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Regulatory role of ATF3 on NO production in LPS/IFN‐γ‐treated macrophages

Activating transcription factor 3(ATF3), known as a stress inducible gene, is a member of the CREB/ATF family of transcription factors which is expressed only under conditions such as inflammation, cell injury or oxidative stress. LPS‐induced ATF3 has been known to suppress productions of Nitric oxide (NO) and cytokines such as IL‐6, and IL‐12 in macrophages. However, the mechanism of action of ATF3 on the macrophage function has not been characterized in detail. In the present study, we examined the regulatory role of ATF3 on inducible nitric oxide synthase (iNOS) expression in LPS/IFN‐γ‐treated macrophages. ATF3 knockdown enhanced NO in macrophages. Western blot and RT‐PCR analysis revealed that protein and mRNA levels of iNOS were also attenuated in ATF3‐knockdown cells. In addition, activities of NF‐κB and AP‐1 were increased by ATF3‐knockdown. These data indicate that ATF3 acts as s negative regulator on iNOS expression via suppression of NF‐κB and AP‐1 activities. Treatment with casein kinase ¥±(CK¥±) inhibitor decreased iNOS expression. LPS/IFN‐γ induced‐phosphorylation and nuclear translocation of ATF3 were also attenuated by CK¥± inhibitor. Overall, these results suggest that ATF3 regulates NO production through modulation of CK¥±, NF‐κB and AP‐1 signaling pathway.