Regulation of nitric oxide-mediated cytotoxic function of macrophages : role of L-arginine consuming enzyme arginase /
In microphages, L-arginase is utilized by nitric oxide synthase (NOS) to form nitric oxide (NO) and L-citrulline and by arginase to form urea and L-ornithine. NO derived from the NOS pathway serves as a major device for microphages to exert their cytotoxic effect. Since the availability of L-arginas...
| Main Author: | |
|---|---|
| Format: | Thesis Book |
| Language: | English |
| Published: |
[Place of publication not identified] :
[publisher not identified] ;
1999.
|
| Subjects: | |
| Online Access: | http://proxy.library.tamu.edu/login?url=http://proquest.umi.com/pqdweb?did=731681821&sid=1&Fmt=2&clientId=2945&RQT=309&VName=PQD |
| Summary: | In microphages, L-arginase is utilized by nitric oxide synthase (NOS) to form nitric oxide (NO) and L-citrulline and by arginase to form urea and L-ornithine. NO derived from the NOS pathway serves as a major device for microphages to exert their cytotoxic effect. Since the availability of L-arginase is a major determinant for NO synthesis in activated macrophage, we hypothesized that the competition between arginase and NOS for their common substrate L-arginase may be an effective mechanism for the regulation of NO production in microphages. We addressed this issue by studying the effects of an arginase inhibitor, L-norvaline, on lipopolysaccharide (LPS)-induced NO production in .1774A.1 mouse microphages. L-Norvaline, a specific arginase inhibitor, enhanced LPS-induced NO production from microphages. This enhancement was dependent upon the extracellular level of L-arginase. We further examined the hypothesis of competition between NOS and arginase in the regulation of NO production in microphages stimulated by cytokine interleukin (IL)-13. IL-13 significantly down-regulated LPS-induced NO production in microphages. The inhibitory effect of IL-13 on NO production was attributed to the induction of arginase through the activation of cAMP/PKA, tyrosine kinase, and p38 mitogen-activated protein kinase. Inhibition of activated arginase by L-norvaline profoundly restored the Y-l3-suppressed NO production. In a co-culture system, we found that over-expression of arginase in microphages led to the release of L-ornithine and putrescine into the medium and subsequently promoted tumor cell growth. The beneficial effect of arginase over-expression on tumor cells was abolished by L-norvaline, suggesting a pivotal role for macrophage arginase in tumor growth. On the other hand, transfection of the arginase gene into microphages significantly attenuated LPS-induced NO production and also reduced cytotoxicity of microphages. Based on these findings, we conclude that the urea cycle enzyme arginase competes with NOS for their common substrate L- arginase and thus regulates NO production. Under certain pathophysiological conditions, activation of arginase in microphages will not only neutralize their cytotoxic activity but also likely promote tumor cell growth by providing them with polyamines. It appears that microphages can play a dual role in tumor growth depending on the activation of the prevailing pathway for NOS or arginase. |
|---|---|
| Item Description: | Vita. "Major Subject: Medical Sciences". |
| Physical Description: | xi, 105 leaves : illustrations ; 28 cm. Issued also on microfiche from University Microfilm Inc. |
| Bibliography: | Includes bibliographical references (leaves 88-103). |