title: Substance P augments Borrelia burgdorferi-induced prostaglandin E2 production by murine microglia.
abstract: Substance P is a ubiquitous CNS neuropeptide and has recently been demonstrated to augment immune cell function during inflammatory events. Central to the ability of substance P to modulate immune cell function is the interaction of substance P with the substance P neurokinin-1 receptor expressed by a variety of immune cells, including microglia. CNS involvement during Lyme disease can occur when Borrelia burgdorferi, the causative agent of Lyme disease, gains access to the CNS. In the present study, we demonstrate that substance P augments B. burgdorferi-induced expression of mRNA encoding COX-2 and subsequent secretion of PGE(2) by cultured, murine microglia. Furthermore, this effect is associated with the ability of substance P to enhance B. burgdorferi-induced NF-kappa B activation, as demonstrated by increased nuclear localization of the p65 (RelA) subunit of NF-kappa B in these cells. Interestingly, we demonstrate that substance P augments B. burgdorferi-induced expression of mRNA encoding two PGE(2) receptors, E-prostanoid receptor subtypes 2 and 4, as well as each receptor protein. In addition, these effects are mediated via interactions between substance P and its high affinity receptor, as evidenced by the absence of augmented PGE(2) synthesis in the presence of a specific neurokinin-1 receptor antagonist or in cells genetically deficient in the expression of these receptors. Taken together, the present demonstration that substance P can exacerbate B. burgdorferi-induced inflammatory responses in microglia in vitro may indicate a role for this neuropeptide in the development of CNS inflammation observed during human neuroborreliosis.
authors.affiliation: Department of Biology, University of North Carolina, Charlotte, NC 28223, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Rasley
authors.forename: Ian
authors.initials: I
authors.lastname: Marriott
authors.forename: Craig R
authors.initials: CR
authors.lastname: Halberstadt
authors.forename: Kenneth L
authors.initials: KL
authors.lastname: Bost
authors.forename: Juan
authors.initials: J
authors.lastname: Anguita
mesh_terms: D000276:Adjuvants, Immunologic / Q000502:physiology*; D000818:Animals; D025065:Borrelia burgdorferi / Q000276:immunology*; D002478:Cells, Cultured; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000096:biosynthesis*; D004790:Enzyme Induction / Q000235:genetics; D007527:Isoenzymes / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000201:enzymology / Q000378:metabolism* / Q000382:microbiology*; D016328:NF-kappa B / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D018040:Receptors, Neurokinin-1 / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D018078:Receptors, Prostaglandin E / Q000096:biosynthesis / Q000235:genetics; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D013373:Substance P / Q000502:physiology*; D015854:Up-Regulation / Q000235:genetics
chemical_list: D000276:Adjuvants, Immunologic; D007527:Isoenzymes; D008565:Membrane Proteins; D016328:NF-kappa B; C545644:PTGER2 protein, human; C545650:PTGER4 protein, human; C545645:Ptger2 protein, mouse; C545651:Ptger4 protein, mouse; D012333:RNA, Messenger; D018040:Receptors, Neurokinin-1; D018078:Receptors, Prostaglandin E; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D013373:Substance P; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C496512:Ptgs1 protein, mouse; D015232:Dinoprostone