The cationic amino acid transporter 2 is induced in inflammatory lung models and regulates lung fibrosis.
BACKGROUND
Arginine is an amino acid that serves as a substrate for the enzymes nitric oxide synthase (NOS) and arginase, leading to synthesis of NO and ornithine, respectively. As such, arginine has the potential to influence diverse fundamental processes in the lung.


METHODS
We used mice deficient in cationic amino acid transporter (CAT) 2 in models of allergic airway inflammation and pulmonary fibrosis.


RESULTS
We report that the arginine transport protein CAT2 was over-expressed in the lung during the induction of allergic airway inflammation. Furthermore, CAT2 mRNA was strongly induced by transgenically over-expressed IL-4, and allergen-induced expression was dependent upon signal-transducer-and-activator-of-transcription (STAT) 6. In situ mRNA hybridization demonstrated marked staining of CAT2, predominantly in scattered mononuclear cells. Analysis of allergic airway inflammation and bleomycin-induced inflammation in CAT2-deficient mice revealed that while inflammation was independent of CAT2 expression, bleomycin-induced fibrosis was dependent upon CAT2. Mechanistic analysis revealed that arginase activity in macrophages was partly dependent on CAT2.


CONCLUSIONS
Taken together, these results identify CAT2 as a regulator of fibrotic responses in the lung.
Niese
Kathryn A
KA
Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave, Cincinnati, Ohio 45229, USA.
Chiaramonte
Monica G
MG
Ellies
Lesley G
LG
Rothenberg
Marc E
ME
Zimmermann
Nives
N
D026923:Amino Acid Transport Systems, Basic / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001119:Arginase / Q000378:metabolism; D001120:Arginine / Q000378:metabolism; D001249:Asthma / Q000139:chemically induced / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D001761:Bleomycin; D003094:Collagen / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D018836:Inflammation Mediators / Q000378:metabolism; D015847:Interleukin-4 / Q000235:genetics / Q000378:metabolism; D008168:Lung / Q000276:immunology / Q000378:metabolism*; D008264:Macrophages / Q000201:enzymology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010047:Ovalbumin; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D050800:STAT6 Transcription Factor / Q000172:deficiency / Q000235:genetics; D015854:Up-Regulation
D026923:Amino Acid Transport Systems, Basic; D016207:Cytokines; D018836:Inflammation Mediators; D012333:RNA, Messenger; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D001761:Bleomycin; C087435:Slc7a2 protein, mouse; D015847:Interleukin-4; D010047:Ovalbumin; D003094:Collagen; D001120:Arginine; D001119:Arginase