Effects of the phosphodiesterase IV inhibitor rolipram on Th1 and Th2 immune responses in mice

Abstract

The present study was designed to investigate the effect of the phosphodiesterase IV inhibitor rolipram on Th1 and Th2 immune responses in mice. Mice were immunized subcutaneously at the base of the tail with ovalbumin (OVA) emulsified with complete Freund's adjuvant (day 0) and were treated daily with oral administration of various doses of rolipram from days 0 to 20. On day 21, production of anti-OVA IgG and proliferative responses to the antigen were determined. Anti-OVA IgG2a and interferon-gamma (IFN-gamma), as indicators of Th1 responses, and anti-OVA IgG1 and interleukin-10 (IL-10), as indicators of Th2 responses, were also measured. The results showed that treatment with rolipram failed to affect the production of OVA-specific IgG but decreased the proliferation of spleen cells to the antigen. Its inhibitory effect on these immune responses was correlated with a marked decrease in IFN-gamma but not IL-10 production, although neither anti-OVA IgG2a nor IgG1 production was affected by rolipram. These results suggest that rolipram may preferentially inhibit Th1 responses more effectively than Th2 responses. Administration of rolipram resulted in suppression of antigen (OVA)-induced arthritis in mice. The suppression of joint inflammation by rolipram was associated with the inhibition of the OVA-specific proliferative responses of spleen cells and IFN-gamma secretion. These results indicate that rolipram may be effective in regulating Th1-mediated diseases such as rheumatoid arthritis.

Safety and Pharmacodynamics of the PDE4 Inhibitor Roflumilast in Advanced B-cell Malignancies

“…Further, we suggest that when used in combination with PI3K δ , SYK or BTK inhibitors, the anti-inflammatory effects of PDE4 inhibitors may prevent the development of the life-threatening inflammatory pneumonitis that was recently reported in patients treated with a combination of PI3K δ and SYK inhibitors(45). This provocative prediction is substantiated in part by the putative role of interferon γ and other cytokines in this treatment-emergent pneumonitis and on the well-established ability of PDE4 inhibitors to reduce the expression and secretion of pro-inflammatory cytokines(9-11, 46-48). …”

Phosphodiesterase 4 Inhibitors Attenuate the Asthma Phenotype Produced by β2-Adrenoceptor Agonists in Phenylethanolamine N-Methyltransferase–Knockout Mice

“…Ova S/C WT and PNMT-KO mice were coadministrated 5 mg/kg roflumilast in 4% methylcellulose solution (24,(31)(32)(33) or 5 mg/kg rolipram in 0.1% methylcellulose (34,35) (Figure 1B), or an equal volume of the appropriate vehicle, via oral gavage. The doses chosen for all drugs were taken on the low end of what has been used in other murine studies.…”

“…Our rationale for this was that, for the b 2 AR agonists, we were attempting to "restore" b 2 AR agonist signaling in the PNMT-KO mice, not necessarily produce a drug effect (24-29, 32, 36). Similarly, for the PDE4 inhibitors we did not want the dose to be highly antiinflammatory, but simply a concentration that would skew b 2 AR signaling toward the Gas-cAMP pathway (22,(31)(32)(33)(34)(35).…”

Phosphodiesterase 4 Inhibition in the Treatment of Psoriasis, Psoriatic Arthritis and Other Chronic Inflammatory Diseases

“…From what is known on PDE4 action on lymphocytes, macrophages/dendritic cells subtypes, eosinophils and mast cells (for review, [29]) the overall net effect of PDE4 inhibitors seems more prominent for IFNγ or IL-17 dominated immune responses than IL-4/5/13 one [66]. Interestingly, a better effect on IFNγ dominated inflammation has been described for Treg in vivo studies [67].…”