ERK1/2 Has Divergent Roles in LPS-Induced Microvascular Endothelial Cell Cytokine Production and Permeability - Sorbonne Université Access content directly
Journal Articles Shock Year : 2021

ERK1/2 Has Divergent Roles in LPS-Induced Microvascular Endothelial Cell Cytokine Production and Permeability

Abstract

Endothelial cells play a major role in inflammatory responses to infection and sterile injury. Endothelial cells express Toll-like receptor 4 (TLR4) and are activated by LPS to express inflammatory cytokines/chemokines, and to undergo functional changes, including increased permeability. The extracellular signal-regulated kinase 1/2 (ERK1/2) mediates pro-inflammatory signaling in monocytes and macrophages, but the role of ERK1/2 in LPS-induced activation of microvascular endothelial cells has not been defined. We therefore studied the role of ERK1/2 in LPS-induced inflammatory activation and permeability of primary human lung microvascular endothelial cells (HMVEC). Inhibition of ERK1/2 augmented LPS-induced IL-6 and vascular cell adhesion protein (VCAM-1) production by HMVEC. ERK1/2 siRNA knockdown also augmented IL-6 production by LPS-treated HMVEC. Conversely, ERK1/2 inhibition abrogated permeability and restored cell-cell junctions of LPS-treated HMVEC. Consistent with the previously described pro-inflammatory role for ERK1/2 in leukocytes, inhibition of ERK1/2 reduced LPS-induced cytokine/chemokine production by primary human monocytes. Our study identifies a complex role for ERK1/2 in TLR4-activation of HMVEC, independent of myeloid differentiation primary response gene (MyD88) and TIR domain-containing adaptor inducing IFN-β (TRIF) signaling pathways. The activation of ERK1/2 limits LPS-induced IL-6 production by HMVEC, while at the same time promoting HMVEC permeability. Conversely, ERK1/2 activation promotes IL-6 production by human monocytes. Our results suggest that ERK1/2 may play an important role in the nuanced regulation of endothelial cell inflammation and vascular permeability in sepsis and injury.
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Dates and versions

hal-04022821 , version 1 (06-06-2023)

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Erika Wong, Fengyun Xu, Jérémie Joffre, Nina Nguyen, Kevin Wilhelmsen, et al.. ERK1/2 Has Divergent Roles in LPS-Induced Microvascular Endothelial Cell Cytokine Production and Permeability. Shock, 2021, 55 (3), pp.349-356. ⟨10.1097/SHK.0000000000001639⟩. ⟨hal-04022821⟩
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