Suppression of IL-12 production by phosphodiesterase inhibition in murine endotoxemia is IL-10 independent.
Phosphodiesterase (PDE) inhibitors are potent regulators of various immune processes. Immune cells contain type IV and type III PDE. Here we studied in mice the effects of rolipram, a selective PDE IV inhibitor, and amrinone, a selective PDE III blocker, on plasma levels of IL-12 (p70), IFN-gamma, IL-1, TNF-alpha, and nitric oxide (NO) induced by intraperitoneal injection of Escherichia coli lipopolysaccharide (LPS) (80 mg/kg). Pretreatment of BALB/c mice with both rolipram (1-25 mg/kg) and amrinone (10-100 mg/kg) decreased plasma IL-12 levels in a dose-dependent manner. Similarly, LPS-elicited plasma IFN-gamma concentrations were suppressed by both rolipram and amrinone. However, LPS-induced plasma IL-1alpha levels were not affected by either of these compounds. In addition, rolipram inhibited IL-12, IFN-gamma, TNF-alpha and nitrite/nitrate (breakdown products of NO) production in C57BL/6 IL-10(+/+) mice as well as in their IL-10-deficient counterparts (C57BL/6 IL-10(-/-)). Our results suggest that rolipram and amrinone decrease the immune activation in endotoxemia through inhibition of the production of pro-inflammatory mediators IL-12, IFN-gamma, TNF-alpha and NO. These effects are not the consequences of the increase in IL-10 production by PDE inhibition.
Haskó
G
G
Department of Pharmacology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest.
Szabó
C
C
Németh
Z H
ZH
Salzman
A L
AL
Vizi
E S
ES
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000676:Amrinone / Q000008:administration & dosage; D000818:Animals; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D019446:Endotoxemia / Q000201:enzymology* / Q000276:immunology*; D007274:Injections, Intraperitoneal; D007371:Interferon-gamma / Q000096:biosynthesis / Q000097:blood; D016753:Interleukin-10 / Q000096:biosynthesis / Q000172:deficiency / Q000502:physiology*; D018664:Interleukin-12 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000097:blood; D008070:Lipopolysaccharides / Q000008:administration & dosage; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000037:antagonists & inhibitors; D011760:Pyrrolidinones / Q000008:administration & dosage; D020889:Rolipram; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors
D008070:Lipopolysaccharides; D011760:Pyrrolidinones; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D018664:Interleukin-12; D009569:Nitric Oxide; D007371:Interferon-gamma; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D000676:Amrinone; D020889:Rolipram