Differential effects of pentoxifylline on the hepatic inflammatory response in porcine liver cell cultures. Increase in inducible nitric oxide synthase expression.
Pentoxifylline (PTX) has been shown to exert hepatoprotective effects in various liver injury models. However, little information is available about the effect of PTX on the hepatic acute phase response. In the present study, the effect of PTX on a lipopolysaccharide (LPS)-induced acute phase response in primary porcine liver cell cultures was examined. During 72 hr of incubation with or without LPS, the ability of PTX to influence the secretion of tumour necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), acute phase proteins, and nitric oxide (NO) was assessed. PTX completely inhibited LPS-induced TNF-alpha production and attenuated IL-6 only after 48 hr of incubation. In contrast, PTX potentiated NO production and the expression of inducible nitric oxide synthase (iNOS) in hepatocytes after stimulation with LPS. The increased expression of iNOS and concurrent production of NO was also observed when liver cell cultures were incubated with dibutyryl cyclic adenosine monophosphate. No effect of PTX on acute phase protein secretion was observed during 72 hr of incubation. The present results show that PTX differentially affects the endotoxin-induced inflammatory response in primary porcine liver cell cultures by suppressing TNF-alpha and IL-6 while potentiating NO production.
Hoebe
K H
KH
Department of Veterinary Pharmacology, Pharmacy and Toxicology, Utrecht University, Yalelaan 16, 3584 CM Utrecht, The Netherlands.
Gonzalez-Ramon
N
N
Nijmeijer
S M
SM
Witkamp
R F
RF
van Leengoed
L A
LA
van Miert
A S
AS
Monshouwer
M
M
D000209:Acute-Phase Proteins / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D016207:Cytokines / Q000187:drug effects / Q000378:metabolism; D019610:Cytoprotection; D015870:Gene Expression / Q000187:drug effects*; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000096:biosynthesis* / Q000187:drug effects / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D009573:Nitrites / Q000378:metabolism; D010431:Pentoxifylline / Q000494:pharmacology*; D020011:Protective Agents / Q000494:pharmacology*; D013552:Swine
D000209:Acute-Phase Proteins; D016207:Cytokines; D009573:Nitrites; D020011:Protective Agents; D000242:Cyclic AMP; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D010431:Pentoxifylline