Modulation of inflammatory response by pentoxifylline is independent of heme oxygenase-1 pathway.
OBJECTIVE
It was reported that some effects of pentoxifylline (PTX) are mediated by heme oxygenase-1 (HO-1) induction. We investigated the role of HO-1 in anti-inflammatory activity of PTX.


METHODS
Experiments were performed in human and murine monocytes and endothelial cells and in HO-1 deficient mice.


RESULTS
PTX dose-dependently decreased expression of HO-1 in cell lines studied. As expected, PTX reduced also production of TNF. This effect was independent of HO-1 activity, as demonstrated in cells treated with HO-1 activators and inhibitors or in cells overexpressing HO-1. Moreover, inhibition of TNF was the same in human endothelial cells of different HO-1 genotypes, showing that PTX is similarly efficient in carriers of more and less active HO-1 promoter variants. In mice, PTX did not influence HO-1 expression, as measured in liver, kidney, spleen, heart, and skin. Accordingly, the response of PTX treated animals to LPS was the same in wild type and HO-1 deficient mice. PTX to a similar extent increased influx of leukocyte into peritoneal cavity, decreased production of TNF and reduced expression of VCAM-1 in vascular intima.


CONCLUSIONS
PTX inhibits production of TNF and may decrease inflammatory reaction both in vitro and in vivo, but these effects are independent of HO-1.
Taha
H
H
Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland.
Grochot-Przeczek
A
A
Was
H
H
Kotlinowski
J
J
Kozakowska
M
M
Marek
A
A
Skrzypek
K
K
Lackowska
B
B
Balcerczyk
A
A
Mustafa
S
S
Dulak
J
J
Jozkowicz
A
A
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology; D019446:Endotoxemia / Q000188:drug therapy / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D010431:Pentoxifylline / Q000494:pharmacology*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011110:Polymorphism, Genetic; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D008070:Lipopolysaccharides; D010726:Phosphodiesterase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D051547:Heme Oxygenase-1; D010431:Pentoxifylline