Regulation of Arginase Expression by T-helper II Cytokines and Isoproterenol

Surgery. 2004 May;135(5):527-35. doi: 10.1016/j.surg.2003.10.007.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 8-Bromo Cyclic Adenosine Monophosphate / pharmacology
  • Adrenergic beta-Agonists / pharmacology*
  • Animals
  • Arginase / biosynthesis
  • Arginase / metabolism*
  • Blotting, Western
  • Cell Line
  • Cytokines / physiology*
  • Drug Synergism
  • Enzyme Induction
  • Interleukin-10 / pharmacology
  • Interleukin-13 / pharmacology
  • Interleukin-4 / pharmacology
  • Isoproterenol / pharmacology*
  • Macrophages / drug effects*
  • Macrophages / enzymology*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Th2 Cells / metabolism*
  • Transforming Growth Factor beta / pharmacology


  • Adrenergic beta-Agonists
  • Cytokines
  • Interleukin-13
  • Transforming Growth Factor beta
  • Interleukin-10
  • Interleukin-4
  • 8-Bromo Cyclic Adenosine Monophosphate
  • Arginase
  • Isoproterenol