title: Peptidoglycan enhances secretion of monocyte chemoattractants via multiple signaling pathways.
abstract: Peptidoglycan (PG) is detected in a high proportion in inflammatory cell-rich regions of human atheromatous plaques. In the present study, we determined the cellular factors involved in PG-mediated chemokine expression in mononuclear cells in order to understand the molecular mechanisms of inflammatory responses to bacterial pathogen-associated molecular patterns in the diseased artery. Exposure of human monocytic leukemia THP-1 cells to PG resulted in not only enhanced secretion of CCL2 and CCL4 but also profound induction of their gene transcripts, which were abrogated by oxidized 1-palmitoyl-2-arachidonosyl-sn-phosphatidylcholine, an inhibitor of Toll-like receptors (TLRs)-2/4, but not by polymyxin B. PG enhanced phosphorylation of Akt and mitogen-activated protein kinases and activated protein kinase C. Pharmacological inhibitors such as SB202190, SP6001250, U0126, Akt inhibitor IV, rapamycin, and RO318220 significantly attenuated PG-mediated up-regulation of CCL2 and CCL4. We propose that PG contributes to vascular inflammation in atherosclerotic plaques by upregulating expression of mononuclear cell chemoattractants via TLR-2, protein kinase C, Akt, mTOR, and mitogen-activated protein kinases.
authors.affiliation: Department of Pharmacology, School of Medicine, Pusan National University, Yangsan 626-870, Republic of Korea.
authors.forename: Sae-A
authors.initials: SA
authors.lastname: Lee
authors.forename: Sun-Mi
authors.initials: SM
authors.lastname: Kim
authors.forename: Yong-Hae
authors.initials: YH
authors.lastname: Son
authors.forename: Chung Won
authors.initials: CW
authors.lastname: Lee
authors.forename: Sung Woon
authors.initials: SW
authors.lastname: Chung
authors.forename: Seong-Kug
authors.initials: SK
authors.lastname: Eo
authors.forename: Byung-Yong
authors.initials: BY
authors.lastname: Rhim
authors.forename: Koanhoi
authors.initials: K
authors.lastname: Kim
mesh_terms: D045744:Cell Line, Tumor; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism*; D054407:Chemokine CCL4 / Q000235:genetics / Q000378:metabolism*; D002630:Chemotactic Factors / Q000378:metabolism*; D006801:Humans; D009000:Monocytes / Q000187:drug effects / Q000276:immunology*; D010457:Peptidoglycan / Q000276:immunology* / Q000494:pharmacology; D010742:Phospholipid Ethers / Q000494:pharmacology; D015398:Signal Transduction; D051195:Toll-Like Receptor 2 / Q000037:antagonists & inhibitors; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors; D014158:Transcription, Genetic
chemical_list: D018932:Chemokine CCL2; D054407:Chemokine CCL4; D002630:Chemotactic Factors; D010457:Peptidoglycan; D010742:Phospholipid Ethers; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; C043051:1-O-hexadecyl-2-arachidonyl-sn-glycero-3-phosphocholine