Type 4 phosphodiesterase-dependent pathways: role in inflammatory processes.

Type 4 phosphodiesterases (PDE4) belong to a superfamily of at least 11 isozymes catalyzing the hydrolysis of cyclic AMP (cAMP) and/or cyclic GMP (cGMP). PDE4 regulate intracellular levels of cAMP and are the predominant PDE expressed in inflammatory cells. Elevation of cAMP produces the inhibition of different inflammatory processes, such as cellular trafficking, cytokine release or reactive oxygen species production. But recent papers showed that the involvement of PDE4 in inflammatory mechanisms cannot be completely attributed to a cAMP-dependent pathway. The wide range of inflammatory mechanisms controlled by PDE4 designated these enzymes as a good target for anti-inflammatory compounds. PDE4 inhibitors have been demonstrated to be very potent in the treatment of chronic inflammatory diseases like asthma or chronic obstructive pulmonary disease (COPD) but their therapeutic window has yet to be improved.