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MTOR Suppresses Environmental Particle-Induced Inflammatory Response in Macrophages
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A7548 - MTOR Suppresses Environmental Particle-Induced Inflammatory Response in Macrophages
Author Block: Z. Li, Y. Wu, S. Ying, W. Li, H. Shen, Z. Chen; Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China.
RATIONALE: Increasing toxicological and epidemiological studies have demonstrated that ambient particulate matter (PM) could cause adverse health effects including inflammation in the lung. Alveolar macrophages(AMs) represent a major type of innate immune responses to foreign substances. However, the detailed mechanisms of inflammatory responses induced by PM exposure in macrophages are still unclear.
METHODS: We monitored temporal changes of protein markers of mechanistic target of rapamycin (MTOR) in AMs in vivo by flow cytometry, and in cultured bone marrow derived macrophages (BMDMs), peritoneal macrophages, and RAW264.7 cells by western blots upon PM exposure. Pharmacological inhibitors and MTOR deficiency BMDMs were applied in vitro. Experimental airway inflammation was induced by PM in mice with specific knockdown of MTOR or Ras homolog enriched in brain (RHEB) in myeloid cells as well as their littermates, and broncho-alveolar lavage fluid cell count, cytokines production, hematoxylin-eosin staining were assayed.
RESULTS: PM treatment rapidly activated MTOR in macrophages. Pharmacological inhibition or genetic knockdown of MTOR in BMDMs leads to an amplified cytokine production upon PM exposure, and mice with specific knockdown of MTOR or RHEB in myeloid cells exhibit significantly aggregated airway inflammation. Mechanistically, MTOR deficiency further enhanced the PM-induced activation of NFKB signaling, and inhibition of this pathway by IKK 16 significantly ameliorated PM-induced inflammatory response in MTOR deficiency macrophages.
CONCLUSIONS: The present study demonstrates that MTOR serves as an early adaptive signaling that suppresses the PM-induced NFKB activation and inflammatory response in lung macrophages, and suggests that activation of MTOR in macrophages may represent a novel therapeutic strategy for PM-related airway disorders.
Author Block: Z. Li, Y. Wu, S. Ying, W. Li, H. Shen, Z. Chen; Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China.
RATIONALE: Increasing toxicological and epidemiological studies have demonstrated that ambient particulate matter (PM) could cause adverse health effects including inflammation in the lung. Alveolar macrophages(AMs) represent a major type of innate immune responses to foreign substances. However, the detailed mechanisms of inflammatory responses induced by PM exposure in macrophages are still unclear.
METHODS: We monitored temporal changes of protein markers of mechanistic target of rapamycin (MTOR) in AMs in vivo by flow cytometry, and in cultured bone marrow derived macrophages (BMDMs), peritoneal macrophages, and RAW264.7 cells by western blots upon PM exposure. Pharmacological inhibitors and MTOR deficiency BMDMs were applied in vitro. Experimental airway inflammation was induced by PM in mice with specific knockdown of MTOR or Ras homolog enriched in brain (RHEB) in myeloid cells as well as their littermates, and broncho-alveolar lavage fluid cell count, cytokines production, hematoxylin-eosin staining were assayed.
RESULTS: PM treatment rapidly activated MTOR in macrophages. Pharmacological inhibition or genetic knockdown of MTOR in BMDMs leads to an amplified cytokine production upon PM exposure, and mice with specific knockdown of MTOR or RHEB in myeloid cells exhibit significantly aggregated airway inflammation. Mechanistically, MTOR deficiency further enhanced the PM-induced activation of NFKB signaling, and inhibition of this pathway by IKK 16 significantly ameliorated PM-induced inflammatory response in MTOR deficiency macrophages.
CONCLUSIONS: The present study demonstrates that MTOR serves as an early adaptive signaling that suppresses the PM-induced NFKB activation and inflammatory response in lung macrophages, and suggests that activation of MTOR in macrophages may represent a novel therapeutic strategy for PM-related airway disorders.
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