Atf3 negatively regulates Ptgs2/Cox2 expression during acute inflammation

Abstract

By generating prostaglandins, cyclooxygenase-2 (Cox-2/Ptgs2) plays a critical role in regulating inflammatory responses. While several inflammatory stimuli have been shown to increase Ptgs2 expression, less is known about how the transcription of this gene is terminated. Here we show that stimulation of macrophages with yeast zymosan, a TLR2/6 and dectin-1 agonist, causes a transient increase in the expression of Ptgs2 accompanied by a simultaneous increase in the expression of the transcriptional repressor, Activating transcription factor-3 (Atf3). The expression of Ptgs2 was significantly higher in resident peritoneal macrophages isolated from Atf3−/− mice than that from Atf3+/+ mice and was associated with higher prostaglandin production upon stimulation with zymosan. In activated macrophages, Atf3 accumulated in the nucleus and chromatin-immunoprecipitation analysis showed that Atf3 is recruited to the Ptgs2 promoter region. In acute peritonitis and in cutaneous wounds, there was increased leukocyte accumulation and higher levels of prostaglandins (PGE2/PGD2) in inflammatory exudates of Atf3−/− mice compared with WT mice. Collectively, these results demonstrate that during acute inflammation Atf3 negatively regulates Ptgs2 and therefore dysregulation of this axis could potentially contribute to aberrant Ptgs2 expression in chronic inflammatory diseases. Moreover, this axis could be a new therapeutic target for suppressing Ptgs2 expression and the resultant inflammatory responses.

Negative pressure wound therapy inhibits inflammation and upregulates activating transcription factor‐3 and downregulates nuclear factor‐κB in diabetic patients with foot ulcerations

“…Therefore, it impedes p65 binding to the target promoters and attenuates their transcription . Meanwhile, ATF‐3 negatively regulates Ptgs2 expression during wound healing, which was another main cause of anti‐inflammatory activity . Similar results were reported in Kwon's study .…”

Characterization of gene expression in naturally occurring feline degenerative joint disease-associated pain

“…In many experimental pain models the expression of COX2 has been found to be increased in the spinal cord in response to inflammation and injury (Vardeh et al, 2009) and contributes to pain, but we did not observe a significant difference in COX2 when we compared DJD and healthy samples. The transcription factor ATF3 has been shown to negatively regulate COX2 levels during acute inflammation in mice (Hellmann et al, 2015) and our results may indicate the same negative regulation is occurring in cats with DJD-pain. However, it is important to remember that our results reflect a single crosssectional chronic time point.…”

IL-33 Signaling Regulates Innate IL-17A and IL-22 Production via Suppression of Prostaglandin E2 during Lung Fungal Infection

“…To this end, we cannot exclude the possibility that IL-33 may affect the expression or function of other PRRs, namely the beta-glucan receptor Dectin-1. Another study has shown that macrophages from mice deficient in Atf3 , an ATF/CREB basic leucine zipper (bZip) transcription factor induced during cellular stress have enhanced COX-2 signaling and PGE2 production after stimulation with zymosan (51). Ongoing studies are interrogating the role of IL-33 in Atf3 induction as well as its effect on Dectin-1.…”