Lipopolysaccharide Modulates Cyclooxygenase-2 Transcriptionally and Posttranscriptionally in Human Macrophages Independently from Endogenous IL-1β and TNF-α

Abstract

The pathogenesis of septicemia can be triggered by LPS, a potent stimulus for PG synthesis. The enzyme cyclooxygenase (COX) is a rate-limiting step in PG production. COX exists as two isoforms: COX-1, which is constitutively expressed in most cell types, and COX-2, which is inducible by LPS and cytokines in a variety of cells. In this study we determined the role of the proinflammatory cytokines IL-1β and TNF-α released by LPS-stimulated U937 human macrophages in the regulation of COX-2. Macrophages exposed to LPS showed a rapid and sustained expression of COX-2 mRNA and protein for up to 48 h, whereas PGE2 production was notably enhanced only after 12 h. LPS increased COX-2 gene transcription and activation of the transcription factor NF-κB in a transient manner. LPS-treated macrophages produced high levels of TNF-α and moderate amounts of IL-1β protein. However, neutralizing Abs against these cytokines had no effect on COX-2 mRNA and protein expression, nor did they affect the stability of COX-2 mRNA. Interestingly, in the presence of LPS or exogenous IL-1β, COX-2 transcripts were stabilized, and actinomycin D inhibited their degradation. Only when LPS or IL-1β was removed did COX-2 mRNA decay with a t1/2 of ≥5 h. In contrast, dexamethasone promoted a faster decay of the LPS-induced COX-2 transcripts (t1/2 = 2.5 h). These results clearly demonstrate that LPS can regulate COX-2 at both transcriptional and posttranscriptional levels independently from endogenous IL-1β and TNF-α in human macrophages.

Systems Approach to Integrating Preclinical Apolipoprotein E-Knockout Investigations Reveals Novel Etiologic Pathways and Master Atherosclerosis Network in Humans

“…After application of IPA to the significant genes in humans we identified a top network, LPS, which included PTGS2 , as LPS is a known COX2 activator. 23 Third, using the genes identified in the mouse sc-58125 network, we tested for enrichment in the human data and found the network genes to be highly significantly enriched in humans (empirical P =0.00008). We believe the 3 different validation methods establish in humans the importance of this COX2 network identified in the high-dimensional mouse data set.…”

Silver and Gold Complexes with NHC-Ligands Derived from Caffeine: Catalytic and Pharmacological Activity

“…Similarly, the co-treatment with LPS and indomethacin, AgL3OAc, or AuL3 (Figure 6a, panels 3, 4, and 6B, respectively) produced no difference Together with iNOS, COX-1 and COX-2 are important pro-inflammatory proteins involved in the synthesis of prostaglandins (PGs) from arachidonic acid and are inhibited by nonsteroidal anti-inflammatory drugs (NSAIDs) [63]. It is well known that COX-1 is constitutively expressed in most human tissues, while COX-2 expression is induced by inflammatory stimuli, including LPS and cytokines, in macrophages [64,65].…”

Immune Modulatory Effects of Nonsteroidal Anti-inflammatory Drugs in the Perioperative Period and Their Consequence on Postoperative Outcome

“…18 In contrast, COX-2 is less widely expressed, but its expression is induced upon activation by proinflammatory mediators, like interleukin 1, tumor necrosis factor α, lipopolysaccharides, and tumor promotors. 19 Although it is generally stated that COX-1 is not involved upon immune activation, its role in inflammation should not be underestimated. Studies in animal models have shown that COX-1 serves an important role in the development of inflammatory sequelae like edema.…”