Activation of triggering receptor expressed on myeloid cells-1 protects monocyte from apoptosis through regulation of myeloid cell leukemia-1.
BACKGROUND
Triggering receptor expressed on myeloid cells-1 (TREM-1) can amplify the proinflammatory response and may contribute to the pathogenesis of inflammatory disease such as sepsis. However, the role of TREM-1 in monocyte fate and the detailed molecular mechanisms evoked by TREM-1 are unknown.


METHODS
Adenoviruses overexpressing TREM-1 were constructed and transfected into a monocytic cell line. After activation of TREM-1 by agonist antibody with or without lipopolysaccharide, apoptosis was induced and assayed using flow cytometry. The signaling pathways downstream of TREM-1 were illustrated by inhibitory experiments. Proapoptotic/antiapoptotic protein levels were measured using immunoblot. In addition, the relationship between the expression levels of TREM-1 in monocytes and the magnitude of monocyte apoptosis were analyzed in septic patients.


RESULTS
Activation of TREM-1 protected monocytes from staurosporine-induced apoptosis. This characteristic was also obtained under lipopolysaccharide stimulation. The protection of TREM-1 against monocyte apoptosis was abrogated after inhibition of extracellular signal-regulated kinase or v-akt murine thymoma viral oncogene homologue signaling. Cross-linking of TREM-1 remarkably up-regulated myeloid cell leukemia-1 protein level, and inhibition of extracellular signal-regulated kinase or v-akt murine thymoma viral oncogene homologue resulted in the reduction of myeloid cell leukemia-1 expression. Inhibition of myeloid cell leukemia-1 abolished the antiapoptotic effect of TREM-1. Furthermore, in septic patients, TREM-1 levels were inversely correlated to the magnitude of apoptosis in monocyte.


CONCLUSIONS
TREM-1 played an important role in apoptosis in monocytes. Activation of TREM-1 protected monocytic cells from apoptosis through activation of both extracellular signal-regulated kinase and v-akt murine thymoma viral oncogene homologue pathways and increased expression of myeloid cell leukemia-1 protein. These findings provide a novel additional mechanism for TREM-1-mediated hyperinflammatory response in monocytes.
Department of Thoracic and Cardiovascular Surgery, Zhejiang University, Hangzhou, People's Republic of China.
Meiting
M
Cai
Qixing
Q
Chen
Chi
C
Chen
Xiwang
X
Liu
Jinchao
J
Hou
Congli
C
Zeng
Qiang
Q
Shu
Xiangming
X
Fang
D018806:APACHE; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000502:physiology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002469:Cell Separation; D000229:Dependovirus / Q000235:genetics; D005260:Female; D005434:Flow Cytometry; D005822:Genetic Vectors; D006801:Humans; D007902:Length of Stay; D020935:MAP Kinase Signaling System / Q000502:physiology; D008297:Male; D008562:Membrane Glycoproteins / Q000502:physiology*; D008875:Middle Aged; D009000:Monocytes / Q000502:physiology*; D009102:Multiple Organ Failure / Q000503:physiopathology; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology*; D060888:Real-Time Polymerase Chain Reaction; D011971:Receptors, Immunologic / Q000502:physiology*; D018805:Sepsis / Q000473:pathology; D015398:Signal Transduction / Q000502:physiology; D013268:Stimulation, Chemical; D000073871:Triggering Receptor Expressed on Myeloid Cells-1
D008562:Membrane Glycoproteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D011971:Receptors, Immunologic; C408842:TREM1 protein, human; D000073871:Triggering Receptor Expressed on Myeloid Cells-1; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt