Microenvironmental arginine depletion by macrophages in vivo

Abstract

Summary.-Since the tumour-selective cytotoxic activity of activated macrophages in vitro can be attributed to depletion of the culture medium of L-arginine by macrophage arginase, a series of experiments was designed to determine whether such a mechanism could operate in vivo.Extracellular fluid obtained from Gullino chambers within established tumours contained high levels of arginase, no detectable arginine and high levels of ornithine. When tumours were disaggregated into single-cell suspensions, arginase was readily detected within tumour macrophages but not within malignant cells. Inflammatory ascites induced in mice by Corynebacterium parvum was rich in arginase, depleted of L-arginine and cytotoxic in vitro to L5178Y and V79 cells. High levels of arginase in the ascites fluid were associated with resistance to challenge with syngeneic L5178Y cells.Lymph collected from the cisterna chyli in rats bearing a macrophage-rich sarcoma on the small bowel contained elevated levels of arginase, was depleted of arginine and contained increased concentrations of ornithine.We conclude that in sites of macrophage infiltration there is microenvironmental arginine depletion due to the action of arginase, and that arginase release could represent an important macrophage effector mechanism against a variety of targets, including malignant cells, virus-infected cells, fungi and parasites.

Arginine metabolism: nitric oxide and beyond

“…Sufficient quantities of arginase can limit the availability of arginine for NO synthesis by intact cells. For example, in wounds [222][223][224] and macrophage cultures [225,226], the extracellular fluid becomes almost completely depleted of arginine, whereas ornithine increases, indicative of high arginase activity. More recently, inhibition of arginase in LPS-treated rodent macrophages was shown to result in enhanced conversion of arginine into citrulline, indicating that arginase and iNOS can compete for arginine [227,228].…”

“…Earlier work from several laboratories [222][223][224][225]253,254] led to the notion that macrophage-derived arginase activity at the site of wounds plays a role in the recovery of host tissues from inflammation and infection, not only by removing arginine as substrate for NO synthesis but also by generating ornithine for the synthesis of proline, which is required for collagen synthesis. Supporting this proposition is the fact that there is an early burst of NO synthesis at the wound site, followed by depletion of arginine and a concomitant rise in the concentrations of ornithine and proline [224,253].…”

Arginase activity and nitric oxide levels may be considered as tumor markers in breast cancer

“…The relationship between the NOS and arginase involves not only the use of the same substrate (Hecker et al, 1995;Meyer et al, 1997). In healthy individuals, sufficient arginase activity can limit the use of arginine for the synthesis of NO [Currie et al, 1979;Vodovotz et al, 1994). In many studies, macrophage- induced arginase activity in wounds has shown to be involved in tissue healing and protecting against inflammation and infection.…”

Arginine Deprivation as a Targeted Therapy for Cancer

“…Thus, one may encounter normal tissue toxicity. These drawbacks may explain why the development of arginase as an antitumor agent has failed despite its activity seen in vitro [28,29]. Nevertheless, recently pegylated arginase has been shown to have activity in hepatocellular carcinoma both in vitro and in vivo due to lack of OCT expression in certain hepatocellular carcinoma cell lines [30].…”