Helicobacter pylori LPS-induced gastric mucosal spleen tyrosine kinase (Syk) recruitment to TLR4 and activation occurs with the involvement of protein kinase Cδ

Abstract

Spleen tyrosine kinase (Syk) has emerged recently as a major effector of proinflammatory genes expression induced by LPS-elicited TLR4 activation, and manifested by the up-amplification in the production of inflammatory mediators, including PGE2 and NO. Here, we investigated the nature of factors involved in the recruitment and interaction of Syk with TLR4 in gastric mucosa in response to H. pylori LPS. We show that stimulation of gastric mucosal cells with the LPS leads to localization of Syk with the membrane-associated TLR4 complex and its activation through phosphorylation on Tyr. Furthermore, we reveal that the membrane translocation of Syk upon the LPS stimulation occurs with the involvement of protein kinase Cδ (PKCδ)-mediated phosphorylation of Syk on Ser. Thus, our findings demonstrate that H. pylori LPS-induced up-regulation in Syk activity proceeds through the stage of PKCδ-mediated Syk phosphorylation on Ser, required for its recruitment to the membrane-anchored TLR4, followed by the kinase activation through phosphorylation on Tyr. Hence, the phase of PKCδ-mediated Syk phosphorylation on Ser affects the extent of amplification in gastric mucosal inflammatory response to H. pylori.

Helicobacter pylori Virulence Factors—Mechanisms of Bacterial Pathogenicity in the Gastric Microenvironment

“…Furthermore, the TLR4-MD-2 pathway significantly affects GC proliferation and migration and the whole process is induced by the LPS-mediated overexpression of CXC chemokine receptor 7 (CXCR7) [179]. Inflammatory responses within the gastric microenvironment can also be enhanced by the LPS-related protein kinase Cδ (PKCδ)-mediated phosphorylation of spleen tyrosine kinase (Syk), pathways activated after LPS binding to TLR4, MMP-9 secretion, as well as PLC/PKC/PI3K activation [180,181]. LPS is involved in the induction of monocyte inflammatory responses as well as monocyte transendothelial migration; it was demonstrated that LPS might be a major activating factor of several monocyte functions [182].…”

Detrimental Role of Nerve Injury-Induced Protein 1 in Myeloid Cells under Intestinal Inflammatory Conditions

“…Ninj1 is reported to modulate the TLR4 signaling cascade, resulting in increased pathogenesis in septic mice [4]. Abundant studies have demonstrated that lipopolysaccharides (LPS) activate TLR families and PKC isoforms [21][22][23][24][25]. Based on their activation requirements, PKC isoforms are categorized into three groups: conventional (α, βI, βII, γ), atypical (ζ, λ/ι), and novel (δ, ε, η, θ) isoforms.…”

Perilla Leaf Extract (PLE) Attenuates COPD Airway Inflammation via the TLR4/Syk/PKC/NF-κB Pathway In Vivo and In Vitro

“…Furthermore, potential mechanisms of the PLE on COPD inflammation were discussed here. Previously, it was found that TLR4, Syk, PKC, and NF-κB play critical roles in inflammatory diseases ( Slomiany and Slomiany, 2018 ; Yang H. et al, 2020 ; Ma et al, 2020 ), and the PLE and its several Syk affinitive components have been proved to act on Syk to relieve allergic airway inflammation ( Yang H. et al, 2020 ) ( Yang et al, 2021 ). TLR4 leads to initiation of Syk-, PKC-, and NF-κB p65-dependent signal cascades in COPD ( Zhang et al, 2018 ; Fan et al, 2019 ; Yang L. et al, 2020 ).…”