The Transcription Factor CREB Enhances Interleukin-17A Production and Inflammation in a Mouse Model of Atherosclerosis

Abstract

It has been demonstrated that 15-lipoxygenase (15-LO) plays a role in atherogenesis, but the underlying mechanisms were unclear. Therefore, the purpose of the present study is to explore the mechanisms of 15-LO role in atherogenesis. 15(S)-hydroxyeicosatetraenoic acid [15(S)-HETE], the major 15-LO-dependent metabolite of arachidonic acid (AA), stimulated the production of reactive oxygen species (ROS) by monocytes through the xanthine oxidase–mediated activation of NADPH oxidase, which led to the Syk-, Pyk2-, mitogen-activated protein kinase (MAPK)–, and cyclic adenosine monophosphate response element–binding protein (CREB)–dependent production of the pro-inflammatory cytokine interleukin-17A (IL-17A). 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 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 enhanced IL-17A production compared to those from ApoE−/−:12/15-LO−/− mice. These events correlated with increased lipid deposits and numbers of monocytes and macrophages in the aortic arches of these mice, which resulted in atherosclerotic plaque formation. Together, these observations suggest that 15(S)-HETE exacerbates atherogenesis by enhancing CREB-dependent IL-17A production.

12/15-Lipoxygenase-dependent ROS production is required for diet-induced endothelial barrier dysfunction

“…We also found that 15(S)-HETE increases XO activity in macrophages ( 22 ). These observations led us to hypothesize that XO might be involved in 15(S)-HETE-induced EC barrier dysfunction.…”

Vascular Endothelial Tight Junctions and Barrier Function Are Disrupted by 15(S)-Hydroxyeicosatetraenoic Acid Partly via Protein Kinase Cϵ-mediated Zona Occludens-1 Phosphorylation at Threonine 770/772

“…We have previously shown that 15(S)-HETE by activating nonreceptor tyrosine kinases, Src and Pyk2, stimulates ZO-2 tyrosine phosphorylation and its dissociation from claudins 1/5 and thereby disrupts aortic endothelial TJs in response to HFD feeding (27). We have also shown that 15(S)-HETE induces reactive oxygen species production via xanthine oxidase and an NADPH oxidase-dependent manner in macrophages (63). Furthermore, our studies have demonstrated that the macrophages from apoE Ϫ/Ϫ :12/15-LO Ϫ/Ϫ mice exhibited lower capacity in the production of oxidants as compared with apoE Ϫ/Ϫ mice in response to HFD feeding (63).…”

“…We have also shown that 15(S)-HETE induces reactive oxygen species production via xanthine oxidase and an NADPH oxidase-dependent manner in macrophages (63). Furthermore, our studies have demonstrated that the macrophages from apoE Ϫ/Ϫ :12/15-LO Ϫ/Ϫ mice exhibited lower capacity in the production of oxidants as compared with apoE Ϫ/Ϫ mice in response to HFD feeding (63). In view of these findings and the present observations, it may be suggested that 15-LO1/15(S)-HETE axis (12/15-LO/12(S)-HETE axis in mice), via triggering both tyrosine and serine/threonine phosphorylation of various endothelial TJ proteins and thereby disrupting endothelial TJs, increasing vascular permeability, and enhancing vascular inflammation, might be playing a contributing role in atherogenesis in response to cardiovascular risk factors such as HFD.…”

The Structure of Human 15-Lipoxygenase-2 with a Substrate Mimic

“…The Murine Homologue of 15-LOX-2 Is an 8-LOX-15-S-HETE (generated by non-enzymatic reduction of 15-S-HPETE) has been shown to be the LOX product that contributes to atherosclerosis in a murine model system (9). However, silencing expression of murine ALOX15B (which produces 8-HPETE from AA rather than 15-HPETE) mitigated plaque formation (8).…”

“…More recently, Magnusson et al (8) demonstrated that silencing production of the ALOX15B protein in human macrophages decreased cellular lipid accumulation, the precipitating factor in foam cell formation. Finally, 15S-hydroxyeicosatetraenoic acid (HETE), derived through non-enzymatic reduction of the product of the 15-LOX reaction, has been shown to promote formation of atherosclerotic lesions in a mouse model system (9).…”