Role of Galectin-3 in Mast Cell Functions: Galectin-3-Deficient Mast Cells Exhibit Impaired Mediator Release and Defective JNK Expression
Huan‐Yuan ChenBhavya Bhavna SharmaLan YuRiaz I. ZuberiI‐Chun WengYuko KawakamiToshiaki KawakamiDaniel K. HsuFu‐Tong Liu
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Abstract Galectin-3 is a member of the β-galactoside-binding animal lectin family expressed in various cell types, including mast cells. To determine the role of galectin-3 in the function of mast cells, we studied bone marrow-derived mast cells (BMMC) from wild-type (gal3+/+) and galectin-3-deficient (gal3−/−) mice. Cells from the two genotypes showed comparable expression of IgE receptor and c-Kit. However, upon activation by FcεRI cross-linkage, gal3−/− BMMC secreted a significantly lower amount of histamine as well as the cytokine IL-4, compared with gal3+/+ BMMC. In addition, we found significantly reduced passive cutaneous anaphylaxis reactions in gal3−/− mice compared with gal3+/+ mice. These results indicate that there is a defect in the response of mast cells in gal3−/− mice. Unexpectedly, we found that gal3−/− BMMC contained a dramatically lower basal level of JNK1 protein compared with gal3+/+ BMMC, which is probably responsible for the lower IL-4 production. The decreased JNK1 level in gal3−/− BMMC is accompanied by a lower JNK1 mRNA level, suggesting that galectin-3 regulates the transcription of the JNK gene or processing of its RNA. All together, these results point to an important role of galectin-3 in mast cell biology.Keywords:
Galectin-3
Galectin
Mediator
Galectins exhibit a variety of biological functions.As a member of galectins,galectin-9 can induce accumulation and activation of eosinophils,it also plays a role in cell differentiation,apoptosis,adhesion,aggregation,modulation of inflammation and metastasis of tumor.This review summarizes the advances in galectin-9 study in these years.
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Abstract Heart failure (HF) is a serious disease syndrome characterized by elevated pro‐inflammatory cytokines and inflammatory mediators presume to have significant contribution on disease progression. Galectins are carbohydrate‐binding proteins responsible of various physiological functions. Role of galectins in heart failure has been ill‐defined. In the present case‐controls study, 136 patients clinically diagnosed with heart failure and 125 healthy Chinese controls were recruited. Levels of galectins (Gal‐1, 3 and 9) and cytokines (IFN‐γ, IL‐17A, IL‐4 and TGF‐β) were quantified by ELISA. Increased levels of galectin‐1 and 3 was observed in HF patients and associated with clinical severity. In addition, pro‐inflammatory cytokines such as IFN‐γ and IL‐17A were increased in patients whereas, anti‐inflammatory TGFβ was decreased. Galectin‐3 was positively correlated with IFN‐γ, IL‐17A and inversely with TGF‐β. Furthermore, ROC curve analysis suggested galectin‐3 as a promising biomarker for diagnosis and HF and clinical severity. Interestingly, a two‐year follow‐up indicated significant association of elevated galectin‐3 with mortality due to HF. In conclusion, galectin‐3 associated with HF and clinical manifestations possibly by inducing pro‐inflammatory cytokines and could be a possible biomarker of HF and severe clinical conditions.
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The purpose of this study was to investigate histamine and skin mast cells in psoriasis before and during 6 months of treatment with high-dose ranitidine. Sixteen psoriasis patients, presenting a mean PASI score of 15.4, were compared with 13 age- and sex-matched healthy controls. Resting extracellular skin levels of histamine and histamine release to mast cell secretagogues, as measured by the microdialysis technique, were increased in involved psoriasis skin compared to normal skin in the controls. Plasma histamine, but not basophil histamine release, was significantly increased in the patients. Mast cells and lymphocytes were significantly increased in numbers in involved versus non-involved skin in the patients, the lymphocytes being predominantly T-lymphocytes expressing HLA-DR activation. During 6 months of ranitidine treatment, mean PASI score of 15.4 decreased to 5.8. The lymphocyte infiltration, but not mast cell numbers, was significantly reduced during treatment, and histamine release to mast cell secretagogues was normalized. These observations suggest that skin mast cells in active psoriasis are functionally hyperreactive. The biochemical findings together with the clinical effect of ranitidine indicate that histamine may be involved in the pathophysiology of psoriasis.
