Reciprocal regulation of the nitric oxide synthase/arginase balance in mouse bone marrow‐derived macrophages by TH 1 and TH 2 cytokines

Abstract

Activation with lipopolysaccharide induces macrophages to produce the enzymes arginase and nitric oxide (NO) synthase. Both enzymes use as a substrate the amino acid L-arginine, which can be either hydrolyzed by arginase to urea and ornithine or oxidized by NO synthase to NO and citrulline. NO is important in the bactericidal and cytotoxic activities of macrophages. An equivalent functional role of arginase and its products is not known. We tested the induction of arginase in bone marrow-derived macrophages by endogenous mediators that are known to induce NO synthase, such as interferon-gamma (IFN-gamma), or suppress the induction of this enzyme, such as interleukin (IL)-4, IL-10, and prostaglandin E2 (PGE2). We find that PGE2 and the TH2 cytokines IL-4 and IL-10 are potent inducers of arginase. In contrast, the TH1 cytokine IFN-gamma does not induce arginase. Simultaneous application of both types of mediators leads to reduced induction of both arginase and NO synthase. Exposure of macrophage cultures to inducers of NO synthase exhausts their ability to respond subsequently to inducers of arginase. Conversely, exposure of the cells to inducers of arginase exhausts their ability to respond subsequently to inducers of NO synthase. The results are consistent with a competition of both enzymes for their substrate, L-arginine, with a reciprocal inhibition in the induction of both enzymes, or a combination of both phenomena. The enzymes NO synthase and arginase appear to define two alternate functional states of macrophages, induced by TH1 and TH2 cytokines, respectively.

M-1/M-2 Macrophages and the Th1/Th2 Paradigm

“…As an example, our results show that M-2 macrophages have a propensity to express arginase/ornithine production. Other recent results have shown that the Th2 cytokine IL-4 also increases macrophage arginase/ornithine production (64). Therefore, if macrophages from an individual have an M-2 propensity and his T lymphocytes have a Th2 propensity, then one would predict that there would be synergy in stimulating the arginase/ornithine pathway.…”

Alternative activation deprives macrophages of a coordinated defense program to Mycobacterium tuberculosis

“…Thus, arginase production directly affects the ability of host cells to induce nitrosative stress. Th1 and Th2 cytokines have previously been shown to antagonistically regulate arginase and iNOS expression [44,45]. Changes in expression levels of the transcripts for arginase 1 and iNOS induced by M. tuberculosis infection were determined for resting as well as alternatively and classically activated macrophages ( Fig.…”

The inhibitory effect of nitrite, a stable product of nitric oxide (NO) formation, on arginase

“…Nevertheless, a reciprocal induction of ~,rginase and NO synthase synthesis regulated by Th-1 and "! 'h-2 cytokines has been reported [10,11]. In addition, both nzymes are inhibited by the end product of the reaction that they catalyze: L-ornithine is a competitive inhibitor of argiJase [12,13] and this can be explained based on their identical ,.tructural parts [13], while NO can block its own excess synhesis via binding to the porphyrin part of the active site of "qO synthase [14,15].…”