Peritoneal Macrophages
Response Elements
High Fat Diet
Atherosclerotic Plaques
Thoracic Aorta
Arachidonic Acid
Cyclic AMP

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

The transcription factor CREB enhances interleukin-17A production and inflammation in a mouse model of atherosclerosis. / Kotla, Sivareddy; Singh, Nikhlesh; Heckle, Mark R.; Tigyi, Gabor; Gadiparthi, Rao.

In: Science Signaling, Vol. 6, No. 293, ra83, 17.09.2013.

Research output: Contribution to journalArticle

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