Inhibitors of
cyclic nucleotide phosphodiesterases are known to suppress
lipopolysaccharide (LPS)-induced tumour
necrosis factor-alpha (
TNF-alpha) production in vitro in human monocytes. The most potent of these have selectivity for type IV
PDEs, suggesting that this class of PDE is the major type involved in the regulation of human
TNF-alpha production. Using compounds of two distinct chemical structural classes, a
quinazolinedione (CP-77059) and a 4 arylpyrrolidinone (
rolipram), we show here that PDE-IV-specific inhibitors are also potent in suppressing LPS-induced
TNF-alpha production in vitro in
sodium periodate-elicited murine macrophages (IC50s of 1 and 33, respectively). We then report the in vivo anti-inflammatory effect of PDE-IV inhibition in five murine models of
inflammation: (i) elevation of serum
TNF-alpha induced by a sublethal LPS injection; (ii) LPS-induced endotoxic
shock; (iii) LPS/
galactosamine-induced endotoxic
shock; (iv)
carrageenan-induced paw oedema; and (v)
adjuvant arthritis. Following a sublethal (5 micrograms/mouse) injection of LPS, serum
TNF-alpha levels in mice peaked sharply, reaching concentrations of 3-12 ng/ml 90 min after injection. In this sublethal LPS assay,
CP-77059 was about 30 times more potent than
rolipram, with a minimum effective dose of 0.1 mg/kg versus 3 mg/kg for
rolipram. This rank order is in keeping with the relative in vitro IC50s for
CP-77059 and
rolipram, as well as their relative Ki against the human PDE-IV
enzyme (46 nM and 220 nM, respectively). In LPS-induced endotoxic
shock,
rolipram and
CP-77059 at relatively high doses of 30 and 10 mg/kg, respectively, significantly reduced serum
TNF-alpha levels, and also inhibited mortality 66%. In the LPS/
galactosamine shock model, in which mice are rendered exquisitely sensitive to LPS by co-injection with
galactosamine, only 0.1 microgram of LPS/mouse is necessary for serum
TNF-alpha elevation and death. Both
rolipram and the
CP-77059 caused dose-dependent reduction of serum
TNF-alpha and lethality. In the
carrageenan-induced paw oedema model, in which there is a pronounced local
TNF-alpha response (without a serum
TNF-alpha elevation),
rolipram significantly inhibited paw swelling as well as localized
TNF-alpha levels in the paw. In the
adjuvant arthritis model, a chronic model of
inflammation also possessing localized
TNF-alpha elevation in the inflamed paw,
rolipram and
CP-77059 suppressed ankle swelling and radiological evidence of joint damage. These data are consistent with a major role for PDE-IV in regulation of
TNF-alpha production and inflammatory responses in murine systems.(ABSTRACT TRUNCATED AT 400 WORDS)