title: Neutrophil recruitment in immunized mice depends on MIP-2 inducing the sequential release of MIP-1alpha, TNF-alpha and LTB(4).
abstract: Neutrophils are thought to play an important role in the tissue damage observed in various autoimmune diseases. Chemokines, cytokines and leukotrienes have recognized roles in the orchestration of neutrophil migration. We have recently shown that antigen-induced neutrophil migration into the peritoneum of immunized mice is mediated by macrophage-inflammatory protein (MIP)-1alpha which interacts with CCR1 and induces the sequential release of TNF-alpha and leukotriene B(4) (LTB(4)). The present study investigates the role of MIP-2 and CXCR2 in the cascade of events leading to mediator generation and neutrophil influx. Antigen challenge of immunized mice induced the expression of CXCR2 and the production of KC and MIP-2 proteins. Antigen-induced neutrophil migration was inhibited by a CXCR2 receptor antagonist (repertaxin) or an anti-MIP-2 antibody, but not by an anti-KC antibody. Administration of MIP-2 promoted a dose-dependent neutrophil migration in naive mice which was inhibited by repertaxin, anti-TNF-alpha, anti-MIP-1alpha antibodies or by MK886 (leukotriene synthesis inhibitor). MIP-2 administration induced the release of MIP-1alpha, TNF-alpha and LTB(4), and the release of the latter two was inhibited by anti-MIP-1alpha antibody treatment. Our studies highlight the intricate balance between mediator production and action during an immune-mediated inflammatory response and suggest a mediator cascade leading to neutrophil influx following antigen challenge of immunized mice: MIP-2 --> MIP-1alpha --> TNF-alpha --> LTB(4).
authors.affiliation: Department of Pharmacology, School of Medicine of Ribeirão Preto, University of São Paulo, São Paulo, Brazil.
authors.forename: Cleber D L
authors.initials: CD
authors.lastname: Ramos
authors.forename: Karla S S
authors.initials: KS
authors.lastname: Fernandes
authors.forename: Claudio
authors.initials: C
authors.lastname: Canetti
authors.forename: Mauro M
authors.initials: MM
authors.lastname: Teixeira
authors.forename: João S
authors.initials: JS
authors.lastname: Silva
authors.forename: Fernando Q
authors.initials: FQ
authors.lastname: Cunha
mesh_terms: D000818:Animals; D000941:Antigens / Q000276:immunology; D002465:Cell Movement; D007114:Immunization; D007958:Leukocyte Count; D007975:Leukotriene B4 / Q000378:metabolism*; D019402:Macrophage Inflammatory Proteins / Q000172:deficiency / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D020556:Neutrophil Infiltration / Q000276:immunology*; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D023063:Receptors, Interleukin-8B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D000941:Antigens; D019402:Macrophage Inflammatory Proteins; D023063:Receptors, Interleukin-8B; D014409:Tumor Necrosis Factor-alpha; D007975:Leukotriene B4