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1.
Sci Signal ; 15(724): eabd2533, 2022 03 08.
Article in English | MEDLINE | ID: mdl-35258998

ABSTRACT

The pathogenesis of sepsis-induced acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) has not yet been fully elucidated. Growth arrest-specific 6 (Gas6) has marked effects on hemostasis and reduces inflammation through its interaction with receptor tyrosine kinases of the TAM family: Tyro3, Axl, and Mer. Here, we found that plasma concentrations of Gas6 and soluble Mer were greater in patients with severe sepsis or septic ALI/ARDS compared with those in normal healthy donors. To determine whether the Gas6-Mer axis was critical in the pathogenesis of ALI/ARDS, we investigated the effects of intravenous administration of the selective Mer inhibitor UNC2250 on lipopolysaccharide (LPS)-induced ALI in mouse models subjected to inhalation of LPS. UNC2250 markedly inhibited the infiltration into the lungs of neutrophils and monocytes with increased amounts of Gas6 and Mer proteins, severe lung damage, and increased amounts of reactive oxygen species (ROS) in LPS-induced ALI in mice. In human pulmonary aortic endothelial cells, LPS induced decreases in the amounts of endothelial nitric oxide synthase, thrombomodulin, and vascular endothelial-cadherin, which was blocked by treatment with UNC2250. UNC2250 also inhibited the LPS-dependent increases in cell proliferation and enhanced apoptosis in HL-60 cells, a human neutrophil-like cell line, and RAW264.7 cells, a mouse monocyte/macrophage cell line. These data provide insights into the potential multiple beneficial effects of the Mer inhibitor UNC2250 as a therapeutic reagent to treat inflammatory responses in ALI/ARDS.


Subject(s)
Respiratory Distress Syndrome , Sepsis , Animals , Endothelial Cells/metabolism , Humans , Lipopolysaccharides/pharmacology , Lung/metabolism , Mice , Mice, Inbred C57BL , Respiratory Distress Syndrome/chemically induced , Respiratory Distress Syndrome/drug therapy , Sepsis/metabolism
2.
Front Immunol ; 11: 589048, 2020.
Article in English | MEDLINE | ID: mdl-33628203

ABSTRACT

A substitution mutation of valine to phenylalanine at codon encoding position 617 of the Janus kinase 2 (JAK2) gene (JAK2V617F ) has been detected in myeloid cells of some individuals with higher levels of proinflammatory cytokine production such as interleukin (IL)-6. However, the mechanisms by which JAK2V617F mutation mediating those cytokines remain unclear. We, therefore, established JAK2V617F -expressing murine macrophages (JAK2V617F macrophages) and found that the levels of p-STAT3 were markedly elevated in JAK2V617F macrophages in association with an increase in IL-6 production. However, inhibition of STAT3 by C188-9 significantly decreased the production of IL-6. Furthermore, the JAK2V617F mutation endowed macrophages with an elevated glycolytic phenotype in parallel with aberrant expression of PKM1. Interestingly, silencing of PKM1 inactivated STAT3 in parallel with reduced IL-6 production. In contrast, ectopic expression of PKM1 elevated IL-6 production via STAT3 activation. Importantly, the JAK2V617F mutation contributed to PKM1 protein stabilization via blockade of lysosomal-dependent degradation via chaperone-mediated autophagy (CMA), indicating that the JAK2V617F mutation could protect PKM1 from CMA-mediated degradation, leading to activation of STAT3 and promoting IL-6 production.


Subject(s)
Interleukin-6/immunology , Janus Kinase 2/immunology , Macrophages/immunology , Pyruvate Kinase/immunology , Animals , Cell Line , Glycolysis , Humans , Interleukin-6/blood , Mice , Myeloproliferative Disorders/blood , Myeloproliferative Disorders/immunology , STAT3 Transcription Factor/immunology
3.
Int J Oncol ; 42(4): 1212-8, 2013 Apr.
Article in English | MEDLINE | ID: mdl-23354547

ABSTRACT

The global incidence of colorectal cancer (CRC) is increasing. Although there are emerging epigenetic factors that contribute to the occurrence, development and metastasis of CRC, the biological significance of epigenetic molecular regulation in different subpopulations such as cancer stem cells remains to be elucidated. In this study, we investigated the functional roles of the H3K4 demethylase, jumonji, AT rich interactive domain 1B (JARID1B), an epigenetic factor required for the continuous cell growth of melanomas, in CRC. We found that CD44(+)/aldehyde dehydrogenase (ALDH)(+) slowly proliferating immature CRC stem cell populations expressed relatively low levels of JARID1B and the differentiation marker, CD20, as well as relatively high levels of the tumor suppressor, p16/INK4A. Of note, lentiviral­mediated continuous JARID1B depletion resulted in the loss of epithelial differentiation and suppressed CRC cell growth, which was associated with the induction of phosphorylation by the c­Jun N­terminal kinase (Jnk/Sapk) and senescence­associated ß­galactosidase activity. Moreover, green fluorescent­labeled cell tracking indicated that JARID1B­positive CRC cells had greater tumorigenicity than JARID1B­negative CRC cells after their subcutaneous inoculation into immunodeficient mice, although JARID1B­negative CRC cells resumed normal growth after a month, suggesting that continuous JARID1B inhibition is necessary for tumor eradication. Thus, JARID1B plays a role in CRC maintenance. JARID1B may be a novel molecular target for therapy­resistant cancer cells by the induction of cellular senescence.


Subject(s)
Adenocarcinoma/metabolism , Cellular Senescence , Colorectal Neoplasms/metabolism , Jumonji Domain-Containing Histone Demethylases/metabolism , Nuclear Proteins/metabolism , Repressor Proteins/metabolism , Adenocarcinoma/pathology , Animals , Antigens, CD20/metabolism , Cell Line, Tumor , Cell Proliferation , Cell Transformation, Neoplastic/metabolism , Colorectal Neoplasms/pathology , Gene Knockdown Techniques , Humans , Mice , Mice, Inbred NOD , Mice, SCID , Neoplasm Transplantation , Neoplastic Stem Cells , RNA, Small Interfering/genetics , Tumor Burden
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