Abstract
Radiation-induced normal brain injury is associated with acute and/or chronic inflammatory responses, and has been a major concern in radiotherapy. Recent studies suggest that microglial activation is a potential contributor to chronic inflammatory responses following irradiation; however, the molecular mechanism underlying the response of microglia to radiation is poorly understood. c-Jun, a component of AP-1 transcription factors, potentially regulates neural cell death and neuroinflammation. We observed a rapid increase in phosphorylation of N-terminal c-Jun (on serine 63 and 73) and MAPK kinases ERK1/2, but not JNKs, in irradiated murine microglial BV2 cells. Radiation-induced c-Jun phosphorylation is dependent on the canonical MEK-ERK signaling pathway and required for both ERK1 and ERK2 function. ERK1/2 directly interact with c-Jun in vitro and in cells; meanwhile, the JNK binding domain on c-Jun is not required for its interaction with ERK kinases. Radiation-induced reactive oxygen species (ROS) potentially contribute to c-Jun phosphorylation through activating the ERK pathway. Radiation stimulates c-Jun transcriptional activity and upregulates c-Jun-regulated proinflammatory genes, such as tumor necrosis factor-α, interleukin-1β, and cyclooxygenase-2. Pharmacologic blockade of the ERK signaling pathway interferes with c-Jun activity and inhibits radiation-stimulated expression of c-Jun target genes. Overall, our study reveals that the MEK-ERK1/2 signaling pathway, but not the JNK pathway, contributes to the c-Jun-dependent microglial inflammatory response following irradiation.
Highlights
Radiation therapy is an important modality of treatment for brain tumors and cancers that have metastasized to the brain
Radiation resulted in a prominent increase in c-Jun phosphorylation on Ser63 and Ser73 (Figure 1A), the critical phosphorylation sites correlating with enhanced transcriptional activity of c-Jun [23]
Our observations strongly suggested that radiation stimulates JNKindependent c-Jun phosphorylation via an activated ERK1/2 pathway, while Jun N-terminal kinase (JNK) are critical for c-Jun phosphorylation in other physiological conditions
Summary
Radiation therapy is an important modality of treatment for brain tumors and cancers that have metastasized to the brain. A growing body of evidence supports the hypothesis that radiation-induced brain injury is driven in part by an acute and/or chronic inflammatory response [2,3]. Radiation stimulates the transformation of resting microglial cells to a reactive state, leading to the up-regulation of proinflammatory cytokines such as tumor necrosis factor-a (TNF-a), interleukins, and cyclooxygenase-2 (COX-2) [3,6,7,8,9]. Excessive amounts of proinflammatory cytokines secreted by activated microglia can cause neurotoxicity in neurodegenerative diseases [5] and have been implicated in radiation-induced brain injury. A common nonsteroidal anti-inflammatory drug, inhibited radiation-induced microglial activation and mitigated impaired neurogenesis by radiation [3]. The molecular mechanisms underlying radiation-stimulated microglial activation remain largely unclear
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