Opposite effects of galectin-1 on alternative metabolic pathways of L-arginine in resident, inflammatory, and activated macrophages

Abstract

Recent evidence has implicated galectins and their carbohydrate ligands as master regulators of the inflammatory response. Galectin-1, a member of this family, has shown specific anti-inflammatory and immunoregulatory effects. To gain insight into the potential mechanisms involved in these effects, we investigated the effects of galectin-1 in L-arginine metabolism of peritoneal rat macrophages. Pretreatment of macrophages with galectin-1 resulted in a dose- and time-dependent inhibition of lipopolysaccharide-induced nitric oxide (NO) production, accompanied by a decrease in inducible nitric oxide synthase (iNOS) expression (the classic pathway of L-arginine). On the other hand, galectin-1 favored the balance toward activation of L-arginase, the alternative metabolic pathway of L-arginine. Inhibition of NO production was not the result of increased macrophage apoptosis because addition of this beta-galactoside-binding protein to macrophages under the same experimental conditions did not affect the apoptotic threshold of these cells. To understand how endogenous galectin-1 is regulated in macrophages under inflammatory stress, we finally explored the ultrastructural distribution, expression, and secretion of galectin-1 in resident, inflammatory, and activated macrophages. This study provides an alternative cellular mechanism based on the modulation of L-arginine metabolism to understand the molecular basis of the anti-inflammatory properties displayed by this carbohydrate-binding protein.

A Novel Function for Galectin-1 at the Crossroad of Innate and Adaptive Immunity: Galectin-1 Regulates Monocyte/Macrophage Physiology through a Nonapoptotic ERK-Dependent Pathway

“…Interaction of these stimuli with specific cell surface receptors may induce five different states of macrophage activation, which may determine the quality and magnitude of adaptive immune responses: 1) "innate activation," which is induced by microbial products that are recognized by pattern recognition receptors and is responsible for the production of proinflammatory cytokines; 2) "humoral activation," which is triggered by cross-linking of Fc and complement receptors and is critical for functions such as phagocytosis and secretion of pro-and anti-inflammatory cytokines; 3) "classical activation," which is typically mediated by the priming stimulus IFN-␥ and is critical for the microbicidal activity of macrophages and DTH responses; 4) "alternative activation," which is triggered by IL-4 and IL-13, induces arginase expression, and determines the generation of Th2 responses; and 5) "deactivation," which is triggered by anti-inflammatory cytokines and uptake of apoptotic cells and results in MHC-II down-regulation and secretion of high levels of IL-10, TGF-␤, and PGE 2 (34). The present study together with our previous observations that galectin-1 favors arginase activity (21) and promotes PGE 2 production (35) suggests that this endogenous lectin might promote a state of "alternative activation" or "deactivation" in elicited macrophages.…”

“…Galectin-1, a prototype member of this protein family, has the potential to regulate the inflammatory response (13)(14)(15)(16) and confer immune privilege to tumor cells (17). How galectin-1 exerts its immunoregulatory activity is poorly understood, primarily because of its pleiotropic nature where it has been shown to affect T cell activation and proliferation (18,19), T cell adhesion to extracellular matrix (20), and NO production (21). Foremost, however, has been the ability of galectin-1 to promote apoptosis of activated T cells through binding to specific carbohydrate ligands on cell surface glycoconjugates (22)(23)(24).…”

T cell apoptosis at the maternal–fetal interface in early human pregnancy, involvement of galectin-1

“…The ␣-2,6-sialylation of poly-N-acetyllactosamine moieties by ST6Gal1 interferes with gal1 binding (22), protecting Th2 cells from gal1-induced cell death (21). Many other effects of gal1 on cell adhesion, T cell proliferation, monocytes, and neutrophils have been reported (17,(23)(24)(25)(26).…”

iNOS affects matrix production in distal lung fibroblasts from patients with mild asthma

“…L-arginine metabolized through arginase yields ornithine, a precursor of proline and polyamines involved in cell growth and proliferation (47). As glucocorticoids have been shown to downregulate iNOS, arginase is instead upregulated (48) and arginase activity has been shown to be upregulated in asthmatics subjects (49).…”