Substance P up-regulates macrophage inflammatory protein-1beta expression in human T lymphocytes.
Substance P (SP) is an important modulator of neuroimmunoregulation. We have demonstrated that human T lymphocytes express SP and neurokinin-1 receptor (NK-1R), a primary SP receptor. In the present study, we investigated whether SP stimulates synthesis of macrophage inflammatory protein-1beta (MIP-1beta) in human T lymphocytes. SP significantly enhanced MIP-1beta expression at both the mRNA and protein level in a human T cell line (Jurkat) containing the SP receptor gene (J-SPR) as determined by real-time PCR and ELISA assays. SP-induced MIP-1beta expression is abrogated by the specific NK-1R antagonist (CP-96,345). The supernatants from SP-stimulated J-SPR T cell cultures enhanced T lymphocyte chemotaxis in vitro, indicating functional activity of SP-induced MIP-1beta. In addition, SP augmented secretion of MIP-1beta from primary cultures of peripheral blood lymphocytes (PBL) isolated from some of the donors. This donor variability was due to differential expression of the primary SP receptor (NK-1R) on PBL from different donors. PBL from two of seven donors that did not respond to SP stimulation had undetectable NK-1R expression. Our mechanistic studies showed that SP activated NF-kappaB promoter-directed luciferase activity, which may be responsible for its effect on MIP-1beta expression in human T cells. Our data provide a potential mechanism by which SP selectively influences cellular immune responses such as beta-chemokine expression in human T lymphocytes through NK-1R, which may have an important in vivo implication in inflammatory diseases.
Guo
Chang Jiang
CJ
Division of Immunologic and Infectious Diseases, Joseph Stokes Jr. Research Institute of The Children's Hospital of Philadelphia, Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Lai
Jian Ping
JP
Luo
Hong Mei
HM
Douglas
Steven D
SD
Ho
Wen Zhe
WZ
D000328:Adult; D001713:Biphenyl Compounds / Q000494:pharmacology; D002460:Cell Line; D002478:Cells, Cultured; D054407:Chemokine CCL4; D002634:Chemotaxis, Leukocyte; D004305:Dose-Response Relationship, Drug; D006801:Humans; D019169:Jurkat Cells; D007700:Kinetics; D019402:Macrophage Inflammatory Proteins / Q000096:biosynthesis* / Q000235:genetics; D016328:NF-kappa B / Q000378:metabolism; D013373:Substance P / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000276:immunology*; D015533:Transcriptional Activation; D015854:Up-Regulation
D001713:Biphenyl Compounds; D054407:Chemokine CCL4; D019402:Macrophage Inflammatory Proteins; D016328:NF-kappa B; D013373:Substance P; C066892:CP 96345