Spontaneous Production of Interleukin-5 and Its Heterogeneous Effect on Eosinophils in an Adult T-Cell Leukemia Patient

ABSTRACTWe examined the functional heterogeneity of eosinophils from an adult T-cell leukemia (ATL) patient with eosinophilia. A 63-year-old man was admitted to our hospital because of lymphadenopathy. The leukocyte count was 10 400 /mm3, with 36.0% eosinophils and 3.0% abnormal lymphocytes. The diagnosis of ATL was based on the presence in serum of anti- human T-cell lymphotrophic virus-1 antibody and on histologic demonstration of ATL cells. The mononuclear cells spontaneously produced eosinophil-related cytokines (granulocyte-macrophage colony stimulating factor, 5600pg/mL; interleukin (IL)-5, 375pg/mL). Peripheral eosinophils were fractionated into normodense eosinophils (NE) and hypodense eosinophils (HE) by a Percoll density gradient method, and these cells were compared in terms of several heterogeneous functions. The NE were more chemotactically attracted to IL-5 than the HE. More apoptotic cells appeared among the NE than among the HE and this difference was correlated with the positive rate of Fas antigen on eosinophils. Survival of the HE was longer than that of the NE. Survival of the HE was prolonged by IL-5 stimulation, but survival of the NE was not. These data suggest that functionally heterogeneous eosinophils were present in this ATL patient with eosinophilia and that IL-5 enhanced this heterogeneity. The response of eosinophils to IL-5 may have contributed to the patho- genesis of eosinophilia in this patient

ハイキシュ マウス モデル ニ オケル ガレクチン-9 ノ ヨボウ コウカ : コウチュウキュウ ユウソウ ト MMP-9 エ ノ エイキョウ

熊本大

Data from: Protective effect of Galectin-9 in murine model of lung emphysema: involvement of neutrophil migration and MMP-9 production

Purpose: Chronic obstructive pulmonary disease (COPD) is characterized by irreversible airflow obstruction and pulmonary emphysema. Persistent inflammation and remodeling of the lungs and airways result in reduced lung function and a lower quality of life. Galectin (Gal)-9 plays a crucial role as an immune modulator in various diseases. However, its role in the pathogenesis of pulmonary emphysema is unknown. This study investigates whether Gal-9 is involved in pulmonary inflammation and changes in emphysema in a porcine pancreatic elastase (PPE)-induced emphysema model. Materials and Methods: Gal-9 was administered to mice subcutaneously once daily from 1 day before PPE instillation to day 5. During the development of emphysema, lung tissue and bronchoalveolar lavage fluid (BALF) were collected. Histological and cytological findings, concentrations of chemokines and matrix metalloproteinases (MMPs) in the BALF, and the influence of Gal-9 treatment on neutrophils were analyzed. Results: Gal-9 suppressed the pathological changes of PPE-induced emphysema. The mean linear intercept (Lm) of Gal-9-treated emphysema mice was significantly lower than that of PBS-treated emphysema mice (66.1 ± 3.3 µm vs. 118.8 ± 14.8 µm, respectively; p < 0.01). Gal-9 decreased the number of neutrophils and levels of MMP-9, MMP-2 and tissue inhibitor of metalloproteinases (TIMP)-1 in the BALF. The number of neutrophils in the BALF correlated significantly with MMPs levels. Interestingly, Gal-9 pretreatment in vitro inhibited the chemotactic activity of neutrophils and MMP-9 production from neutrophils. Furthermore, in Gal-9-deficient mice, PPE-induced emphysema progressed significantly compared with that in wild–type (WT) mice (108.7 ± 6.58 µm vs. 77.19 ± 6.97 µm, respectively; p < 0.01). Conclusions: These results suggest that Gal-9 protects PPE-induced inflammation and emphysema by inhibiting the infiltration of neutrophils and decreasing MMPs levels. Exogenous Gal-9 could be a potential therapeutic agent for COPD

Gal-9 prevents PPE-induced neutrophil and lymphocyte inflammation in BALF.

<p>PPE-treated mice were given either Gal-9 in PBS or PBS alone from 1 day before PPE instillation to day 5, and BALF was collected on days 1, 3, 7, and 14. The number of total cells was counted, and cell differentiation was determined (n = 5–10). The number of total cells was high on day 7 in PPE (+) Gal-9 (-) (open circle) and the number of total cells in PPE (+) Gal-9 (+) (crosed circle) on day 7 was significantly lower than that of in PPE (+) Gal-9 (-) (A). Similarly, neutrophils and lymphocytes were significantly lower in PPE (+) Gal-9 (+) on day 7 than in PPE (+) Gal-9 (-) (B and D), and macrophages were not significantly difference between in PPE (+) Gal-9 (+) and in PPE (+) Gal-9 (-) (C). Data are presented as the mean ± SEM. *p < 0.05, **p < 0.01. Abbreviations: BALF, bronchoalveolar lavage fluid; PPE, porcine pancreatic elastase; PBS, phosphate buffered saline; Gal-9, galectin-9; SEM, standard error of the mean.</p

Gal-9 treatment decreases levels of MMP-9, MMP-2 and TIMP-1 but not neutrophil chemoattractants in BALF.

<p>PPE-treated mice were given either Gal-9 in PBS or PBS alone from 1 day before PPE instillation to day 5. BALF was collected on days 1, 3, 7, and 14, and the levels of MMP-9, MMP-2, TIMP-1, KC, MIP-2, and LIX protein were determined (A–F; n = 4–10). On day 7, the levels of MMP-9, MMP-2, TIMP-1 was significantly lower in PPE (+) Gal-9 (+) (closed circle) than in PPE (+) Gal-9 (-) (open circle) (A-C), but the levels of KC, MIP-2, and LIX did not differ (D-F). Data are presented as the mean ± SEM. *p < 0.05. Abbreviations: Gal-9, galectin-9; MMP-9, matrix metalloproteinase-9; MMP-2, matrix metalloproteinase-2; TIMP-1, tissue inhibitor of metalloproteinases-1; BALF, bronchoalveolar lavage fluid; KC, keratinocyte-derived cytokine; MIP-2, macrophage inflammatory protein-2; LIX, lipopolysaccharide-induced CXC chemokine; PPE, porcine pancreatic elastase; PBS, phosphate buffered saline; SEM, standard error of the mean.</p

Gal-9 inhibits the MMP-9 secretion from neutrophils.

<p>Mice were subcutaneously administered either Gal-9 (3 μg/animal) or PBS alone at 0h and 24h, then thioglycollate medium was injected intraperitoneally to induce neutrophils. Five hours later, neutrophils were harvested by peritoneal lavage and incubated for 1 h. The level of MMP-9 in culture supernatant was significantly lower in Gal-9-treated mice than in PBS-treated mice (n = 5 per each group). Data are presented as the mean ± SEM. *p < 0.05. Abbreviations: Gal-9, galectin-9; PBS, phosphate buffered saline; MMP-9, matrix metalloproteinase-9; SEM, standard error of the mean.</p