Differential Roles of Galectin-1 and Galectin-3 in Regulating Leukocyte Viability and Cytokine Secretion

Abstract

Galectin-1 (Gal-1) and galectin-3 (Gal-3) exhibit profound but unique immunomodulatory activities in animals but their molecular mechanisms are incompletely understood. Early studies suggested that Gal-1 inhibits leukocyte function by inducing apoptotic cell death and removal, but recent studies show that some galectins induce exposure of the common death signal phosphatidylserine (PS) independently of apoptosis. In this study, we report that Gal-3, but not Gal-1, induces both PS exposure and apoptosis in primary activated human T cells, whereas both Gal-1 and Gal-3 induce PS exposure in neutrophils in the absence of cell death. Gal-1 and Gal-3 bind differently to the surfaces of T cells and only Gal-3 mobilizes intracellular Ca2+ in these cells, although Gal-1 and Gal-3 bind their respective T cell ligands with similar affinities. Although Gal-1 does not alter T cell viability, it induces IL-10 production and attenuates IFN-γ production in activated T cells, suggesting a mechanism for Gal-1-mediated immunosuppression in vivo. These studies demonstrate that Gal-1 and Gal-3 induce differential responses in T cells and neutrophils, and identify the first factor, Gal-3, capable of inducing PS exposure with or without accompanying apoptosis in different leukocytes, thus providing a possible mechanism for galectin-mediated immunomodulation in vivo.

Redundant and Antagonistic Functions of Galectin-1, -3, and -8 in the Elicitation of T Cell Responses

“…However, the antiproliferative effect could not be ascribed to cell death induction, because apoptosis was only observed when activated splenocytes were incubated in the presence of Gal-3 and not with Gal-1 or Gal-8. Of note, our results are in line with a previous report that Gal-3, but not Gal-1, induces apoptosis of primary activated T cells (21). Therefore, further studies are necessary to properly address the mechanism by which these Gals are exerting their antiproliferative effect on activated T cells.…”

“…Apoptosis was discounted as a mechanism responsible for the antagonistic effects of Gal-3, because this Gal was shown to induce apoptosis of activated, but not resting, T cells (data not shown). In agreement, Gal-3 failed to induce phosphatidylserine exposure in resting T cells, indicating that T cell activation is required to sensitize cells to Gal-3-induced apoptosis (21). Although the negative effect of Gal-3 on TCR activation was absent in the presence of a higher dose of Ag, Gal-3 was still able to inhibit Gal-1-and Gal-8-induced costimulation only when they were added simultaneously.…”

“…After the first step of purification, Gal-1 was alkylated in the presence of 0.1 M iodoacetamide (Sigma) overnight at 4˚C. The use of alkylated Gal-1 prevents oxidation that leads to a loss of activity and, at the same time, overcomes the need to use reducing agents, such as DTT, which is known to introduce deleterious effects in cell cultures (20,21). Gal-8 was biotinylated using EZ-Link Sulfo-NHS-Biotin (Pierce, Rockford, IL), following the manufacturer's instructions.…”

Intra-articular lentivirus-mediated delivery of galectin-3 shRNA and galectin-1 gene ameliorates collagen-induced arthritis

“…14,15 Recently, galectin-1 was shown to induce the production of interleukin-10 and attenuate the secretion of interferon-g in activated T cells, and galectin-3 was shown to promote the production of proinflammatory cytokines, such as interleukin-6 and tumor necrosis factor-a, in synovial fibroblasts. 16,17 A single injection of syngenic DBA/1 fibroblasts engineered to secret galectin-1 at the onset of disease abrogated experimental arthritis in mice. 18 Furthermore, microarray analysis of peripheral mononuclear cells has identified galectin-3 as a blood biomarker in the rat CIA model.…”

The Endoplasmic Reticulum Chaperone Cosmc Directly Promotes in Vitro Folding of T-synthase

“…1D). Human galectin-3 was chosen as one of the controls, because like Cosmc it is also a non-glycosylated recombinant protein, and has a similar size (ϳ30 kDa) to Cosmc (30,31). Importantly, addition of recombinant human BiP, a general ER chaperone, did not promote the renaturation of heat-denatured HPC4-sT-syn (Fig.…”