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Capmatinib suppresses LPS-induced interaction between HUVECs and THP-1 monocytes through suppression of inflammatory
Hyung Sub Park1, A M Abd El-Aty2, Ji Hoon Jeong3
1Department of Surgery, Seoul National University College of Medicine, Seoul, South Korea; Department of Surgery, Seoul National University Bundang Hospital, Seongnam, South Korea.
Background:
Capmatinib (CAP) is a drug that has been used to treat non-small cell lung cancer (NSCLC) in adults. Presently, its novel effects on skeletal muscle insulin signaling, inflammation, and lipogenesis in adipocytes have been uncovered with a perspective of drug repositioning. However, the impact of CAP on LPS-mediated interaction between human umbilical vein endothelial cells (HUVECs) and THP-1 monocytes has yet to be investigated.
Methods:
HUVECs and THP-1 monocytes were treated with LPS and CAP. The protein expression levels were determined using Western blotting. Target protein knockdown was conducted using small interfering (si) RNA transfection. Interactions between HUVECs and THP-1 cells were assayed using green fluorescent dye.
Results:
This study found that CAP treatment ameliorated cell adhesion between THP-1 monocytes and HUVECs and the expression of adhesive molecules, such as intracellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin. Moreover, phosphorylation of inflammatory markers, such as NFκB and IκB as well as TNFα and monocyte chemoattractant protein-1 (MCP-1) released from HUVECs and THP-1 monocytes, was prevented by CAP treatment. Treatment with CAP augmented PPARδ and IL-10 expression. siRNA-associated suppression of PPARδ and IL-10 abolished the effects of CAP on cell interaction between HUVECs and THP-1 cells and inflammatory responses. Further, PPARδ siRNA mitigated CAP-mediated induction of IL-10 expression.
Conclusion:
These findings imply that CAP improves inflamed endothelial-monocyte adhesion via a PPARδ/IL-10-dependent pathway. The current study provides in vitro evidence for a therapeutic approach for treating atherosclerosis.
Insights
Capmatinib (CAP) reduces inflammation and cell adhesion in endothelial and monocyte interactions. This drug works through a PPARδ/IL-10 pathway, offering potential for atherosclerosis treatment.
Area of Science:
- Endocrinology and Metabolism
- Immunology
- Cardiovascular Biology
Background:
- Capmatinib (CAP) is approved for non-small cell lung cancer (NSCLC).
- Emerging research reveals CAP's effects on insulin signaling, inflammation, and lipogenesis.
- The impact of CAP on endothelial-monocyte interactions, crucial in inflammation, remained unexplored.
Purpose of the Study:
- To investigate the effect of Capmatinib (CAP) on lipopolysaccharide (LPS)-induced interactions between human umbilical vein endothelial cells (HUVECs) and THP-1 monocytes.
- To elucidate the molecular mechanisms underlying CAP's action in endothelial-monocyte adhesion and inflammation.
Main Methods:
- HUVECs and THP-1 monocytes were stimulated with LPS and treated with CAP.
- Protein expression of adhesion molecules and inflammatory markers was analyzed via Western blotting.
- siRNA was used to suppress target proteins (PPARδ, IL-10), and cell adhesion was quantified using fluorescent dye assays.
Main Results:
- CAP treatment significantly reduced THP-1 monocyte adhesion to HUVECs and downregulated key adhesion molecules (ICAM-1, VCAM-1, E-selectin).
- CAP inhibited the phosphorylation of inflammatory signaling pathways (NFκB, IκB) and reduced the release of TNFα and MCP-1.
- CAP upregulated PPARδ and IL-10 expression, and blocking these via siRNA abolished CAP's anti-inflammatory and anti-adhesive effects.
Conclusions:
- Capmatinib ameliorates endothelial-monocyte adhesion and inflammation through a PPARδ/IL-10-dependent mechanism.
- These findings suggest CAP as a potential therapeutic agent for atherosclerosis by targeting endothelial inflammation.
