Abstract
Galectin-9 (Gal-9), a lectin having a β-galactoside-binding domain, can induce apoptosis of Th1 cells by binding to TIM-3. In addition, Gal-9 inhibits IgE/Ag-mediated degranulation of mast cell/basophilic cell lines by binding to IgE, thus blocking IgE/Ag complex formation. However, the role of Gal-9 in mast cell function in the absence of IgE is not fully understood. Here, we found that recombinant Gal-9 directly induced phosphorylation of Erk1/2 but not p38 MAPK in a human mast cell line, HMC-1, which does not express FcεRI. Gal-9 induced apoptosis and inhibited PMA/ionomycin-mediated degranulation of HMC-1 cells. On the other hand, Gal-9 induced cytokine and/or chemokine production by HMC-1 cells, dependent on activation of ERK1/2 but not p38 MAPK. In addition, the lectin activity of Gal-9 was required for Gal-9-mediated cytokine secretion by HMC-1 cells. These observations suggest that Gal-9 has dual properties as both a regulator and an activator of mast cells.
Highlights
IntroductionGalectin-9 (Gal-9) was first identified as a chemoattractant and activating factor for eosinophils. [1,2,3] It is abundantly expressed in various tissues, especially the epithelium of the gastrointestinal tract, and in a variety of cells such as macrophages, eosinophils, mast cells, fibroblasts and synovial cells. [4,5,6,7].Gal-9 influences various biological functions such as cell aggregation, adhesion, apoptosis, survival, activation and differentiation by binding to T-cell immunoglobulin and mucin domain-containing protein 3 (TIM-3). [5,8,9] Like Gal-9, Tim-3 is expressed on various types of cells, including Th1 cells, [9] Tc1 cells, [10] Th17 cells, [11] NK cells, [12] NKT cells, [13,14] dendritic cells (DC) [15] and mast cells (MCs). [16,17] It is known that Gal-9 has anti-tumor activity by promoting activation of NK cells [18] and cytotoxic T lymphocytes by enhancing DC maturation. [19] Gal-9 induces aggregation of melanoma and breast cancer cell lines and suppresses metastasis. [20,21,22] It was suggested that Gal-9 is a negative regulator of development of autoimmune diseases such as experimental autoimmune encephalomyelitis (EAE) and collagen-induced arthritis (CIA) in mice
We found that recombinant human galectin-9 (rhGal-9) induced phosphorylation of Erk1/2, but not p38 MAPK, in HMC-1 cells (Figure 2), suggesting that rhGal-9 may influence the function of HMC-1 cells
We demonstrated that Gal-9 has dual roles in the functions of a human mast cell line, HMC-1
Summary
Galectin-9 (Gal-9) was first identified as a chemoattractant and activating factor for eosinophils. [1,2,3] It is abundantly expressed in various tissues, especially the epithelium of the gastrointestinal tract, and in a variety of cells such as macrophages, eosinophils, mast cells, fibroblasts and synovial cells. [4,5,6,7].Gal-9 influences various biological functions such as cell aggregation, adhesion, apoptosis, survival, activation and differentiation by binding to T-cell immunoglobulin and mucin domain-containing protein 3 (TIM-3). [5,8,9] Like Gal-9, Tim-3 is expressed on various types of cells, including Th1 cells, [9] Tc1 cells, [10] Th17 cells, [11] NK cells, [12] NKT cells, [13,14] dendritic cells (DC) [15] and mast cells (MCs). [16,17] It is known that Gal-9 has anti-tumor activity by promoting activation of NK cells [18] and cytotoxic T lymphocytes by enhancing DC maturation. [19] Gal-9 induces aggregation of melanoma and breast cancer cell lines and suppresses metastasis. [20,21,22] It was suggested that Gal-9 is a negative regulator of development of autoimmune diseases such as experimental autoimmune encephalomyelitis (EAE) and collagen-induced arthritis (CIA) in mice. Like anti-TIM-3 mAb, [10] Gal-9 can suppress development of EAE by inducing Th1 cell apoptosis via TIM-3. [28] the reason for that apparent discrepancy is unclear, the report using anti-TIM-3 mAbs did not fully characterize them, i.e., whether they were agonistic, blocking or depletion Abs These observations suggest that the biological function of Gal-9 may be mediated independently of TIM-3 in certain settings. In the present study we examined the role of Gal-9 in the functions of a human mast cell line, HMC-1, which does not express FceRI, in the absence of IgE/Ag stimulation. We found that human Gal-9 enhanced cytokine secretion, but suppressed survival and degranulation, of HMC-1 These observations suggest that Gal-9 has dual properties as a regulator and activator of mast cells
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