title: Substance P regulates macrophage inflammatory protein 3alpha/chemokine C-C ligand 20 (CCL20) with heme oxygenase-1 in human periodontal ligament cells.
abstract: Although substance P (SP), a potent proinflammatory peptide, is involved in inflammation and immune responses, the effect of SP on the expression of macrophage inflammatory protein 3alpha[MIP-3alpha, chemokine C-C ligand 20 (CCL20)] in periodontal ligament (PDL) cells is unknown. Equally enigmatic is the link between SP, the stress protein heme oxygenase-1 (HO-1), and CCL20 production. We investigated whether SP induces the release of chemokine CCL20 from immortalized PDL (IPDL) cells, and further clarify SP-mediated pathways. We also examined the relationship between HO-1 and CCL20 by treating PDL cells with SP. Incubating IPDL cells with SP increased expression of CCL20 mRNA and CCL20 protein in a dose-time-dependent manner. Highly selective p38 and extracellular-regulated kinase 1/2 (ERK1/2) inhibitors abrogated SP-induced expression of CCL20 in IPDL cells. SP is also responsible for initiating phosphorylation of IkappaB, degradation of IkappaB and activation of nuclear factor (NF)-kappaB. SP induced expression of HO-1 in both a concentration- and time-dependent manner, and CCL20 reflected similar patterns. The inductive effects of SP on HO-1 and CCL20 were enhanced by HO-1 inducer hemin and the membrane-permeable guanosine 3',5'-monophosphate (cGMP) analogue 8-bromo-cGMP. Conversely, this pathway was inhibited by the HO-1 inhibitor zinc protoporphyrin IX (ZnPP IX) and the selective inhibitor of guanylate cyclase, 1H-(1,2,4)oxadiazole(4,3-a)quinoxalin-1-one (ODQ). We report herein the pathway that connects SP along with other modulators of neuroimmunoregulation to the induction of HO-1 and the inflammatory mediator macrophage inflammatory protein (MIP)-3alpha/CCL20 in IPDL cells, which play an important role in the development of periodontitis or inflammation during orthodontic tooth movement.
authors.affiliation: Department of Oral and Maxillofacial Pathology, Dental College, Wonkwang University, Iksan, South Korea.
authors.forename: S-K
authors.initials: SK
authors.lastname: Lee
authors.forename: S-H
authors.initials: SH
authors.lastname: Pi
authors.forename: S-H
authors.initials: SH
authors.lastname: Kim
authors.forename: K-S
authors.initials: KS
authors.lastname: Min
authors.forename: H-J
authors.initials: HJ
authors.lastname: Lee
authors.forename: H-S
authors.initials: HS
authors.lastname: Chang
authors.forename: K-H
authors.initials: KH
authors.lastname: Kang
authors.forename: H-R
authors.initials: HR
authors.lastname: Kim
authors.forename: H-I
authors.initials: HI
authors.lastname: Shin
authors.forename: S-K
authors.initials: SK
authors.lastname: Lee
authors.forename: E-C
authors.initials: EC
authors.lastname: Kim
mesh_terms: D016923:Cell Death / Q000187:drug effects; D002461:Cell Line, Transformed; D002472:Cell Transformation, Viral; D002478:Cells, Cultured; D054418:Chemokine CCL20 / Q000235:genetics / Q000378:metabolism*; D016207:Cytokines / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D018836:Inflammation Mediators / Q000494:pharmacology; D019402:Macrophage Inflammatory Proteins / Q000235:genetics / Q000378:metabolism*; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000502:physiology; D010513:Periodontal Ligament / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics; D013373:Substance P / Q000494:pharmacology*
chemical_list: C108355:CCL20 protein, human; D054418:Chemokine CCL20; D016207:Cytokines; D020672:I-kappa B Proteins; D018836:Inflammation Mediators; D019402:Macrophage Inflammatory Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D012333:RNA, Messenger; D000072000:NF-KappaB Inhibitor alpha; D013373:Substance P; D051547:Heme Oxygenase-1