Upregulation of Cyclooxygenase-2 by 4-Nonylphenol is Mediated Through the Cyclic Amp Response Element Activation Pathway

Abstract

The organic compound nonylphenol (NP) belongs to the family of alkylphenols and is a product of industrial synthesis formed during phenol alkylation. Nonylphenol is considered to be an endocrine disruptor due to weak ability to mimic estrogen and subsequently to disrupt the natural balance of hormones in a given organism. Since the endocrine and immune systems share portions of common signaling pathways, it is conceivable that NP may also affect immune system functions. However, the influence of NP on inflammation and macrophages responsiveness to NP is unclear. Thus, the effects of NP were investigated on cyclooxygenase (COX)-2 expression in cultured macrophages. NP induced COX-2 protein and gene expression in murine macrophage RAW264.7 cells and enhanced COX-2 promoter activity and prostaglandin E(2) production. Transfection of RAW264.7 cells with hCOX-2 or various deletion and mutation promoter constructs revealed that the cyclic AMP response element (CRE) was the predominant mediator responsive to NP-induced effects. Moreover, transfection with pCRE-Luc plasmid followed by immunoblotting demonstrated that NP activated CRE sites and CRE binding protein (CREB) phosphorylation. NP also increased nuclear CREB accumulation and CREB binding to the COX-2 promoter. Phosphatidylinositol 3 (PI3)-kinase, Akt, and the mitogen-activated protein kinases (MAP kinases) p38 and JNK were also significantly activated by NP. Our data demonstrate that NP induces COX-2 expression through the PI3-kinase/Akt/MAP kinases/CRE pathway. These findings provide insight into the signal transduction pathways involved in the inflammatory responses induced by NP in macrophages.

Nonylphenol regulates cyclooxygenase-2 expression via Ros-activated NF-κB pathway in sertoli TM4 cells

“…Consistent with the COX‐2 expression, PGE2 as a result of COX‐2 activity also increased in NP‐challenged TM4 cells. The similar results were found in NP‐stimulated RAW264.7 cells (Han et al, ) and mouse brain (Zhang et al, ). IL‐6 is a pleiotropic cytokine produced by a variety of cell types.…”

Nonylphenol increases tumor formation and growth by suppressing gender‐independent lymphocyte proliferation and macrophage activation

“…28 NP also activated phosphatidylinositol 3 (PI3)-kinase, Akt, p38 kinase, JNK, and the phosphorylation of cyclic AMP response element binding protein (CREB) in macrophages. 29 In addition, it altered the activities of plasma membrane Ca 21 -ATPase, Ca 21 /Mg 21 -ATPase, and Na 1 /K 1 -ATPase in Sertoli cells. 30 NP was also shown to inhibit NF-jB transactivation in murine macrophages activated with LPS.…”

“…One study revealed that NP activated neutrophils through the activation of protein kinase C, p38 kinase, and ERK . NP also activated phosphatidylinositol 3 (PI3)‐kinase, Akt, p38 kinase, JNK, and the phosphorylation of cyclic AMP response element binding protein (CREB) in macrophages . In addition, it altered the activities of plasma membrane Ca 2+ ‐ATPase, Ca 2+ /Mg 2+ ‐ATPase, and Na + /K + ‐ATPase in Sertoli cells .…”

Nonylphenol polyethoxylates induce phosphorylation of histone H2AX

“…Activated immune cells like macrophages would generate ROS. Indeed, Han et al [42] showed that inflammatory responses were induced by NP in murine macrophage RAW264.7 cells.…”