Regulation of macrophage tumor necrosis factor production by prostaglandin E2

doi:10.1016/0006-291X(86)91224-6

Biochemical and Biophysical Research Communications

Volume 137, Issue 1, 29 May 1986, Pages 404-410

https://doi.org/10.1016/0006-291X(86)91224-6 Get rights and content

Abstract

We have studied the role of prostaglandin E₂ on the modulation of tumor necrosis factor by immunologically elicited and lipopolysaccharide treated murine macrophages. Indomethacin, a potent inhibitor of prostaglandin E₂ production, caused a dose dependent augmentation of lipopolysaccharide induced tumor necrosis factor production (2–3 fold at 10⁻⁷ molar). Tumor necrosis factor was released into the extracellular environment and no activity was found to be associated with membrane or cytosolic fractions. Prostaglandin E₂ added to the lipopolysaccharide treated cultures suppressed tumor necrosis factor in a dose dependent manner. In these studies, 10⁻⁷ molar PGE₂ reduced tumor necrosis factor production to basal levels. These data suggest that PGE₂ may be a potent autoregulatory factor that dramatically influences tumor necrosis factor production.

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Eicosanoid pathway on host resistance and inflammation during Mycobacterium tuberculosis infection is comprised by LTB<inf>4</inf> reduction but not PGE<inf>2</inf> increment
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Citation Excerpt :
Furthermore, the inhibition of prostaglandins by NSAIDs is responsible for the TNF-α rise. Prostaglandin E2 is a potent inhibitor of TNF-α release from both macrophages (Kunkel et al., 1986) and mast cells (Hogaboam et al., 1993). In turn, the up-regulation of serum TNF-α by indomethacin is probably responsible for diminished mucosal NO production, which is a potent gastroprotective mediator.
Gastric ulcer is one of the main prevalent gastrointestinal multi-etiological disorders with many associated complications and adverse effects. Our aim was to develop safer antiulcer therapies based on methanol or ethyl acetate extracts of tubers and aerial parts from Cyperus alternifolius.
Gastric ulceration was experimentally generated by administration of single oral doses of indomethacin (30 mg/kg) to fasted rats. The animals received methanol or ethyl acetate extracts of C. alternifolius tuber and methanol or ethyl acetate extracts of aerial parts at two dose levels (50 or 100 mg/kg). Ranitidine (50 mg/kg) was used as standard anti-ulcer drug. After 4 h, the ulcer number and the total ulcer score were determined and TNF-α was assessed. Also, pathological and histochemical examination for gastric mucosa were performed.
The metabolome heterogeneity of the different extracts was explored using (UPLC-MS) aided by supervised pattern recognition, i.e., orthogonal partial least squares discriminate analysis (OPLS-DA). A second OPLS-DA model was employed to link the UPLC-MS derived metabolome of the different extracts to their antiulcer activity to identify activity mediating metabolites.
The extracts significantly reduced ulcer number, total ulcer score and TNF-α content in the stomach. Methanol or ethyl acetate extracts of tubers were most effective even more than ranitidine. In parallel, the histopathological examination showed an improvement of damaged mucosa. A high PAS reaction was observed in the treated groups indicating a relieve of the mucosal layer. A mechanistic clue of the C. alternifolius antiulcer potential was provided by the identification of its bioactive compounds using OPLS-DA. Both methanol extracts of tubers and aerial parts were more enriched in phenolic acids. The ethyl acetate extract of the aerial part was more abundant in two aldehydes. A mechanism of action was postulated based on their reported actions viz. α-carbonic anhydrase inhibition, anti-inflammatory and analgesic activity by its antioxidant activity and downregulation of several inflammatory mediators.
This is the first study to report on the antiulcer activity of C. alternifolius tubers with identification of the key bioactive compounds and the mode of action. Future phytochemical and biological evaluation of the identified bioactive compounds are needed to confirm the plant tubers as safer alternative or adjunct therapy compared to conventional antiulcer drugs.
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The pathogenesis of nonsteroidal anti-inflammatory drug (NSAID) enteropathy is still unclear, and consequently, there is no approved therapeutic strategy for ameliorating such damage. On the other hand, molecular treatment strategies targeting tumor necrosis factor (TNF) exerts beneficial effects on NSAID-induced intestinal lesions in rodents and rheumatoid arthritis patients. Thus, TNF appears to be a potential therapeutic target for both the prevention and treatment of NSAID enteropathy. However, the causative relationship between TNF and NSAID enteropathy is largely unknown. Currently approved anti-TNF agents are highly expensive and exhibit numerous side effects. Hence, in this review, the pivotal role of TNF in NSAID enteropathy has been summarized and plant-derived polyphenols have been suggested as useful alternative anti-TNF agents because of their ability to suppress TNF activated inflammatory pathways both in vitro and in vivo.

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Regulation of macrophage tumor necrosis factor production by prostaglandin E2

Abstract

J. Exp. Med

J. Immunol

Science

Lymphokines

Regulation of macrophage tumor necrosis factor production by prostaglandin E₂