Resveratrol Attenuates Staphylococcus Aureus-Induced Monocyte Adhesion through Downregulating PDGFR/AP-1 Activation in Human Lung Epithelial Cells.

I-Ta Lee,Chuen-Mao Yang,Chien-Chung Yang,Chih-Chung Lin,Chih-Chung Lin,Li-Der Hsiao,Chien-Chung Yang,Ming-Yen Wu,Chien-Chung Yang

doi:10.3390/ijms19103058

Abstract

Staphylococcus aureus (S. aureus) is a very common Gram-positive bacterium. It is widely distributed in air, soil, and water. S. aureus often causes septicemia and pneumonia in patients. In addition, it is considered to play a key role in mediating cell adhesion molecules upregulation. Resveratrol is a natural antioxidant with diverse biological effects, including the modulation of immune function, anti-inflammation, and cancer chemoprevention. In this study, we proved that S. aureus-upregulated vascular cell adhesion molecule-1 (VCAM-1) expression in human lung epithelial cells (HPAEpiCs) was inhibited by resveratrol. We also observed that resveratrol downregulated S. aureus-enhanced leukocyte count in bronchoalveolar lavage (BAL) fluid in mice. In HPAEpiCs, S. aureus stimulated c-Src, PDGFR, p38 MAPK, or JNK1/2 phosphorylation, which was inhibited by resveratrol. S. aureus induced the adhesion of THP-1 cells (a human monocytic cell line) to HPAEpiCs, which was also reduced by resveratrol. Finally, we found that S. aureus induced c-Src/PDGFR/p38 MAPK and JNK1/2-dependent c-Jun and ATF2 activation and in vivo binding of c-Jun and ATF2 to the VCAM-1 promoter, which were inhibited by resveratrol. Thus, resveratrol functions as a suppressor of S. aureus-induced inflammatory signaling, not only by inhibiting VCAM-1 expression but also by diminishing c-Src, PDGFR, JNK1/2, p38 MAPK, and AP-1 activation in HPAEpiCs.

Highlights

Staphylococcus aureus (S. aureus) is considered to be an important human pathogen, which often causes skin, respiratory, and urinary tract infections and bacteremia [1]
We reported here for the first time that in HPAEpiCs, resveratrol reduced S. aureus-induced vascular cell adhesion molecule-1 (VCAM-1) expression via the inhibition of c-Src, platelet-derived growth factor receptor (PDGFR), c-Jun N-terminal kinase (JNK)1/2, p38 mitogen-activated protein kinase (MAPK), and activator protein-1 (AP-1) activation
S. aureus Induces VCAM-1 Expression in HPAEpiCs via c-Src c-Src has been shown to be involved in VCAM-1 upregulation induced by LPS [9]

Summary

Introduction

Staphylococcus aureus (S. aureus) is considered to be an important human pathogen, which often causes skin, respiratory, and urinary tract infections and bacteremia [1]. S. aureus is recognized by TLR2, which induces innate immune responses by activating many protein kinases, inflammatory cytokines and chemokines, or transcription factors [4]. Previous studies have shown that the induction of adhesion molecules on the cell surface plays a very important role in the inflammatory responses [5]. Vascular cell adhesion molecule-1 (VCAM-1) is a cell surface glycoprotein that regulates the adhesion of PMNs, thereby promoting the migration of PMNs across the vascular endothelium barrier and interacting with lung epithelial cells [8]. LPS has been shown to enhance VCAM-1 expression via the TLR4/myeloid differentiation primary response 88 (MyD88)/c-Src/p38 mitogen-activated protein kinase (MAPK)-dependent activating transcription factor 2 (ATF2) pathway [9]. We investigated whether S. aureus could stimulate VCAM-1 expression via these signaling components in human pulmonary alveolar epithelial cells (HPAEpiCs) and the lungs of mice

Methods

Results

Conclusion