Thus, there is often a poor correlation between Cox-2 mRNA and protein levels because Cox-2 mRNA is rapidly degraded. The instability of Cox-2 mRNA is due to the presence of adenylate- and uridylate- 
rich element in the 39-untranslated region, which can be bound by proteins that can alter Cox-2 mRNA stability and translation. AMN107 RNA-binding proteins that interact with the Cox-2 ARE include the CELF/Bruno-like family member CUGBP2 and the embryonic lethal abnormal vision like protein Human antigen R. HuR is a ubiquitous RNA-binding protein that is abundantly localized to the nucleus, where it is first interacts with Cox-2 mRNA. HuR subsequently shuttles between the nucleus and cytoplasm upon stimulation. It is believed that cytoplasmic localization is important for the mRNAstabilizing effects of HuR. Whether the AhR regulates Cox-2 mRNA stability by controlling HuR expression or localization is not known. Herein, we used lung cells CP-358774 devoid of AhR expression, together with our established in vitro and in vivo models of cigarette smoke exposure and show that the AhR-dependent retention of nuclear HuR is responsible for the destabilization of Cox-2 mRNA by a mechanism that was independent of AhR:DNA binding activity. Therefore, despite its dubious distinction as a transcriptional regulator of toxicological outcomes, we propose that the AhR plays an important role in the suppression of inflammation that extends beyond its ability to respond to man-made toxicants. The AhR was discovered nearly four decades ago as the receptor responsible for the induction of aryl hydrocarbon hydroxylase activity in response to the potent anthropogenic ligand dioxin. Although it is generally accepted that the majority of deleterious effects of dioxin arise from dioxin binding to the AhR and subsequent alterations in gene expression patterns, one of the eminent unresolved questions is why organisms would possess a receptor for dioxin at all. The fact though that the AhR is ubiquitously expressed in mammals, being present in all major cell types in humans, and is highlyconserved throughout evolution suggests a prominent role for this receptor in mammalian physiology. Early pioneering studies using AhR-null mice not only revealed that the AhR is responsible for dioxin toxicity, but have also implicated the AhR in cell proliferation, differentiation, migration, development, tissue homeostasis and vasculogenesis. We have published that low/absent AhR levels increase inflammation and structural cell apoptosis, findings which argue for a prominent role of the AhR in normal physiology. In our current study, we sought to identify the mechanism by which the AhR prevents inflammatory protein expression and report that AhR-dependent retention of nuclear HuR suppresses COX-2 expression by a post-transcriptional mechanism. One of the most significant findings from this study is that the AhR suppresses COX-2 protein expression in the absence of a functional DNA-binding domain. This suggests that the AhR suppresses inflammation by a mechanism that is independent of its transcriptional abilities. In its paradigm as ligand-activated transcription factor, the AhR utilizes a classic mechanism of action involving nuclear translocation and binding to specific DNA recognition sequences to activate genes associated with toxicological outcomes. This canonical AhR pathway is believed to mediate the toxicity of dioxin and similar compounds due to DREmediated upregulation of phase I and II drug-metabolizing enzymes. However, recent evidence indicates that the AhR has a separate mode of action beyond direct transcriptional regulation, thereby representing an AhR pathway that is distinct from the one associated with dioxininduced toxicity. Others have also shown that, suggesting that some AhR activity may be required to effectively prevent inflammation.