Increased
arginase I activity is associated with allergic disorders such as
asthma. How
arginase I contributes to and is regulated by allergic inflammatory processes remains unknown. CD4+ Th2 lymphocytes (Th2 cells) and
IL-13 are two crucial immune regulators that use STAT6-dependent pathways to induce allergic airways
inflammation and enhanced airways responsiveness to spasmogens (airways hyperresponsiveness (AHR)). This pathway is also used to activate
arginase I in isolated cells and in hepatic
infection with helminths. In the present study, we show that
arginase I expression is also regulated in the lung in a STAT6-dependent manner by Th2-induced allergic
inflammation or by
IL-13 alone. IL-13-induced expression of
arginase I correlated directly with increased synthesis of
urea and with reduced synthesis of NO. Expression of
arginase I, but not
eosinophilia or mucus hypersecretion, temporally correlated with the development, persistence, and resolution of IL-13-induced AHR. Pharmacological supplementation with
l-arginine or with NO donors amplified or attenuated IL-13-induced AHR, respectively. Moreover, inducing loss of function of
arginase I specifically in the lung by using RNA interference abrogated the development of IL-13-induced AHR. These data suggest an important role for metabolism of
l-arginine by
arginase I in the modulation of IL-13-induced AHR and identify a potential pathway distal to
cytokine receptor interactions for the control of IL-13-mediated bronchoconstriction in
asthma.