Abstract
Antibiotics exert several effects on host cells including regulation of immune components. Antimicrobial peptides (AMPs), e.g., cathelicidins and defensins display multiple functions in innate immunity. In colonic mucosa, cathelicidins are induced by butyrate, a bacterial fermentation product. Here, we investigated the effect of antibiotics on butyrate-induced expression of cathelicidins and beta-defensins in colon epithelial cells. Real-time PCR analysis revealed that ciprofloxacin and clindamycin reduce butyrate-induced transcription of the human cathelicidin LL-37 in the colonic epithelial cell line HT-29. Suppression of LL-37 peptide/protein by ciprofloxacin was confirmed by Western blot analysis. Immunohistochemical analysis demonstrated that ciprofloxacin suppresses the rabbit cathelicidin CAP-18 in rectal epithelia of healthy and butyrate-treated Shigella-infected rabbits. Ciprofloxacin also down-regulated butyrate-induced transcription of the human beta-defensin-3 in HT-29 cells. Microarray analysis of HT-29 cells revealed upregulation by butyrate with subsequent down-regulation by ciprofloxacin of additional genes encoding immune factors. Dephosphorylation of histone H3, an epigenetic event provided a possible mechanism of the suppressive effect of ciprofloxacin. Furthermore, LL-37 peptide inhibited Clostridium difficile growth in vitro. In conclusion, ciprofloxacin and clindamycin exert immunomodulatory function by down-regulating AMPs and other immune components in colonic epithelial cells. Suppression of AMPs may contribute to the overgrowth of C. difficile, causing antibiotic-associated diarrhea.
Highlights
Antimicrobial peptides/proteins (AMPs) are important effectors of the immediate host defense, exerting antimicrobial activity and immunomodulation [1,2,3,4]
A selection of antibiotics, i.e., ciprofloxacin, clindamycin, ofloxacin, levofloxacin, pivmecillinam, azithromycin, ceftriaxone, ampicillin, and isoniazid were screened by real-time PCR for their effect on the CAMP gene expression in HT-29 cells in the presence or absence of sodium butyrate (NaB)
We demonstrate that ciprofloxacin and clindamycin significantly suppress butyrate-mediated induction of cathelicidin in the colon epithelial cell line HT-29
Summary
Antimicrobial peptides/proteins (AMPs) are important effectors of the immediate host defense, exerting antimicrobial activity and immunomodulation [1,2,3,4]. HBDs are predominantly expressed in epithelial cells [8]. A bacterial fermentation product in colon, upregulates cathelicidins in colonic epithelial cells of human and rabbit [16,17], and, playing an important role in host-microbes interaction in the colonic mucosa. Clindamycin, extended-spectrum penicillin, cephalosporin and fluoroquinolones including ciprofloxacin are the major antibiotics implicated in C. difficile associated diarrhoea (CDAD) [23]. We determined the effect of several antibiotics on the constitutive and butyrate-induced expression of cathelicidins in colon epithelial cells in vivo and/or in vitro. Since ciprofloxacin suppressed the butyrate-mediated induction of cathelicidins, we investigated the influence of ciprofloxacin on the induction of human β-defensins (HBDs) in vitro.
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