tailieunhanh - Báo cáo y học: "Neutrophil elastase downmodulates native GCSFR expression and granulocyte-macrophage colony formatio"

Tuyển tập báo cáo các nghiên cứu khoa học quốc tế ngành y học dành cho các bạn tham khảo đề tài: Neutrophil elastase downmodulates native GCSFR expression and granulocyte-macrophage colony formation. | Piper et al. Journal of Inflammation 2010 7 5 http content 7 1 5 JOURNAL OF INFLAMMATION RESEARCH Open Access Neutrophil elastase downmodulates native G-CSFR expression and granulocyte-macrophage colony formation Melissa G Piper1 2 8 Pam R Massullo3 Megan Loveland4 Lawrence J Druhan2 5 Tamila L Kindwall-Keller6 Jing Ai2 4 Alexander Copelan7 Belinda R Avalos2 4 8 Abstract Background The granulocyte colony-stimulating factor receptor G-CSFR plays a critical role in maintaining homeostatic levels of circulating neutrophils PMN . The mechanisms modulating G-CSFR surface expression to prevent chronic neutrophilia are poorly understood. Here we report that neutrophil elastase NE proteolytically cleaves the G-CSFR on human PMN and blocks G-CSFR-mediated granulopoiesis in vitro. Methods Human peripheral blood PMN isolated from healthy donors were incubated with NE. Expression of the G-CSFR was analyzed by flow cytometry and western blot analyses. Detection of G-CSFR cleavage products from the culture supernatants was also performed. Human bone marrow mononuclear cells were also cultured in the presence or absence of NE to determine its effects on the proliferation of granulocyte-macrophage colony forming units CFU-GM . Results Treatment of PMN with NE induced a time-dependent decrease in G-CSFR expression that correlated with its degradation and the appearance of proteolytic cleavage fragments in conditioned media. Immunoblot analysis confirmed the G-CSFR was cleaved at its amino-terminus. Treatment of progenitor cells with NE prior to culture inhibited the growth of granulocyte-macrophage colony forming units. Conclusions These findings indicate that in addition to transcriptional controls and ligand-induced internalization direct proteolytic cleavage of the G-CSFR by NE also downregulates G-CSFR expression and inhibits G-CSFR-mediated granulopoiesis in vitro. Our results suggest that NE negatively regulates granulopoiesis through a novel .