Regulation of arginase expression by T-helper II cytokines and isoproterenol.
BACKGROUND
Trauma causes a release of catecholamines, transforming growth factor-beta (TGF-beta), and T-helper II cytokines (TH2). Individually, these substances also induce arginase in macrophages. The purpose of this study was to determine the synergistic interactions between isoproterenol, TGF-beta, and TH2 cytokines on arginase expression in macrophages.


METHODS
Confluent RAW 264.7 macrophages were incubated with various combinations of interleukins 4, 10, and 13 (IL-4, IL-10, IL-13), and TGF-beta with isoproterenol over 48 hours. Arginase activity, as well as arginase I expression by Western blot and reverse transcriptase-polymerase chain reaction, were measured.


RESULTS
Although isoproterenol, IL-4, IL-10, and IL-13 individually induced arginase, significant synergy between the combination of isoproterenol with either TGF-beta or the TH2 cytokines was observed. All cytokines except IL-10 also induced arginase I protein and mRNA. Arginase II protein was detected in cells exposed to IL-10.


CONCLUSIONS
We conclude that isoproterenol synergizes with IL-4, IL-13, and TGF-beta to increase arginase I mRNA and protein, as well as arginase activity in RAW 264.7 macrophages. Further, IL-10 synergizes with isoproterenol to increase arginase activity and arginase II protein. These synergistic mechanisms may compete with nitric oxide synthase for l-arginine substrate, thus shunting away available arginine from nitric oxide production and contributing to cellular immunosuppression observed after trauma.
Barksdale
Andrew R
AR
Department of Surgery, University of Kentucky College of Medicine, Lexington, KY 40536, USA.
Bernard
Andrew C
AC
Maley
Mary E
ME
Gellin
Gloria L
GL
Kearney
Paul A
PA
Boulanger
Bernard R
BR
Tsuei
Betty J
BJ
Ochoa
Juan B
JB
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D001119:Arginase / Q000096:biosynthesis / Q000378:metabolism*; D015153:Blotting, Western; D002460:Cell Line; D016207:Cytokines / Q000502:physiology*; D004357:Drug Synergism; D004790:Enzyme Induction; D016753:Interleukin-10 / Q000494:pharmacology; D018793:Interleukin-13 / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology; D007545:Isoproterenol / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects* / Q000201:enzymology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018418:Th2 Cells / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000494:pharmacology
D000318:Adrenergic beta-Agonists; D016207:Cytokines; D018793:Interleukin-13; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D015847:Interleukin-4; D015124:8-Bromo Cyclic Adenosine Monophosphate; D001119:Arginase; D007545:Isoproterenol