Reduced stem cell mobilization in mice receiving antibiotic modulation of the intestinal flora: involvement of endotoxins as cofactors in mobilization.
Since endotoxins are potent inducers of stem cell mobilization, we hypothesized that their presence in the gut may play a role in cytokine-induced mobilization. To address this possibility we added ciprofloxacin and polymyxin B to the drinking water of Balb/c mice mobilized with either interleukin-8 (IL-8), granulocyte colony-stimulating factor (G-CSF), or flt3 ligand (FL). The yield of colony-forming units (CFUs) was significantly reduced in all mice treated with these antibiotics when compared with controls (IL-8: 192 +/- 61 vs 290 +/- 64, P <.05; G-CSF: 1925 +/- 1216 vs 3371 +/- 1214, P <.05; FL: 562 +/- 213 vs 1068 +/- 528, P <.05). Treatment with ciprofloxacin eliminated only aerobic Gram-negative bacteria from the feces without effect on mobilization. Polymyxin B treatment did not result in decontamination but significantly reduced the number of mobilized hematopoietic progenitor cells (HPCs) most likely due to the endotoxin binding capacity of polymyxin B. More than 90% of the gastrointestinal flora consists of anaerobic bacteria. Elimination of the anaerobic flora by metronidazol led to a significantly reduced number of mobilized HPCs when compared with controls (IL-8: 55 +/- 66 vs 538 +/- 216, P <.05). Germ-free OF1 mice showed a significantly reduced mobilization compared with their wild-type controls (IL-8 controls: 378 +/- 182, IL-8 germ free: 157 +/- 53, P <.05). Finally, we performed reconstitution experiments adding Escherichia coli-derived endotoxins to the drinking water of decontaminated mice. This resulted in partial restoration of the IL-8-induced mobilization (67 +/- 28 vs 190 +/- 98.1, P <.01). Our results indicate that endotoxins serve as cofactors in cytokine-induced mobilization. Modification of the endotoxin content by antibiotic treatment may affect the yield of cytokine-induced mobilization.
Velders
Gerjo A
GA
Laboratory of Experimental Hematology, Leiden University Medical Center, Leiden, the Netherlands.
van Os
Ronald
R
Hagoort
Henny
H
Verzaal
Perry
P
Guiot
Henri F L
HF
Lindley
Ivan J D
IJ
Willemze
Roel
R
Opdenakker
Ghislain
G
Fibbe
Willem E
WE
D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage*; D001772:Blood Cell Count; D003114:Colony-Forming Units Assay; D016207:Cytokines / Q000494:pharmacology; D004731:Endotoxins / Q000097:blood / Q000494:pharmacology*; D005856:Germ-Free Life; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D019650:Hematopoietic Stem Cell Mobilization; D015850:Interleukin-6 / Q000097:blood; D016209:Interleukin-8 / Q000494:pharmacology; D007422:Intestines / Q000187:drug effects* / Q000276:immunology / Q000382:microbiology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000097:blood; D008565:Membrane Proteins / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D011994:Recombinant Proteins / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000900:Anti-Bacterial Agents; D016207:Cytokines; D004731:Endotoxins; D015850:Interleukin-6; D016209:Interleukin-8; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; C084881:flt3 ligand protein; D016179:Granulocyte Colony-Stimulating Factor; D020780:Matrix Metalloproteinase 9