Effects of theophylline and rolipram on leukotriene C₄ (LTC₄) synthesis and chemotaxis of human eosinophils from normal and atopic subjects

Abstract

1 The effects of the non-selective phosphodiesterase (PDE) inhibitor theophylline and the selective PDE4 inhibitor rolipram on leukotriene C4 (LTC4) synthesis and chemotaxis of complement 5a (C5a)-and platelet-activating factor (PAF)-stimulated human eosinophils obtained from normal and atopic donors were investigated. (IC50 3 nM) inhibited CSa-and PAF-stimulated eosinophil chemotaxis. The combination of PGE2 with theophylline resulted in an additive effect. 6 Both C5a-and PAF-stimulated eosinophil chemotaxis and LTC4 generation were significantly elevated in eosinophils from atopic individuals compared to normal subjects. However, eosinophils from normal and atopic individuals were not different with respect to their total cyclic AMP-PDE and PDE4 isoenzyme activities as well as the potencies of theophylline and rolipram to suppress LTC4 generation and chemotaxis.

Prostaglandin D2 is a potent chemoattractant for human eosinophils that acts via a novel DP receptor

“…41 The ability of PGD 2 to activate eosinophils while at the same time stimulating adenylyl cyclase is intriguing, as increased cAMP levels would be expected to attenuate eosinophil responses. The phosphodiesterase-4 inhibitor rolipram has been shown to inhibit eosinophil migration and CD11b expression in response to eotaxin, 42 PAF, 18,43,44 and C5a. Stimulation of adenylyl cyclase with forskolin 44 or isoproterenol 43 or addition of dibutyryl cAMP 43 had similar effects.…”

“…18,19 As stimulatory effects of PGD 2 have often been attributed to other prostanoid receptors, including FP 31,32 and TP 33,34 receptors, we tested the effects of PGF 2␣ , PGE 2 , and U46619, a TP receptor agonist, on eosinophil migration. None of these compounds exhibited significant chemoattractant effects on these cells, with the possible exception of PGF 2␣ at the highest concentration tested ( Figure 1A).…”

“…1 A number of studies have clearly shown that agents that raise adenosine 3Ј,5Ј-cyclic monophosphate (cAMP) levels in eosinophils inhibit various responses, including LTC 4 release, chemotaxis, and degranulation. 18,19 This raises the possibility that PGD 2 can activate eosinophils by a mechanism unrelated to the DP receptor. The objectives of the current study were to determine whether PGD 2 has a direct chemotactic effect on eosinophils and, if so, to investigate the hypothesis that this effect is mediated by a novel receptor for this compound.…”

Leukotrienes: Underappreciated Mediators of Innate Immune Responses

“…Increases in intracellular levels of cAMP can inhibit LT synthesis by a variety of enzymatic mechanisms (90), and commonly used cAMP-elevating drugs such as ␤-adrenergic agonists, theophylline, and phosphodiesterase inhibitors have been reported to inhibit LT synthesis by leukocytes (91). Although its clinical significance is unclear, in vivo cAMP elevation has been reported to impair pulmonary bacterial clearance in an animal model of pneumonia (92).…”

Roles of roflumilast, a selective phosphodiesterase 4 inhibitor, in airway diseases

“…Theophylline and PDE4 inhibitor (rolipram) suppressed platelet activating factor (PAF) and C5a-stimulated eosinophils decreasing leukotriene C4 (LTC4) synthesis and chemotaxis (12). In addition, rolipram caused concentrationdependent inhibition of zymosan-stimulated superoxide anion generation by human eosinophils (13).…”