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Fidaxomicin and OP-1118 Inhibit Clostridium difficile Toxin A- and B-Mediated Inflammatory Responses via Inhibition of NF-κB Activity
- Source :
- Antimicrobial agents and chemotherapy. 62(1)
- Publication Year :
- 2017
-
Abstract
- Clostridium difficile causes diarrhea and colitis by releasing toxin A and toxin B. In the human colon, both toxins cause intestinal inflammation and stimulate tumor necrosis factor alpha (TNF-α) expression via the activation of NF-κB. It is well established that the macrolide antibiotic fidaxomicin is associated with reduced relapses of C. difficile infection. We showed that fidaxomicin and its primary metabolite OP-1118 significantly inhibited toxin A-mediated intestinal inflammation in mice in vivo and toxin A-induced cell rounding in vitro . We aim to determine whether fidaxomicin and OP-1118 possess anti-inflammatory effects against toxin A and toxin B in the human colon and examine the mechanism of this response. We used fresh human colonic explants, NCM460 human colonic epithelial cells, and RAW264.7 mouse macrophages to study the mechanism of the activity of fidaxomicin and OP-1118 against toxin A- and B-mediated cytokine expression and apoptosis. Fidaxomicin and OP-1118 dose-dependently inhibited toxin A- and B-induced TNF-α and interleukin-1β (IL-1β) mRNA expression and histological damage in human colonic explants. Fidaxomicin and OP-1118 inhibited toxin A-mediated NF-κB phosphorylation in human and mouse intestinal mucosae. Fidaxomicin and OP-1118 also inhibited toxin A-mediated NF-κB phosphorylation and TNF-α expression in macrophages, which was reversed by the NF-κB activator phorbol myristate acetate (PMA). Fidaxomicin and OP-1118 prevented toxin A- and B-mediated apoptosis in NCM460 cells, which was reversed by the addition of PMA. PMA reversed the cytoprotective effect of fidaxomicin and OP-1118 in toxin-exposed human colonic explants. Fidaxomicin and OP-1118 inhibit C. difficile toxin A- and B-mediated inflammatory responses, NF-κB phosphorylation, and tissue damage in the human colon.
- Subjects :
- 0301 basic medicine
030106 microbiology
Bacterial Toxins
Interleukin-1beta
Clostridium difficile toxin A
Clostridium difficile toxin B
Apoptosis
Pharmacology
medicine.disease_cause
Cell Line
03 medical and health sciences
Enterotoxins
Mice
Intestinal mucosa
Bacterial Proteins
medicine
Animals
Humans
Pharmacology (medical)
Fidaxomicin
Colitis
Intestinal Mucosa
Phosphorylation
Mechanisms of Action: Physiological Effects
Inflammation
Chemistry
Toxin
Clostridioides difficile
Tumor Necrosis Factor-alpha
NF-kappa B
Epithelial Cells
Clostridium difficile
medicine.disease
Infectious Diseases
Aminoglycosides
RAW 264.7 Cells
Tetradecanoylphorbol Acetate
Tumor necrosis factor alpha
medicine.drug
Subjects
Details
- ISSN :
- 10986596
- Volume :
- 62
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Antimicrobial agents and chemotherapy
- Accession number :
- edsair.doi.dedup.....8f88ef67156202d1970a9e3703ce024d