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Compound 48/80
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Galectin-1 and galectin-3 have roles in cancer and inflammation. Galectin-1 has recently emerged as a significant protein produced by tumour cells to promote tumour development, angiogenesis and metastasis and consequently represents an important target to inhibit. The design of inhibitors targeting the carbohydrate recognition domain that is known to recognize galactose is an important approach in the fight against cancer. Based on the analysis of crystal structures, we pursued the concept that if the galactose was replaced with talose (the C2 epimer of galactose) as a scaffold, then O2 substituents would be directed closer to the protein surface and provide opportunity to design inhibitors that are more specific towards particular galectins. Our elucidation of X-ray crystal structures of two of our synthesized talosides in complex with galectin-1 and galectin-3 provides the first atomic information on the interactions of galectins, and indeed any protein, with talosides. These results have enabled a structure-based rationale for the specificity differences shown by galectin-1 and galectin-3 towards these talosides and demonstrate new opportunities for further exploitation as specific inhibitors of galectins.
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Abstract Thirty‐five synovial fluid (SF) specimens were examined for the presence of mast cells and for their histamine content. Mast cells were seen in SF cells from 27 of 35 fluids, and histamine was measurable in 19 of 34. There was a strong correlation between mast cell number and histamine content. No consistent relationship was found between either the mast cell number or histamine level and the patients' diagnoses, except that the 2 patients with systemic mastocytosis had markedly elevated values for both SF mast cell number and histamine content. SF mast cells from one of the mastocytosis patients were studied for histamine release; significant amounts of histamine were released upon exposure to anti‐human IgE, but not compound 48/80. Thus, mast cells similar to those present in connective tissue are frequently present in SF in numbers which correlate with SF histamine levels. These mast cells contain active proteases and are capable of degranulation. Mast cells were consistently present in large numbers in the SF of patients with systemic mastocytosis, but their numbers were highly variable in fluids of patients with other diseases.
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To investigate whether galectins 1, 3, and 8 are expressed in human cholesteatomas and whether any such expression does correlate with the level of apoptosis, which is, as we have previously shown, predictive of recurrence.7The analysis of 52 cholesteatomas resected by the same surgeon by means of canal wall up and canal wall down procedures.The immunohistochemical levels of expression of galectins 1, 3, and 8 were quantitatively determined (using computer-assisted microscopy) on conventional histological slides by means of specific anti-galectin-1, anti-galectin-3, and anti-galectin-8 antibodies. The level of apoptosis in each cholesteatoma under study had already been determined 7 by means of the in situ labeling of nuclear DNA fragmentation (Tolt-mediated dUTP nick end labeling [TUNEL] staining).Galectin-1 was expressed markedly in both the epithelial and the connective tissue areas of all the cholesteatomas under study. The levels of expression of galectin-3 and galectin-8 were considerably lower than that of galectin-1. The level of expression of galectin-3 correlated both highly and positively with the level of apoptosis.An upregulation of galectin-3 (known to have an antiapoptotic and antianoikis effect in certain model systems) expression, which is associated with pronounced apoptotic activity, could have a physiologically protective effect against the characteristically substantial apoptotic features occurring in recurrent cholesteatomas.
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Histamine is a chemical mediator synthesized and stored within secretory granules of human basophils and mast cells [1,2]. The central role of histamine as a mediator of allergic reactions is unchallenged and is also supported by the efficacy of antihistamines in relieving symptoms of the early-phase allergic response [3]. However, a recent hypothesis suggests that the role of histamine is not limited to the early-phase reaction, but may also have a role in the regulation of the late-phase response. This paper describes certain effects of histamine on human inflammatory cell activation, and in particular, its ability to directly activate human lung macrophages and the molecular mechanism for this interaction. These studies have important implications for the therapeutic potential of antihistamines in the treatment of patients with allergic disorders.
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Histamine H4 receptor
Allergic response
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Galectin-1
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The allergic process is believed to consist of two phases: early and late. The early phase reaction is mainly induced by histamine released from mast cells. Histamine binding specific cell receptors produces clinical allergic symptoms. This mediator also activates neutrophils and eosinophils as well as being a chemoattractant for these cells. Histamine increases IL-8 level and evokes leukocyte rolling on endothelial cells. Thus histamine participates in both early and late-phase allergic responses.
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Allergic Inflammation
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