Arginase is greatly elevated in
asthma and is thought to play a role in the pathophysiology of this disease. As inhibitors of
phosphodiesterase 4 (PDE4), the predominant PDE in macrophages, elevate cAMP levels and reduce
inflammation, they have been proposed for use in treatment of
asthma and
chronic obstructive pulmonary disease. As cAMP is an inducer of
arginase, we tested the hypothesis that a
PDE4 inhibitor would enhance macrophage
arginase induction by key
cytokines implicated in
asthma and other
pulmonary diseases. RAW 264.7 cells were stimulated with
IL-4 or
transforming growth factor (
TGF)-beta, with and without the
PDE4 inhibitor rolipram.
IL-4 and
TGF-beta increased
arginase activity 16- and 5-fold, respectively.
Rolipram alone had no effect but when combined with
IL-4 and
TGF-beta synergistically enhanced
arginase activity by an additional 15- and 5-fold, respectively. The increases in
arginase I
protein and
mRNA levels mirrored increases in
arginase activity. Induction of
arginase II
mRNA was also enhanced by
rolipram but to a much lesser extent than
arginase I. Unlike its effect in RAW 264.7 cells,
IL-4 alone did not increase
arginase activity in human alveolar macrophages (AM) from healthy volunteers. However, combining
IL-4 with agents to induce cAMP levels induced
arginase activity in human AM significantly above the level obtained with cAMP-inducing agents alone. In conclusion, agents that elevate cAMP significantly enhance induction of
arginase by
cytokines. Therefore, consequences of increased
arginase expression should be evaluated whenever PDE inhibitors are proposed for treatment of inflammatory disorders in which
IL-4 and/or
TGF-beta predominate.