title: Substance P enhances NF-kappaB transactivation and chemokine response in murine macrophages via ERK1/2 and p38 MAPK signaling pathways.
abstract: The neuropeptide substance P (SP), as a major mediator of neuroimmunomodulatory activity, modulates diverse functions of immune cells, including macrophages. In the current study, we focused on the yet uncertain role of SP in enhancing the inducible/inflammatory chemokine response of macrophages and the signaling mechanism involved. We studied the effect on the murine monocyte/macrophage cell line RAW 264.7 as well as isolated primary macrophages. Our data show that SP, at nanomolar concentrations, elicited selective chemokine production from murine macrophages. Among the chemokines examined, macrophage inflammatory protein-2 and monocyte chemoattractant protein-1 are two major chemokines that were synthesized by macrophages in response to SP. Furthermore, SP treatment strongly induced the classic pathway of IkappaB-dependent NF-kappaB activation and enhanced DNA binding as well as transactivation activity of the transcription factor. SP-evoked transcriptional induction of chemokines was specific, since it was blocked by treatment with selective neurokinin-1 receptor antagonists. Moreover, SP stimulation of macrophages activated the ERK1/2 and p38 MAPK but not JNKs. Blockade of these two MAPK pathways with specific inhibitors abolished SP-elicited nuclear translocation of phosphorylated NF-kappaB p65 and NF-kappaB-driven chemokine production, suggesting that the two MAPKs lie in the signaling pathways leading to the chemokine response. Collectively, our data demonstrate that SP enhances selective inflammatory chemokine production by murine macrophages via ERK/p38 MAPK-mediated NF-kappaB activation.
authors.affiliation: Department of Pharmacology, National University of Singapore, Singapore.
authors.forename: Jia
authors.initials: J
authors.lastname: Sun
authors.forename: Raina Devi
authors.initials: RD
authors.lastname: Ramnath
authors.forename: Liang
authors.initials: L
authors.lastname: Zhi
authors.forename: Ramasamy
authors.initials: R
authors.lastname: Tamizhselvi
authors.forename: Madhav
authors.initials: M
authors.lastname: Bhatia
mesh_terms: D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D018925:Chemokines / Q000235:genetics / Q000378:metabolism*; D004247:DNA / Q000378:metabolism; D004789:Enzyme Activation; D020935:MAP Kinase Signaling System; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000201:enzymology / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D064729:Neurokinin-1 Receptor Antagonists; D010766:Phosphorylation; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011499:Protein Processing, Post-Translational; D018040:Receptors, Neurokinin-1 / Q000378:metabolism; D013373:Substance P / Q000378:metabolism*; D013997:Time Factors; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D018925:Chemokines; D064729:Neurokinin-1 Receptor Antagonists; D047428:Protein Kinase Inhibitors; D018040:Receptors, Neurokinin-1; C498144:Rela protein, mouse; D051996:Transcription Factor RelA; D013373:Substance P; D004247:DNA; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases