Cellular Signaling Molecules Associated with Peptidoglycan-Induced CCL3 Up-Regulation

Abstract

Peptidoglycan (PGN) is detected in infl ammatory cell-rich regions of human atheromatous plaques. The present study investigated the effects of PGN on CC chemokine ligand 3 (CCL3) expression, which is elevated in the atherosclerotic arteries, and determined cellular factors involved in PGN-mediated CCL3 up-regulation in mononuclear cells, with the goal of understanding the molecular mechanisms of infl ammatory responses to bacterial pathogen-associated molecular patterns in diseased arteries. Exposure of human monocytic leukemia THP-1 cells to PGN resulted in enhanced secretion of CCL3 and profound induction of the CCL3 gene transcript. Both events were abrogated by oxidized 1-palmitoyl-2-arachidonosyl-sn-phosphatidylcholine, an inhibitor of Toll-like receptors 2/4. Pharmacological inhibitors such as U0126, SP6001250, Akt inhibitor IV, rapamycin, RO318220, diphenyleneiodonium chloride, and N-acetylcysteine also signifi cantly attenuated PGN-mediated CCL3 up-regulation. However, polymyxin B, LY294002, and SB202190 did not infl uence CCL3 expression. We propose that PGN contributes to enhanced CCL3 expression in atherosclerotic plaques and that Toll-like receptors (TLR2), Akt, mTOR, mitogen-activated protein kinase, and reactive oxygen species are involved in that process. (Holven et al., 2003). In addition, drugs with anti-atherogenic properties, such as hydroxymethylglutaryl-CoA reductase inhibitors, down-regulate CC chemokine ligands and receptors. Simvastatin suppresses expression of the chemokines CCL2, CCL3, and CCL4, as well as the chemokine receptors CCR1, CCR2, CCR4, and CCR5, in endothelial cells and macrophages (Veillard et al., 2006).

The Role of Src Kinase in Macrophage-Mediated Inflammatory Responses

“…SARM forms a complex with TRIF directly and negatively regulates the function of TRIF by blocking TRIF-mediated IRF7 and NF- κ B activities, resulting in the inhibition of inflammatory gene activation. Therefore, the activation of these adaptor molecules initiates a signaling cascade that leads to changes in gene expression in stimulated cells [ 41 , 42 , 46 ].…”