Effects of rolipram, a selective inhibitor of type 4 phosphodiesterase, on lipopolysaccharide-induced uveitis in rats.
OBJECTIVE
To investigate effects of rolipram, an inhibitor of type 4 phosphodiesterase, on lipopolysaccharide (LPS)-induced uveitis in Wistar rats.


METHODS
A total of 100 microg LPS was injected into the rat footpad. Rolipram (Wako Pure Chemical, Osaka, Japan) was injected intraperitoneally 30 minutes before administration of LPS. Levels of intracameral protein, cells, E-selectin, tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, and nitrite were determined. E-selectin, TNF-alpha, IL-6, and inducible nitric oxide synthase (iNOS) mRNAs and immunohistochemical reactivity of nuclear factor (NF)-kappa B and TNF-alpha were also examined in the iris-ciliary body.


RESULTS
After LPS injection, intracameral protein and cells increased from 18 to 30 hours later. Rolipram, however, inhibited elevation of protein and cells. After LPS injection, mRNA levels of E-selectin, TNF-alpha, and IL-6 in the iris-ciliary body increased 3 hours later, and iNOS mRNA increased 6 hours later. Elevation of mRNA levels for E-selectin, TNF-alpha, and IL-6 was inhibited by rolipram. After LPS injection, intracameral TNF-alpha and IL-6 levels increased 4 to 6 hours later, and nitrite levels increased 14 to 20 hours later. Elevation of TNF-alpha and IL-6 levels was decreased by rolipram. Rolipram did not affect iNOS mRNA and nitrite levels. Immunoreactivity of NF-kappa B was strong 1 hour after LPS injection, and was decreased by rolipram. Immunoreactivity of TNF-alpha was strong 4 hours after LPS injection and was decreased by rolipram.


CONCLUSIONS
NF-kappa B translocation and expression of E-selectin, TNF-alpha, and IL-6 are involved in the pathogenesis of LPS-induced uveitis and are inhibited by rolipram. The inhibitory effect of rolipram in uveitis may be independent of iNOS synthesis.
Department of Ophthalmology, Toyama Medical and Pharmaceutical University, Sugitani, Toyama, Japan. ophthal@ms.toyama-mpu.ac.jp
Zai-Long
ZL
Chi
Seiji
S
Hayasaka
Xue-Yun
XY
Zhang
Yoriko
Y
Hayasaka
Hu-Shan
HS
Cui
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000818:Animals; D001082:Aqueous Humor / Q000378:metabolism; D002924:Ciliary Body / Q000378:metabolism; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D019040:E-Selectin / Q000235:genetics / Q000378:metabolism; D004926:Escherichia coli; D007124:Immunoenzyme Techniques; D007274:Injections, Intraperitoneal; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D007498:Iris / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D009573:Nitrites / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020889:Rolipram / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D014606:Uveitis, Anterior / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*
D019040:E-Selectin; D015850:Interleukin-6; D008070:Lipopolysaccharides; D016328:NF-kappa B; D009573:Nitrites; D010726:Phosphodiesterase Inhibitors; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D020889:Rolipram