Cyclooxygenase 2 (COX-2) inhibition increases the inflammatory response in the brain during systemic immune stimuli

The products of arachidonic acid metabolism are key mediators of inflammatory responses in the central nervous system, and yet we do not know the mechanisms of their regulation. The phospholipase A2 enzymes are sources of cellular arachidonic acid, and the enzymes cyclooxygenase-2 (COX-2) and microsomal PGE synthase-1 (mPGES-1) are essential for the synthesis of inflammatory PGE2 in the brain. These studies seek to determine the function of cytosolic phospholipase A2α (cPLA2α) in inflammatory PGE2 production in the brain. We wondered whether cPLA2α functions in inflammation to produce arachidonic acid or to modulate levels of COX-2 or mPGES-1. We investigated these questions in the brains of wild-type mice and mice deficient in cPLA2α (cPLA2α−/−) after systemic administration of LPS. cPLA2α−/− mice had significantly less brain COX-2 mRNA and protein expression in response to LPS than wild-type mice. The reduction in COX-2 was most apparent in the cells of the cerebral blood vessels and the leptomeninges. The brain PGE2 concentration of untreated cPLA2α−/− mice was equal to their wild-type littermates. After LPS treatment, however, the brain concentration of PGE2 was significantly less in cPLA2α−/− than in cPLA2α+/+ mice (24.4 ± 3.8 vs. 49.3 ± 11.6 ng/g). In contrast to COX-2, mPGES-1 RNA levels increased equally in both mouse genotypes, and mPGES-1 protein was unaltered 6 h after LPS. We conclude that cPLA2α regulates COX-2 levels and modulates inflammatory PGE2 levels. These results indicate that cPLA2α inhibition is a novel anti-inflammatory strategy that modulates, but does not completely prevent, eicosanoid responses.

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Novel effects of the cyclooxygenase-2-selective inhibitor NS-398 on IL-1β-induced cyclooxygenase-2 and IL-8 expression in human ovarian granulosa cells

Innate Immunity ◽

10.1177/1753425916654011 ◽

2016 ◽

Vol 22 (6) ◽

pp. 452-465 ◽

Cited By ~ 5

Author(s):

Hui-Ling Ou ◽

David Sun ◽

Yen-Chun Peng ◽

Yuh-Lin Wu

Keyword(s):

Inflammatory Response ◽

Granulosa Cells ◽

Cell Cycle Progression ◽

Nuclear Translocation ◽

Selective Inhibitor ◽

Cyclooxygenase 2 ◽

Cycle Progression ◽

Ovarian Granulosa Cell ◽

Cox 2 ◽

The Impact

Ovulation is a critical inflammation-like event that is central to ovarian physiology. IL-1β is an immediate early pro-inflammatory cytokine that regulates production of several other inflammatory mediators, such as cyclooxygenase 2 (COX)-2 and IL-8. NS-398 is a selective inhibitor of COX-2 bioactivity and thus this drug is able to mitigate the COX-2-mediated production of downstream prostaglandins and the subsequent inflammatory response. Here we have investigated the action of NS-398 using a human ovarian granulosa cell line, KGN, by exploring IL-1β-regulated COX-2 and IL-8 expression. First, NS-398, instead of reducing inflammation, appeared to further enhance IL-1β-mediated COX-2 and IL-8 production. Using selective inhibitors targeting various signaling molecules, MAPK and NF-κB pathways both seemed to be involved in the impact of NS-398 on IL-1β-induced COX-2 and IL-8 expression. NS-398 also promoted IL-1β-mediated NF-κB p65 nuclear translocation but had no effect on IL-1β-activated MAPK phosphorylation. Flow cytometry analysis demonstrated that NS-398, in combination with IL-1β, significantly enhanced cell cycle progression involving IL-8. Our findings demonstrate a clear pro-inflammatory function for NS-398 in the IL-1β-mediated inflammatory response of granulosa cells, at least in part, owing to its augmenting effect on the IL-1β-induced activation of NF-κB.

