title: MIP-1alpha[CCL3] acting on the CCR1 receptor mediates neutrophil migration in immune inflammation via sequential release of TNF-alpha and LTB4.
abstract: In the present study, we investigated the involvement of macrophage-inflammatory protein-1alpha (MIP-1alpha)[CC chemokine ligand 3 (CCL3)], MIP-1beta[CCL4], regulated on activation, normal T expressed and secreted (RANTES)[CCL5], and CC chemokine receptors (CCRs) on neutrophil migration in murine immune inflammation. Previously, we showed that ovalbumin (OVA)-triggered neutrophil migration in immunized mice depends on the sequential release of tumor necrosis factor alpha (TNF-alpha) and leukotriene B(4)(LTB(4)). Herein, we show increased mRNA expression for MIP-1alpha[CCL3], MIP-1beta[CCL4], RANTES[CCL5], and CCR1 in peritoneal cells harvested from OVA-challenged, immunized mice, as well as MIP-1alpha[CCL3] and RANTES[CCL5] but not MIP-1beta[CCL4] proteins in the peritoneal exudates. OVA-induced neutrophil migration response was muted in immunized MIP-1alpha[CCL3](-/-) mice, but it was not inhibited by treatment with antibodies against RANTES[CCL5] or MIP-1beta[CCL4]. MIP-1alpha[CCL3] mediated neutrophil migration in immunized mice through induction of TNF-alpha and LTB(4) synthesis, as these mediators were detected in the exudates harvested from OVA-challenged immunized wild-type but not MIP-1alpha[CCL3](-/-) mice; administration of MIP-1alpha[CCL3] induced a dose-dependent neutrophil migration, which was inhibited by treatment with an anti-TNF-alpha antibody in TNF receptor 1 (p55(-/-))-deficient mice or by MK 886 (a 5-lipoxygenase inhibitor); and MIP-1alpha[CCL3] failed to induce LTB(4) production in p55(-/-) mice. MIP-1alpha[CCL3] used CCR1 to promote neutrophil recruitment, as OVA or MIP-1alpha[CCL3] failed to induce neutrophil migration in CCR1(-/-) mice, in contrast to CCR5(-/-) mice. In summary, we have demonstrated that neutrophil migration observed in this model of immune inflammation is mediated by MIP-1alpha[CCL3], which via CCR1, induces the sequential release of TNF-alpha and LTB(4). Therefore, whether a similar pathway mediates neutrophil migration in human immune-inflammatory diseases, the development of specific CCR1 antagonists might have a therapeutic potential.
authors.affiliation: Department of Pharmacology, School of Medicine of Ribeirão Preto, University of São Paulo, Brazil.
authors.forename: Cleber D L
authors.initials: CD
authors.lastname: Ramos
authors.forename: Claudio
authors.initials: C
authors.lastname: Canetti
authors.forename: Janeusa T
authors.initials: JT
authors.lastname: Souto
authors.forename: João S
authors.initials: JS
authors.lastname: Silva
authors.forename: Cory M
authors.initials: CM
authors.lastname: Hogaboam
authors.forename: Sergio H
authors.initials: SH
authors.lastname: Ferreira
authors.forename: Fernando Q
authors.initials: FQ
authors.lastname: Cunha
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001327:Autoimmune Diseases / Q000276:immunology / Q000503:physiopathology; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018946:Chemokine CCL5 / Q000235:genetics / Q000276:immunology; D019742:Chemokines, CC / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000276:immunology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007249:Inflammation / Q000276:immunology / Q000503:physiopathology; D007975:Leukotriene B4 / Q000276:immunology* / Q000378:metabolism; D019402:Macrophage Inflammatory Proteins / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology*; D010047:Ovalbumin / Q000276:immunology / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D054389:Receptors, CCR1; D019707:Receptors, Chemokine / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics; D047888:Receptors, Tumor Necrosis Factor, Type I; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D053319:Tumor Necrosis Factor Decoy Receptors; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology* / Q000378:metabolism; D015854:Up-Regulation / Q000276:immunology
chemical_list: D000906:Antibodies; C515300:CCR1 protein, human; C496534:Ccl3 protein, mouse; C496535:Ccl4 protein, mouse; C515301:Ccr1 protein, mouse; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018946:Chemokine CCL5; D019742:Chemokines, CC; D004791:Enzyme Inhibitors; D019402:Macrophage Inflammatory Proteins; D012333:RNA, Messenger; D054389:Receptors, CCR1; D019707:Receptors, Chemokine; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D053319:Tumor Necrosis Factor Decoy Receptors; D014409:Tumor Necrosis Factor-alpha; D007975:Leukotriene B4; C069521:recombinant human tumor necrosis factor-binding protein-1; D010047:Ovalbumin