Inhibition of arginase I activity by RNA interference attenuates IL-13-induced airways hyperresponsiveness.
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.
Yang
Ming
M
Division of Molecular Biosciences, The John Curtin School of Medical Research, Australian National University, Canberra, Australia.
Rangasamy
Danny
D
Matthaei
Klaus I
KI
Frew
Ailsa J
AJ
Zimmmermann
Nives
N
Mahalingam
Suresh
S
Webb
Dianne C
DC
Tremethick
David J
DJ
Thompson
Philip J
PJ
Hogan
Simon P
SP
Rothenberg
Marc E
ME
Cowden
William B
WB
Foster
Paul S
PS
D000818:Animals; D001119:Arginase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D001120:Arginine / Q000378:metabolism; D001249:Asthma / Q000209:etiology / Q000378:metabolism; D016535:Bronchial Hyperreactivity / Q000209:etiology*; D015971:Gene Expression Regulation, Enzymologic; D018793:Interleukin-13 / Q000502:physiology*; D008168:Lung / Q000201:enzymology / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D020030:Nitric Oxide Donors / Q000378:metabolism; D034622:RNA Interference; D050800:STAT6 Transcription Factor; D018418:Th2 Cells
D018793:Interleukin-13; D020030:Nitric Oxide Donors; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D001120:Arginine; D001119:Arginase