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Deprecated: Implicit conversion from float 251.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 J+Immunol 2009 ; 182 (3): 1648-59 Nephropedia Template TP
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Myeloid-specific Expression of Api6/AIM/Sp? Induces Systemic Inflammation and Adenocarcinoma in the Lung #MMPMID19155514
Qu P; Du H; Li Y; Yan C
J Immunol 2009[Feb]; 182 (3): 1648-59 PMID19155514show ga
In order to study the functional role of apoptosis inhibition of myeloid lineage cells in tumor formation, apoptosis inhibitor 6 (Api6/AIM/Sp?) was overexpressed in a myeloid-specific c-fms-rtTA/(TetO)7-CMV-Api6 bitransgenic mouse model under the control of the c-fms promoter/intron 2. In this bitransgenic system, Api6-Flag fusion protein was expressed in myeloid lineage cells after doxycycline treatment. Induction of Api6 abnormally elevated levels of macrophages, neutrophils and dendritic cells in the bone marrow, blood and lung in vivo. BrdU incorporation and Annexin V binding studies showed systemically-increased cell proliferation and inhibition of apoptosis in myeloid lineage cells. Api6 overexpression activated oncogenic signaling pathways including Stat3, Erk1/2 and p38 in myeloid lineage cells in multiple organs of the bitransgenic mice. In the lung, severe inflammation and massive tissue remodeling were observed in association with increased-expression of pro-cancer cytokines/chemokines, decreased-expression of pro-apoptosis molecule genes and increased-expression of matrix metalloproteinase genes as a result of Api6 overexpression. Oncogenic CD11b+/Gr-1+ myeloid-derived suppressor cells (MDSCs) were systemically increased. After Api6 overexpression, lung adenocarcinoma was observed in bitransgenic mice with a 35% incidence rate. These studies suggest that dysregulation of myeloid cell populations by extracellular Api6 signaling leads to abnormal myelopoiesis and lung cancer.