title: Substance P regulates natural killer cell interferon-gamma production and resistance to Pseudomonas aeruginosa infection.
abstract: Studies have shown that after Pseudomonas aeruginosa (P. aeruginosa) corneal infection, BALB/c mice that are capable of resolving the disease, locally produce IFN-gamma. As T cells are not detected in the infected cornea of these mice, antibody depletion was used to test whether NK cells produce the cytokine. After depletion, decreased corneal IFN-gamma mRNA and increased disease severity, bacterial load, and PMN infiltrate resulted. Further work determined if substance P (SP), a pro-inflammatory neuropeptide, participated in regulation of this response. To this end, mice were treated with the SP antagonist, spantide I that blocks SP interaction with neurokinin-1, its major receptor. The treatment significantly decreased corneal IFN-gamma and IL-18 protein levels and corneal perforation resulted. In vitro experiments using isolated splenic NK cells confirmed their ability to respond to IL-18 and SP and to secrete IFN-gamma protein. We conclude: that for development of the BALB/c resistance response, NK cells are required to produce IFN-gamma; that the cells express the neurokinin-1 receptor; and that SP directly regulates IFN-gamma production through this receptor. The data suggest a unique link between the nervous system and development of innate immunity in the cornea.
authors.affiliation: Department of Anatomy/Cell biology, Wayne State University, Detroit, USA.
authors.forename: Shahrzad
authors.initials: S
authors.lastname: Lighvani
authors.forename: Xi
authors.initials: X
authors.lastname: Huang
authors.forename: Prachi P
authors.initials: PP
authors.lastname: Trivedi
authors.forename: Robert H
authors.initials: RH
authors.lastname: Swanborg
authors.forename: Linda D
authors.initials: LD
authors.lastname: Hazlett
mesh_terms: D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D003315:Cornea / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D005260:Female; D007150:Immunohistochemistry; D007371:Interferon-gamma / Q000276:immunology* / Q000378:metabolism; D020382:Interleukin-18 / Q000276:immunology / Q000378:metabolism; D007634:Keratitis / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D011552:Pseudomonas Infections / Q000276:immunology*; D012333:RNA, Messenger / Q000032:analysis; D018040:Receptors, Neurokinin-1 / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013373:Substance P / Q000031:analogs & derivatives* / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology
chemical_list: D000700:Analgesics; D020382:Interleukin-18; D012333:RNA, Messenger; D018040:Receptors, Neurokinin-1; D013373:Substance P; D007371:Interferon-gamma; C042867:spantide