[ Vol. 13 No. 2 ] (May - August 2012 )
A possible role for arginine in the proteasomal regulation of inflammatory cytokines

Charles W. Van Way Ill
ShockTrauma Research Center, University of Missouri (United States)


Background:Hemorrhagic shock exposes cells and tissues to hypoxia, and serves as a primary trigger of inflammation. Considerable efforts have been undertaken to reduce post-traumatic systemic inflammation through administration of modifying agents. One such agent is arginine, a conditionally essential basic amino acid. In addition to serving as a primary substrate for nitric oxide synthase, arginine is a nitrogen donor in a number of biosynthetic reactions. Circulating plasma levels of arginine are notably reduced under conditions of stress, suggesting that administration of arginine might be of therapeutic benefit under such conditions. There have been a number of studies in experimental animals subject to hemorrhagic shock. In general, the conclusion from such studies is that addition of arginine to the resuscitation regimen promotes overall survival.

We have expose inflammatory mediator cells to an in vitro environment of controlled hypoxia to determine the consequences of hypoxia on mechanisms that regulate inflammation. Recent observations from our group have indicated that the cellular proteasome, in addition to eliminating ubiquinated proteins, serves as a key regulator of inflammatory mediator production. This is accomplished by the cellular control of the types of proteolytic subunits expressed by the proteasome. Under conditions of stress, the cellular proteasome can replace its normal complement of proteases with proteases that define the more biologically active immunoproteasome. We thus have hypothesized that the exposure to hypoxia will induce such changes in the proteasome, and further that the inclusion of arginine in the cell culture medium would modulate the changes induced by hypoxia and influence the production of inflammatory mediators in a dose-dependent fashion.

Our approach was to expose the RAW 264.7 macrophage-like mouse cell line to either hypoxic or normal culture conditions. Besides assessing growth rates, we monitored levels of ATP as a measure of the energy-generating potential of the cells. We also measured levels of the individual proteases of the cellular proteasome as a reflection of the cellular response to hypoxia, and measured changes in the proteolytic activities of the proteasomes. Finally, we assessed the consequences of inclusion of arginine in the culture medium as a potential mediator of the cellular response to hypoxia. Our results provide convincing evidence for a potentially important role for arginine in modulating the inflammatory potential of macrophages under hypoxic conditions.


The 14th Congress of Parenteral and Enteral Nutrition Society of Asia
“From Nutrition Support to Nutrition Therapy”
October 14-16, 2011, Taipei, Taiwan 
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