Arginine pathways and the inflammatory response: Interregulation of nitric oxide and polyamines: Review article

Abstract

An early response to an acute inflammatory insult, such as wound healing or experimental glomerulonephritis, is the conversion of arginine to the cytostatic molecule nitric oxide (NO). This 'anti-bacterial' phase is followed by the conversion of arginine to ornithine, which is the precursor for the pro-proliferative polyamines as well as proline for the production of extracellular matrix. This latter, pro-growth phase constitutes a 'repair' phase response. The temporal switch of arginine as a substrate for the cytostatic iNOS/NO axis to the pro-growth arginase/ ornithine/polyamine and proline axis is subject to regulation by inflammatory cytokines as well as interregulation by the arginine metabolites themselves. Arginine is also the precursor for another biogenic amine, agmatine. Here we describe the capacity of these three arginine pathways to interregulate, and propose a model whereby agmatine has the potential to serve in the coordination of the early and repair phase pathways of arginine in the inflammatory response by acting as a gating mechanism at the transition from the iNOS/NO axis to the arginase/ODC/polyamine axis. Due to the pathophysiologic and therapeutic potential, we will further examine the antiproliferative effects of agmatine on the polyamine pathway.

Aberrant regulation of argininosuccinate synthetase by TNF‐α in human epithelial ovarian cancer

“…AS is located at the cross-roads of inflammation and metabolism and, being considered a rate-limiting enzyme in arginine production, may play an important role in a variety of pathways including generation of nitric oxide, stroma (collagen) and polyamines. 20 TNF-a induced AS in a subset of ovarian cancer cell lines characterised by autocrine TNF-a signaling. Although cultured normal OSE cells expressed AS at comparable levels to the primary malignant cells and ovarian cancer cell lines in vitro, the induction of AS mRNA and protein seen by 24 hr of stimulation with TNF-a was confined to the malignant cells.…”

“…The term Ôarginine switchÕ has recently been coined emphasising that a balance exists between the processes of inflammation and repair, which are dysregulated in cancer. 20 Both inflammatory cytokines and metabolites, such as NO and agmatine, regulate the arginine switching mechanism. For example, NO has been shown to negatively regulate AS activity in intestinal epithelial cells following IL-1b treatment, possibly via post-translational modification in the form of S-nitrosylation at the Cys-132 residue.…”

Agmatine Suppresses Mesangial Cell Proliferation by Modulating Polyamine Metabolism

“…iNOS mediated NO generation plays a significant role in the early phase of GN. Importantly, agmatine is purported as a gating mechanism between these two arginine dependent pathways in GN, i.e., the early NO anti-proliferative/bactericidal phase and the later polyamine pro-proliferative, repair phase (Satriano 2004). In vivo studies using the anti-Thy-1 GN rat model support the proposed positive effects of agmatine in GN, in particular by suppressing proliferation and improving of renal function (Ishizuka et al 2000).…”

Adipose tissue remodeling and obesity

“…A hallmark feature of the M2 population is that they express F4/80, CD301, IL-10, and arginase 1 (37,38), the latter of which has been shown to inhibit NOS (iNOS) activity (41). Such a combination of factors may help to preserve normal adipocyte function by promoting tissue repair and angiogenesis in the increasing AT mass (42). Conversely, M1 macrophages, induced by LPS and the Th1 cytokine IFN-γ, express a repertoire of proinflammatory factors, which include F4/80, CD11c, TNF-α, IL-6, iNOS, and CCR2 (14,38).…”