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Interleukin (IL)-6, But Not IL-1, Induction in the Brain Downstream of Cyclooxygenase-2 Is Essential for the Induction of Febrile Response against Peripheral IL-1α

Endocrinology ◽

10.1210/en.2004-0054 ◽

2004 ◽

Vol 145 (11) ◽

pp. 5044-5048 ◽

Cited By ~ 26

Author(s):

Kyoko Kagiwada ◽

Dai Chida ◽

Tomoya Sakatani ◽

Masahide Asano ◽

Aya Nambu ◽

...

Keyword(s):

Prostaglandin E2 ◽

Cyclooxygenase 2 ◽

Signaling Cascade ◽

Endogenous Pyrogen ◽

Febrile Response ◽

Cox 2 ◽

The Brain ◽

Deficient Mice

Abstract IL-1 is an endogenous pyrogen produced upon inflammation or infection. Previously, we showed that, upon injection with turpentine, IL-1 is induced in the brain in association with the development of fever. The role of endogenous IL-1 in the brain and the signaling cascade to activate thermosensitive neurons, however, remain to be elucidated. In this report, febrile response was analyzed after peripheral injection of IL-1α. We found that a normal febrile response was induced even in IL-1α/β-deficient mice, indicating that production of IL-1 in the brain is not necessarily required for the response. In contrast, IL-6-deficient mice did not exhibit a febrile response. Cyclooxygenase (Cox)-2 expression in the brain was strongly induced 1.5 h after injection of IL-1α, whereas IL-6 expression was observed 3 h after the injection. Cox-2 expression in the brain was not influenced by IL-6 deficiency, whereas indomethacin, an inhibitor of cyclooxygenases, completely inhibited induction of IL-6. These observations suggest a mechanism of IL-1-induced febrile response in which IL-1 in the blood activates Cox-2, with the resulting prostaglandin E2 inducing IL-6 in the brain, leading to the development of fever.

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Cyclooxygenase-2 Deficiency Attenuates Lipopolysaccharide-induced Inflammation, Apoptosis and Acute Lung Injury in Adult Mice

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00140.2021 ◽

2022 ◽

Author(s):

Leif D. Nelin ◽

Yi Jin ◽

Bernadette Chen ◽

Yusen Liu ◽

Lynette K. Rogers ◽

...

Keyword(s):

Lung Injury ◽

Inflammatory Response ◽

Lung Diseases ◽

Weight Ratio ◽

Dry Weight ◽

Cyclooxygenase 2 ◽

Mrna Levels ◽

Adult Mice ◽

Cox 2 ◽

Lps Treatment

Many lung diseases are caused by an excessive inflammatory response, and inflammatory lung diseases are often modeled using lipopolysaccharide (LPS) in mice. Cyclooxygenase-2 (COX-2) encoded by the Ptgs2 gene is induced in response to inflammatory stimuli including lipopolysaccharide (LPS). The objective of this study was to test the hypothesis that mice deficient in COX-2 (Ptgs2-/-) will be protected from LPS-induced lung injury. Wild type (WT, CD1 mice) and Ptgs2-/- mice (on a CD1 background) were treated with LPS or vehicle for 24 hours. LPS-treatment resulted in histological evidence of lung injury, which was attenuated in the Ptgs2-/- mice. LPS-treatment increased the mRNA levels for tumor necrosis factor (TNF)-α, interleukin (IL)-10, and monocyte chemoattractant protein (MCP)-1 in the lungs of WT mice, and the LPS-induced increases in these levels were attenuated in the Ptgs2-/- mice. The protein levels of active caspase-3 and caspase-9 were lower in the LPS-treated lungs of Ptgs2-/- mice than in LPS-treated WT mice, as were the number of TUNEL positive cells in lung sections. LPS exposure resulted in greater lung wet-to-dry weight ratio (W/D) in WT mice, suggestive of pulmonary edema; while in LPS-treated Ptgs2-/- mice the W/D was not different from controls and less than in LPS-treated WT mice. These results demonstrate that COX-2 is involved in the inflammatory response to LPS, and suggest that COX-2 not only acts as a downstream participant in the inflammatory response, but also acts as a regulator of the inflammatory response likely through a feed-forward mechanism following LPS stimulation.

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