原创力文档regulation of progranulin expression in human microglia and proteolysis of progranulin by matrix metalloproteinase-12 (mmp-12)监管progranulin表达人类的小胶质细胞和蛋白质水解progranulin的矩阵metalloproteinase-12(mmp-12).pdfVIP
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regulation of progranulin expression in human microglia and proteolysis of progranulin by matrix metalloproteinase-12 (mmp-12)监管progranulin表达人类的小胶质细胞和蛋白质水解progranulin的矩阵metalloproteinase-12(mmp-12)
Regulation of Progranulin Expression in Human
Microglia and Proteolysis of Progranulin by Matrix
Metalloproteinase-12 (MMP-12)
Hyeon-Sook Suh*, Namjong Choi, Leonid Tarassishin, Sunhee C. Lee
Department of Pathology, Albert Einstein College of Medicine, Bronx, New York, United States of America
Abstract
Background: The essential role of progranulin (PGRN) as a neurotrophic factor has been demonstrated by the discovery that
haploinsufficiency due to GRN gene mutations causes frontotemporal lobar dementia. In addition to neurons, microglia in
vivo express PGRN, but little is known about the regulation of PGRN expression by microglia.
Goal: In the current study, we examined the regulation of expression and function of PGRN, its proteolytic enzyme
macrophage elastase (MMP-12), as well as the inhibitor of PGRN proteolysis, secretory leukocyte protease inhibitor (SLPI), in
human CNS cells.
Methods: Cultures of primary human microglia and astrocytes were stimulated with the TLR ligands (LPS or poly IC), Th1
cytokines (IL-1/IFNc), or Th2 cytokines (IL-4, IL-13). Results were analyzed by Q-PCR, immunoblotting or ELISA. The roles of
MMP-12 and SLPI in PGRN cleavage were also examined.
Results: Unstimulated microglia produced nanogram levels of PGRN, and PGRN release from microglia was suppressed by
the TLR ligands or IL-1/IFNc, but increased by IL-4 or IL-13. Unexpectedly, while astrocytes stimulated with proinflammatory
factors released large amounts of SLPI, none were detected in microglial cultures. We also identified MMP-12 as a PGRN
proteolytic enzyme, and SLPI as an inhibitor of MMP-12-induced PGRN proteolysis. Experiments employing PGRN siRNA
demonstrated that microglial PGRN was involved in the cytokine and chemokine production following TLR3/4 activation,
with its effect on TNFa being the most conspicuous.
Conclusions: Our study
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