Inhibition of Ca2+ influx by pentoxifylline in NR8383 alveolar macrophages.
Pentoxifylline (PTF), a phosphodiesterase (PDE) inhibitor, can prevent inflammation and tissue damage in animal and in vitro human studies. However, the underlying mechanism remains unclear. Since Ca2+ is a critical signal regulating the release of inflammatory mediators in macrophages, the effects of PTF on Ca2+ influx were examined in NR8383 alveolar macrophages (AMs). PTF induced a dose-dependent inhibition on Ca2+ influx activated by zymosan and by protein kinase C (PKC) activators 1,2-dioctanoyl-sn-glycerol (DOG) or phorbol-12-myristate 13-acetate (PMA). The inhibition appeared to be specifically on the receptor-operated Ca2+ entry. The capacitative Ca2+ entry was not affected by PTF. The inhibition was not due to altered cAMP levels since the zymosan-activated Ca2+ influx was not affected by the adenylate cyclase activator forskolin, nor by dibutyryl cAMP. Pretreatment with protein tyrosine kinase (PTK) inhibitor genistein abolished zymosan-induced, but not DOG-induced Ca2+ influx, suggesting that PTK is an upstream element of the signaling cascade and not the target of PTF. The Ca2+ entry activated by zymosan and by PKC activators was inhibited by the mitogen-activated protein kinase (MAPK) inhibitor PD98059. Moreover, activation of MAPK by C6-ceramide (C6C) triggered a similar Ca2+ influx as elicited by zymosan and PKC activators, suggesting that MAPK is an element of the pathway. The C6C-induced Ca2+ influx was also inhibited by PTF. These results indicate that PTF blocks the receptor-operated Ca2+ influx in NR8383 AMs by inhibiting PDE which may acts as a downstream element of the signaling pathway or by direct interaction with Ca2+ channels.
Sun
X
X
Department of Pediatrics, University of Texas Health Science Center at San Antonio, 78284, USA.
Martinez
J R
JR
Zhang
G H
GH
D000818:Animals; D015220:Calcium Channels / Q000187:drug effects / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D002460:Cell Line; D004075:Diglycerides / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D016676:Macrophages, Alveolar / Q000187:drug effects* / Q000378:metabolism*; D010431:Pentoxifylline / Q000494:pharmacology*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D015054:Zymosan / Q000494:pharmacology
D015220:Calcium Channels; D004075:Diglycerides; D005419:Flavonoids; D010726:Phosphodiesterase Inhibitors; C044295:1,2-dioctanoylglycerol; D015054:Zymosan; D011493:Protein Kinase C; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D013755:Tetradecanoylphorbol Acetate; D010431:Pentoxifylline; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one