Abstract
In many different cell types, pro-inflammatory agonists induce the expression of cyclooxygenase 2 (COX-2), an enzyme that catalyzes rate-limiting steps in the conversion of arachidonic acid to a variety of lipid signaling molecules, including prostaglandin E2 (PGE2). PGE2 has key roles in many early inflammatory events, such as the changes of vascular function that promote or facilitate leukocyte recruitment to sites of inflammation. Depending on context, it also exerts many important anti-inflammatory effects, for example increasing the expression of the anti-inflammatory cytokine interleukin 10 (IL-10), and decreasing that of the pro-inflammatory cytokine tumor necrosis factor (TNF). The tight control of both biosynthesis of, and cellular responses to, PGE2 are critical for the precise orchestration of the initiation and resolution of inflammatory responses. Here we describe evidence of a negative feedback loop, in which PGE2 augments the expression of dual specificity phosphatase 1, impairs the activity of mitogen-activated protein kinase p38, increases the activity of the mRNA-destabilizing factor tristetraprolin, and thereby inhibits the expression of COX-2. The same feedback mechanism contributes to PGE2-mediated suppression of TNF release. Engagement of the DUSP1-TTP regulatory axis by PGE2 is likely to contribute to the switch between initiation and resolution phases of inflammation.
Highlights
The cyclooxygenase enzymes COX-1 and cyclooxygenase 2 (COX-2), encoded by the genes Ptgs[1] and Ptgs[2], catalyze rate-limiting steps in the synthesis of various prostanoid signaling molecules from the lipid precursor arachidonic acid[1, 2]
Tnf and Ptgs[2] mRNAs were measured by quantitiative PCR, and fold enrichment was calculated relative to the pre-immune control (PI) control
The graph shows mean ± SEM of three independent bone marrow macrophages (BMMs) cultures of each genotype. (e) Zfp36+/+ and Zfp36aa/aa BMMs were stimulated with LPS for the times indicated and COX-2 protein was detected by western blotting
Summary
The cyclooxygenase enzymes COX-1 and COX-2, encoded by the genes Ptgs[1] and Ptgs[2], catalyze rate-limiting steps in the synthesis of various prostanoid signaling molecules from the lipid precursor arachidonic acid[1, 2]. Efficient expression requires the stabilization of Ptgs[2] mRNA via the mitogen-activated protein kinase (MAPK) p38 signaling pathway, and MAPK p38 inhibitors accelerate the degradation of Ptgs[2] mRNA21, 22 This post-transcriptional regulation is mediated by an adenosine/uridine-rich element (ARE) immediately 3′ to the Ptgs[2] translation termination codon. When inserted into a stable reporter mRNA, the Ptgs[2] ARE confers rapid decay that is mediated by shortening of the protective poly-(A) tail (deadenylation), and can be prevented by activation of MAPK p3823–25 This sequence element is similar to MAPK p38-responsive mRNA destabilizing elements present in pro-inflammatory mRNAs such as Tnf, Csf[2], Cxcl[1], Il6 and many others[26]
Sign-in/Register to view highlights & summary 
Published Version
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call