c-Kit modifies the inflammatory status of smooth muscle cells

PeerJ

article

Lei Song¹  Laisel Martinez²  Zachary M. Zigmond¹  Diana R. Hernandez²  Roberta M. Lassance-Soares²  Guillermo Selman²  Roberto I. Vazquez-Padron² 

[1] Department of Molecular and Cellular Pharmacology, Leonard M. Miller School of Medicine, University of Miami;DeWitt Daughtry Family Department of Surgery, Division of Vascular Surgery, Leonard M. Miller School of Medicine, University of Miami

关键词: c-Kit;    POVPC;    TAK1;    Smooth muscle cell;    NF-κB;    Inflammation;    NLK;   

DOI  :  10.7717/peerj.3418

学科分类：社会科学、人文和艺术（综合）

来源: Inra

【 摘 要 】

Backgroundc-Kit is a receptor tyrosine kinase present in multiple cell types, including vascular smooth muscle cells (SMC). However, little is known about how c-Kit influences SMC biology and vascular pathogenesis.MethodsHigh-throughput microarray assays and in silico pathway analysis were used to identify differentially expressed genes between primary c-Kit deficient (KitW/W–v) and control (Kit+/+) SMC. Quantitative real-time RT-PCR and functional assays further confirmed the differences in gene expression and pro-inflammatory pathway regulation between both SMC populations.ResultsThe microarray analysis revealed elevated NF-κB gene expression secondary to the loss of c-Kit that affects both the canonical and alternative NF-κB pathways. Upon stimulation with an oxidized phospholipid as pro-inflammatory agent, c-Kit deficient SMC displayed enhanced NF-κB transcriptional activity, higher phosphorylated/total p65 ratio, and increased protein expression of NF-κB regulated pro-inflammatory mediators with respect to cells from control mice. The pro-inflammatory phenotype of mutant cells was ameliorated after restoring c-Kit activity using lentiviral transduction. Functional assays further demonstrated that c-Kit suppresses NF-κB activity in SMC in a TGFβ-activated kinase 1 (TAK1) and Nemo-like kinase (NLK) dependent manner.DiscussionOur study suggests a novel mechanism by which c-Kit suppresses NF-κB regulated pathways in SMC to prevent their pro-inflammatory transformation.

【 授权许可】

CC BY