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Indomethacin augments lipopolysaccharide-induced expression of inflammatory molecules in the mouse brain.

ABSTRACT: Indomethacin and other non-steroidal anti-inflammatory drugs (NSAIDs) are used to relieve pain and fever including during infections. However, some studies suggest that NSAIDs protect against neuroinflammation, while some find no effects or worsening of neuroinflammation. We evaluated the effect of indomethacin alone on in combination with minocycline, a drug that inhibits neuroinflammation, on the expression of transcripts of neuroinflammatory molecules-induced by lipopolysaccharide (LPS) in the brain of mice. Inoculation of male BALB/c mice with LPS induced the expression of the microglia marker ionized calcium binding adaptor molecule protein, mRNA expression of the genes for cytokines interleukin-1beta (Il1b) and tumor necrosis factor-alpha (Tnf) and inducible nitric oxide synthase gene (Nos2), but not Il10, in the brain. Treatment with indomethacin had no significant effect on the cytokines or Nos2 mRNA expression in naïve animals. However, pretreatment with indomethacin increased LPS-induced Nos2 mRNA and inducible nitric oxide (iNOS) protein expression, but had no significant effect on LPS-induced mRNA expression of the cytokines. Minocycline reduced LPS-induced Il1b and Tnf, but not Nos2, mRNA expression. Treatment with indomethacin plus minocycline had no effect on LPS-induced Il1b, Tnf and Nos2 mRNA expression. In conclusion these results show that indomethacin significantly augments LPS-induced Nos2 mRNA and iNOS protein expression in the brain. In the presence of indomethacin, minocycline could not inhibit LPS-induced pro-inflammatory cytokine expression. Thus, indomethacin could exacerbate neuroinflammation by increasing the expression of iNOS and also block the anti-inflammatory effects of minocycline.

SUBMITTER: Mohamed MY

PROVIDER: S-EPMC7680052 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Indomethacin augments lipopolysaccharide-induced expression of inflammatory molecules in the mouse brain.

Mohamed Mona Yasin MY Masocha Willias W

PeerJ 20201118

Indomethacin and other non-steroidal anti-inflammatory drugs (NSAIDs) are used to relieve pain and fever including during infections. However, some studies suggest that NSAIDs protect against neuroinflammation, while some find no effects or worsening of neuroinflammation. We evaluated the effect of indomethacin alone on in combination with minocycline, a drug that inhibits neuroinflammation, on the expression of transcripts of neuroinflammatory molecules-induced by lipopolysaccharide (LPS) in th ...[more]

PMID: 33240677

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Project description:Previous studies have revealed that activation of the Toll‑like receptor 4 (TLR4)‑mediated proinflammatory signaling pathway plays an important role in acute inflammation, sepsis and chronic inflammatory disorders. Moreover, TLR4 significantly contributes to lipopolysaccharide (LPS)‑induced immune response. Thus, modulation of the TLR4 pathway is an important strategy to specifically target these pathologies. The aim of the present study was to develop a complete human anti‑TLR4 IgG2 antibody by screening human TLR4 Fab from a phage‑display library and integrating it with constant regions of the heavy chain of human IgG2 via antibody engineering. ELISA, a BLItz system and fluorescence‑activated cell sorting were used to assess its affinity. Furthermore, mouse‑derived peritoneal macrophages were treated with human anti‑TLR4 IgG2 and induced with LPS in vitro. Reverse transcription‑quantitative PCR and western blotting were used to determine mRNA expression levels of cytokines and phosphorylation levels of signaling pathways, respectively. It was found that human anti‑TLR4 IgG2 bound to TLR4 with a high affinity of 8.713x10‑10 M, and that preincubation with anti‑TLR4 IgG2 inhibited the LPS‑induced production of tumor necrosis factor‑α, interferon‑β and interleukin‑6 mRNA expression levels in mouse peritoneal macrophages. It was also demonstrated that human anti‑TLR4 IgG2 inhibited LPS‑induced TLR4 signaling by reducing the phosphorylation of the NF‑κB, mitogen‑activated protein kinase and interferon regulatory factor 3 signaling pathways. In addition, human anti‑TLR4 IgG2 protected mice from LPS challenge with a survival rate of 40% and also significantly increased the survival time in the cecal ligation and puncture model. Therefore, it was speculated that human anti‑TLR4 IgG2 plays a protective role against sepsis‑associated injury and is potentially applicable for the treatment of infection‑associated immune dysfunction.

Project description:IntroductionThe intestinal structure is the foundation for various activities and functions in poultry. An important question concerns the changes in the intestinal status under endotoxin stimulation. This study aimed to investigate the mechanism of intestinal injury induced by lipopolysaccharide (LPS) in Wahui pigeons.MethodsThirty-six 28-day-old healthy Wahui pigeons were randomly divided into two groups. The experimental group was injected with LPS (100 μg/kg) once per day for five days, and the control group was treated with the same amount of sterile saline. Blood and the ileum were collected from pigeons on the first, third, and fifth days of the experiment and used for oxidative stress assessment, inflammatory factor detection, histopathological examination, and positive cell localization. In addition, intestinal injury indices and mRNA expression levels (tight junction proteins, inflammatory cytokines, and factors related to autophagy and apoptosis) were evaluated.ResultsVilli in the ileum were shorter in the LPS group than in the control group, and D-lactic acid levels in the serum were significantly increased. Glutathione and catalase levels significantly decreased, but the malondialdehyde content in the serum increased. TNF-α and IL-10 were detected at higher levels in the serum, with stronger positive signals and higher mRNA expression levels, in the LPS group than in the control group. In addition, the levels of TLR4, MyD88, NF-κB, and HMGB1 in the inflammatory signaling pathway were also upregulated. Finally, the mRNA expression of Claudin3, Occludin, and ZO-1 was significantly decreased; however, that of Beclin1 and Atg5 was increased in the LPS group.ConclusionIleal pathological changes and oxidative stress were caused by LPS challenge; it is proposed that this triggering regulates the inflammatory response, causing excessive autophagy and apoptosis, promoting intestinal permeability, and leading to intestinal injury in Wahui pigeons.

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Indomethacin augments lipopolysaccharide-induced expression of inflammatory molecules in the mouse brain.

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Indomethacin augments lipopolysaccharide-induced expression of inflammatory molecules in the mouse brain.

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